Review

published: 13 May 2016

doi: 10.3389/fped.2016.00051

Relevant Outcomes in Pediatric

Acute Respiratory Distress
Syndrome Studies
Nadir Yehya1* and Neal J. Thomas2
1
Department of Anesthesiology and Critical Care Medicine, Children’s Hospital of Philadelphia, University of Pennsylvania,
Philadelphia, PA, USA, 2 Department of Pediatrics and Public Health Science, Division of Pediatric Critical Care Medicine,
Penn State Hershey Children’s Hospital, Hershey, PA, USA

Despite distinct epidemiology and outcomes, pediatric acute respiratory distress syn-
drome (PARDS) is often managed based on evidence extrapolated from treatment of
adults. The impact of non-pulmonary processes on mortality as well as the lower mor-
tality rate compared to adults with acute respiratory distress syndrome (ARDS) renders
the utilization of short-term mortality as a primary outcome measure for interventional
studies problematic. However, data regarding alternatives to mortality are profoundly
understudied, and proposed alternatives, such as ventilator-free days, may be them-
selves subject to hidden biases. Given the neuropsychiatric and functional impairment
in adult survivors of ARDS, characterization of these morbidities in children with PARDS
Edited by:
Kanwaljeet J. S. Anand,
is of paramount importance. The purpose of this review is to frame these challenges in
Stanford University School of the context of the existing pediatric literature, and using adult ARDS as a guide, suggest
Medicine, USA potential clinically relevant outcomes that deserve further investigation. The goal is to
Reviewed by: identify important areas of study in order to better define clinical practice and facilitate
Brian Benneyworth,
Indiana University School of future interventional trials in PARDS.
Medicine, USA
Keywords: pediatrics, ARDS, outcomes, acute respiratory distress syndrome, children, acute lung injury
Dincer Riza Yildizdas,
Çukurova University, Turkey
*Correspondence:
Nadir Yehya INTRODUCTION
yehyan@[Link]
Pediatric intensivists were not present for either the 1994 American-European Consensus Conference
Specialty section: (AECC) (1) or the 2012 Berlin re-definition (2) of acute respiratory distress syndrome (ARDS), and
This article was submitted to so pediatric considerations were not addressed. Despite this limitation, AECC and Berlin definitions
Pediatric Critical Care, were historically applied to children without modification, despite the different epidemiology and
a section of the journal outcomes of pediatric ARDS. To address this deficiency, the Pediatric Acute Lung Injury Consensus
Frontiers in Pediatrics
Conference (PALICC) was convened to propose specific definitions for pediatric acute respiratory
Received: 15 March 2016 distress syndrome (PARDS) (3). Notable differences in the PALICC definition are use of oxygenation
Accepted: 02 May 2016 index (OI) instead of PaO2/FiO2, the ability to diagnose PARDS in the absence of arterial blood gas
Published: 13 May 2016
analysis by using non-invasive measures of hypoxemia based on SpO2 [oxygen saturation index
Citation: (OSI)], and less restrictive radiographic criteria.
Yehya N and Thomas NJ (2016)
Irrespective of definitions utilized, cohort studies and clinical trials have generally demonstrated
Relevant Outcomes in Pediatric
Acute Respiratory Distress
lower mortality for PARDS (relative to adult ARDS), as well as an appreciable decrease in mortality
Syndrome Studies. over time (4, 5). Adult studies have demonstrated decreased pulmonary capacity, decreased quality
Front. Pediatr. 4:51. of life, and worsened neurocognition among survivors of ARDS (6–8); however, comparable studies
doi: 10.3389/fped.2016.00051 are lacking in PARDS. An appreciation of long-term sequelae is important for characterizing the

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Yehya and Thomas Outcomes in Pediatric ARDS

epidemiology of this syndrome. Additionally, the already low and While mortality may be problematic as a primary endpoint for
further decreasing mortality rate makes short-term survival an a general PARDS population, there remain subgroups of children
impractical endpoint for most clinical trials in PARDS, neces- with PARDS who still have a substantial mortality risk, yet with a
sitating the identification of clinically relevant patient-centered reasonable chance of survival. CALIPSO is an example of limiting
outcomes to test future interventions. The purpose of this review an intervention to a subgroup of PARDS with substantial mortal-
is to identify the challenges in identifying appropriate outcomes ity (>50%), albeit at the risk of difficult recruitment and reduced
for current and future studies in PARDS, framed in the context generalizability. Indeed, recently, successful trials in adult ARDS
of the existing literature. Additionally, using adult ARDS studies of neuromuscular blockade (33) and prone positioning (34)
as a guide, potential alternative outcomes that deserve further employed this strategy, as ARDS et Curarisation Systematique
investigation in PARDS are suggested. (ACURASYS) limited enrollment to patients with PaO2/FiO2
≤150, rather than the typical ≤300. Prone position in severe
MORTALITY ARDS (PROSEVA) required even more stringent enrollment
criteria, as it requires PaO2/FiO2 ≤150 after 12–24 h of initial
Pediatric acute respiratory distress syndrome has lower mortality stabilization, thereby excluding patients who rapidly improved
than adult ARDS (4, 5), with mortality decreasing over time. with standard ventilator management. In both cases, the goal
Unfortunately, short-term mortality – such as 28- to 60-day was enrichment of a higher risk population in which the tested
mortality, pediatric intensive care unit (PICU) mortality, and intervention could plausibly impact mortality with a reasonable
hospital mortality – remains an objective, easily obtained, clini- sample size. This, simultaneously, avoids unnecessarily exposing
cally relevant, and patient-centered outcome. As such, it is the patients to treatment when they have low risk of mortality and
most consistently reported endpoint in cohort studies (Table 1) high probability of survival irrespective of randomization arm,
(5, 9–23) and in clinical trials (Table 2) (24–32). However, predic- thereby diluting any potential treatment effect. For PARDS to
tors of mortality in PARDS are often not specific to PARDS but reproduce this, predictors of mortality risk need to be identified
are characteristic of risk factors in several conditions that result in and validated. These predictors need to be available early in the
critical illness. Notably, immunocompromised status (5, 21, 26) PARDS course to allow enrollment within a timeframe amenable
and multisystem organ failure (MSOF) (5, 12, 17) are associated for interventions to work, ideally within 48 h of PARDS onset.
with increased mortality risk in several PARDS studies, includ- This strategy has particular appeal for testing interventions for
ing clinical trials (26). However, immunocompromised status “refractory” PARDS, such as high-frequency oscillatory ventila-
and MSOF have little pulmonary specificity, are associated with tion (HFOV), prone positioning, methylprednisolone, inhaled
mortality in sepsis, and are component variables of severity of nitric oxide (iNO), and extracorporeal membrane oxygenation
illness scoring systems. Thus, a generalization of this observa- (ECMO).
tion states that children die with PARDS, rather than because
of PARDS. In such cases, the associated PARDS has resolved at
the time of death, despite the persistence of mechanical ventila- DURATION OF MECHANICAL
tion. Further complicating the use of mortality as an endpoint is VENTILATION
elective withdrawal of potentially futile care, either for persistent
MSOF, underlying refractory malignancy, or for presumed poor Duration of ventilation is a common outcome described in PARDS
neurologic prognosis, none of which are specific for PARDS. studies, especially when this outcome is limited to survivors. This
One example is worth examining in further detail. A outcome has face validity, as more severe PARDS can reasonably
multicenter randomized controlled trial (RCT) of exogenous be expected to require a longer duration of mechanical ventila-
surfactant (calfactant) in moderate and severe PARDS (OI > 7) tion. The 2012 Berlin definition (2) demonstrated an increase in
demonstrated improved mortality associated with calfactant duration of mechanical ventilation in survivors across increasing
treatment (26). However, imbalance in the proportion of severity classes of ARDS, which was confirmed in LUNG SAFE
immunocompromised patients, with over-representation in the (Large Observational Study to Understand the Global Impact of
placebo arm, likely contributed to this effect, and after adjust- Severe Acute Respiratory Failure) (35). This observation has been
ment for immunocompromised status, the association between corroborated in PARDS when using oxygenation at 24 h, rather
calfactant treatment and improved mortality was no longer than at PARDS onset (5).
evident (p = 0.07). Furthermore, patients received treatment To be used as a valid endpoint, the definition of “duration of
within 48 h of intubation, but the proportion of patients success- mechanical ventilation” needs to be limited to survivors, given
fully extubated did not differ between the groups and curves for the risk of contamination of this endpoint with non-survivors
cumulative successful extubation did not begin to diverge until with a short-duration of ventilation. Alternatively, liberation
12 days after intubation, suggesting that factors unrelated to the from ventilation can be analyzed as the primary outcome of
initial PARDS insult, such as immunocompromised status, may interest, with death treated as a competing outcome. Appropriate
have been responsible for mortality and prolonged ventilation. A statistical techniques must be employed for quantifying the effect
follow-up trial of calfactant was restricted to immunocompro- of an intervention while accounting for competing events (36).
mised children [Calfactant for Acute Lung Injury in Pediatric Furthermore, given the increased utilization of non-invasive
Stem Cell Transplant and Oncology Patients (CALIPSO)] using ventilation both prior to (37–39) and after endotracheal intuba-
mortality as the primary outcome. tion, duration of mechanical ventilation requires clear definition

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Yehya and Thomas Outcomes in Pediatric ARDS

TABLE 1 | Reported outcomes in cohorts using PARDS-type inclusion criteria and ≥100 patients.

Years Centers Countries Cases Outcomes Comments Reference

1986–1990 1 USA 100 Mortality (72%) PaO2 ≤75 with FiO2 ≥0.5; bilateral infiltrates; 74% (9)
immunocompromised
1990–1991 14 France 123 Mortality (60%) Intubated; FiO2 ≥0.5 on PEEP; bilateral infiltrates (10)
1993–1995 1 Canada 131 Mortality (27%) Intubated; PEEP ≥6 and FiO2 ≥0.5 for 12 h (11)
Ventilator days survivors (8,
range 1–27)
1997–1998 10 USA, Canada 232 Mortality (40%) Intubated; HFOV (22)
1996–2000 2 USA 328 Mortality (22%) Non-invasive and intubated; AECC ALI with PF ≤300 (12)
VFD (15 ± 11)
2004–2005 12 Australia, New Zealand 117 Mortality (35%) Non-invasive and intubated; AECC ALI with PF ≤300 (13)
2005–2006 26 China 358 Mortality (44%) Any respiratory support; AECC ALI with PF ≤300 (14)
2000–2007 1 USA 398 Mortality (20%) Intubated; PF ≤300; 192 with bilateral infiltrates (15)
VFD (17, IQR 0–24)
2007–2010 5 USA 168 Mortality (11%) Intubated; AECC ALI with PF ≤300; excluded SCT (16)
VFD (20, IQR 10–23)
2009–2010 7 USA, Canada, Belgium, 328 Mortality (38%) Intubated; HFOV (23)
Switzerland, Netherlands
2010–2011 21 Spain 146 Mortality (26%) Intubated; AECC ARDS with PF ≤200 (17)
2009–2011 7 Italy, Spain, France, 221 Mortality (17%) Intubated; Berlin ARDS with PF ≤300; age 1–18 months (18)
Austria, Netherlands ECMO/death (19%)
2009–2013 1 USA 312 Mortality (22%) Intubated; Berlin ARDS with SpO2 cutoffs (19)
2008–2014 5 USA 299 Mortality (13%) Non-invasive and intubated; AECC ARDS with PF ≤200 (20)
2009–2014 12 USA 222 Mortality (60%) Intubated; SCT (21)
Ventilator days survivors (9, IQR
4–16)
2011–2014 1 USA 283 Mortality (13%) Intubated; AECC ALI and Berlin ARDS with PF ≤300 (5)
VFD (17, IQR 3–21)
Ventilator days survivors (10,
IQR 7–17)

AECC, American-European Consensus Conference; ALI, acute lung injury; ARDS, acute respiratory distress syndrome; HFOV, high-frequency oscillatory ventilation; PEEP, positive
end-expiratory pressure; PF, PaO2/FiO2; SCT, stem cell transplant; VFD, ventilator-free days.

regarding whether non-invasive support is included. Both Berlin appropriately to minimal invasive support given their underlying
(mild) ARDS (2) and PALICC PARDS (3) definitions make PARDS severity, but the actual act of removing the endotracheal
allowances for non-invasive support, suggesting that screening tube may be delayed, or ultimately attempted and unsuccessful,
for studies based on these criteria would allow for inclusion of for reasons related primarily to their airway. Given the substantial
a substantial number of non-intubated patients. This potential number of comorbidities described in PARDS, reasons for pro-
for increased enrollment needs consistent and well-delineated longed intubation unrelated to the actual PARDS risk factor have
reporting of what is meant by “duration of mechanical ventilation.” the potential to confound the utility of duration of ventilation
Therefore, while the endpoint “duration of ventilation in as an endpoint. An alternative has been proposed to only count
survivors” retains face validity and likely reflects the severity of the duration of time until successful completion of an extuba-
PARDS, it is unclear exactly how “patient-centric” this outcome tion readiness test, irrespective of whether or not the patient is
is. Specifically, it is unclear whether a given child would be bet- actually extubated (40). However, this has not been validated nor
ter served with 10 days of invasive mechanical ventilation and described in an actual practice or trial and does not address the
extubated to high-flow cannula or whether 8 days of invasive prior criticism of not being patient-centered, as the child remains
ventilation followed by 4 days of non-invasive bi-level positive intubated.
airway pressure (BiPAP) with full-facemask interface. Indeed, the
answer likely varies between patients for a multitude of variables, VENTILATOR-FREE DAYS
including sedation requirements, strength, airway status, and
indication for intubation. Perhaps, the most commonly adopted surrogate endpoint in
Finally, duration of ventilation in survivors is complicated by PARDS trials, recently (Table 2), is ventilator-free days (VFD)
the prevalence of subglottic stenosis, poor secretion tolerance, at some arbitrary endpoint (e.g., at 28 days). VFD at 28 days are
or severe upper airway obstruction from poor airway tone as typically derived by subtracting duration of ventilation in sur-
an indication for prolonged intubation. Such patients may wean vivors from 28 and scoring non-survivors and those requiring

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Yehya and Thomas Outcomes in Pediatric ARDS

TABLE 2 | Reported outcomes in select placebo-controlled randomized clinical trials in acute respiratory failure and PARDS.

Trial Years Intervention Total Primary outcome Other reported outcomes Reference
subjects

HFOV 1990–1994 HFOV versus 58 Mortality (34% HFOV; 41% Ventilator days in survivors; supplemental O2 (24)
conventional conventional) requirement; chronic lung disease
Weaning 1999–2001 Protocolized PSV or VSV 179 Days to extubation (median 2 for no Successful extubation (25)
protocol versus no protocol protocol; 1.6 PSV; 1.8 VSV)
Calfactant 2000–2003 Intratracheal calfactant 152 VFD (13 ± 8 for calfactant; 12 ± 11 Mortality; failure of conventional ventilation; (26)
versus air placebo for air) oxygenation; supplemental O2 requirement;
PICU and hospital LOS
Prone 2001–2004 Prone versus supine 101 VFD (16 ± 8 for supine; 16 ± 8 for Mortality; organ failure-free days; supplemental (27)
position position prone) O2 requirement; PCPC; POPC
Inhaled 2003–2005 iNO versus nitrogen 53 VFD (15 ± 8 for iNO; 9 ± 9 for Mortality; ECMO/death (28)
nitric oxide placebo placebo)
Lucinactant 2007–2010 Intratracheal lucinactant 165 Adjusted LSM of ventilator days (4 Mortality; VFD; PICU and hospital LOS (29)
versus air placebo for lucinactant; 4.5 for air)
PED- 2008–2010 Intratracheal calfactant 109 Mortality (12% for calfactant; 9% VFD; oxygenation; PICU and hospital LOS (30)
CARDS versus air placebo for air)
RESTORE 2009–2013 Protocolized sedation 2449 Ventilator days (median 6.5 for Mortality; duration of weaning; duration of (31)
versus usual care protocol; 6.5 for usual care) non-invasive ventilation; PICU and hospital LOS
Steroids 2010–2014 Methylprednisolone 35 Ventilator days (10 ± 7 for steroids; Mortality; VFD; oxygenation; PICU and hospital (32)
versus placebo 10 ± 5 for placebo) LOS

ECMO, extracorporeal membrane oxygenation; HFOV, high-frequency oscillatory ventilation; LSM, least squares means; LOS, length of stay; PCPC, pediatric cerebral performance
category; PED-CARDS, pediatric calfactant in acute respiratory distress syndrome; POPC, pediatric overall performance category; PICU, pediatric intensive care unit; PSV, pressure-
support ventilation; RESTORE, randomized evaluation of sedation titration for respiratory failure; VFD, ventilator-free days; VSV, volume support ventilation.

≥28 ventilator days as 0 (41). It has also been defined as “days mechanical ventilation and ARDS are in the causal pathway for
alive and free of mechanical ventilation” (42), which creates non-survival. However, even in adults, this assumption can be
confusion for cases where the patient is extubated on day 10, but problematic. The ARDSNet corticosteroid trial (43) failed to
dies on day 20 (10 days alive and free of mechanical ventilation demonstrate superiority of methylprednisolone for persistent
is VFD = 10; non-survival at day 28 suggests VFD = 0). This ARDS for the primary outcome of mortality at 60 days (29.2%
composite endpoint combines mortality and duration of ventila- mortality in methylprednisolone, 28.6% in placebo, p = 1).
tion by penalizing non-survivors, unlike duration of ventilation. However, methylprednisolone treatment was associated with
Similar to duration of ventilation in survivors, VFD at 28 days 4.4 additional VFD and 2.7 additional ICU-free days at 28 days.
has demonstrated correlation across severity of Berlin ARDS Significantly, more patients in the methylprednisolone arm
(2) and PALICC PARDS (3) categories, with worse oxygenation required re-initiation of ventilation (28 versus 9%, p = 0.006).
categories associated with fewer VFD. This composite endpoint These discrepant results make interpretation of the trial difficult:
potentially represents efficiency, as an outcome of an interven- mortality is reported at 60 days, but VFD at 28 days. Mortality is
tion, which both reduces mortality and duration of ventilation, nominally higher in the methylprednisolone group, but VFD are
can be detected with a smaller sample size (42). also more favorable for methylprednisolone. Thus, in this case,
The same caveats regarding clarity of non-invasive support are the reporting of VFD offers no advantages or power relative to
required for VFD as mentioned for duration of ventilation (41). reporting on mortality alone: when an intervention has opposite
However, VFD has a major limitation as a composite endpoint, effects on duration of ventilation and mortality, VFD merely
as the merged individual endpoints (mortality and ventilator confuses the interpretation.
duration) are not equivalent and interchangeable. A child requir- In pediatrics, the utilization of VFD at 28 days is potential sus-
ing 30 days of mechanical ventilation, but surviving, cannot be pect for these same reasons, as PARDS mortality is much lower,
considered identical to a child who dies after 7 days of ventila- and persistent hypoxemia is unlikely to be the cause of mortality.
tion, although both would be recorded as VFD = 0. Composite Thus, the effect on mortality is less certain to be in the same direc-
endpoints are best utilized when the separate endpoints are of tion as duration of ventilation. For instance, a trial of ECMO for
equivalent importance for the patient, such as stroke or myocar- severe refractory PARDS may result in improved nominal mor-
dial infarction in hypertensive adults. When initially described tality rates but would likely result in prolonged duration of venti-
for adult ARDS, VFD was demonstrated to be useful only when lation, thereby complicating the interpretation and utility of VFD.
the more pejorative outcome of mortality was improved along- Finally, several interventions sorely in need of testing in PARDS,
side duration of ventilation (42). Given the >30% mortality in including fluid management, sedation protocols, weaning, and
adult ARDS (35), this is a reasonable expectation: interventions extubation readiness all clearly impact length of ventilation much
which shorten ventilation should improve mortality, assuming more so than they will impact mortality, hampering the utility of

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Yehya and Thomas Outcomes in Pediatric ARDS

VFD as an outcome unless these parameters are protocolized in POST-DISCHARGE OUTCOMES

the context of the trial.
There have been no studies examining long-term mortality in
PARDS, but outcomes, such as 90-day, 6-month, or 12-month
NEED FOR EXTRACORPOREAL SUPPORT mortality, are unlikely to represent significant differences com-
AS AN OUTCOME pared to short-term mortality. Additionally, long-term mortality
is more likely to result from either the underlying condition or
A more recently reported composite outcome for PARDS inves- an unrelated cause and is unlikely to be a sequelae of PARDS.
tigations has been the composite of need for ECMO or death Therefore, alternative post-discharge outcomes are needed
(18, 28). This attempts to address the limitations of VFD and the (Table 3). Recent attention has focused on the development of
low mortality (and thus difficult to adequately power) of PARDS. new morbidities in the PICU as a relevant outcome (45, 46), with
The underlying assumption is that lung injury severe enough to up to twice the prevalence of mortality.
require ECMO is essentially refractory to conventional mechani- Few studies have investigated the physical or neurocogni-
cal ventilation, and thus need for ECMO would be a death in tive quality of life in survivors of PARDS (47–51). The existing
any center unable to provide ECMO. Therefore, “ECMO” is studies are of extremely limited sample size (all n ≤ 11) and
close enough to “death” to justify combination as a composite outdated, with ventilator management not reflective of current
endpoint. PICU practices (52, 53). In 1985, Fanconi et al. (47) published on
The European Society for Pediatric and Neonatal Intensive pulmonary function testing (PFT) of nine survivors of PARDS
Care (ESPNIC) used this definition to test the utility of the Berlin ventilated between 1978 and 1982 (five of whom experienced
criteria in children (18) and demonstrated that the inclusion of a peak pressures >40 cmH2O) at a mean 2.3-year follow-up. Seven
“severe” ARDS category improved validity with an increased risk of the nine were considered “hypoxemic,” with PaO2 <80 mmHg
of ECMO/death in children with Berlin-defined severe ARDS, on room air, and eight of nine had ventilation inequalities on
whereas risks were similar when defined using AECC definitions. multibreath nitrogen washout. Increased peak pressures and
It should be noted, however, that the incidence of ECMO/death increased exposure to FiO2 >0.5 during PARDS correlated
(18.6%) was only marginally increased over the incidence of with increased ventilation inequalities, suggesting a potential
mortality (17.2%), and that comparable analyses for the outcome association between ventilator management and long-term
mortality yielded identical conclusions. pulmonary outcome. In a separate study published in 1996,
A recently published RCT (28) for iNO (total n = 53) reported 11 PARDS survivors ventilated between 1986 and 1993 (mean
both mortality (28% placebo, 8% iNO, χ2 p = 0.07) and ECMO/ PaO2/FiO2 160; 9 of 11 with peak pressures >40 cmH2O) with
death (48% placebo, 8% iNO, p < 0.01). The trial was powered PFT performed at a mean 23-month follow-up demonstrated
for a difference in VFD at 28 days, for which it required a sample obstructive physiology in three children and mixed obstruction
size of 169 children, and was stopped early for slow enrollment. and restrictive physiology in an additional four children (49).
Of note, the difference in the reported VFD in this trial was The most recent investigation of PARDS survivors (51) occurred
also significant. While the primary outcome of more VFD was in children ventilated between 1986 and 1998 (all experienced
achieved despite the small sample size, the reporting of ECMO/ pressure-controlled ventilation, with all peak pressures
death in this study points to a potential mechanism, whereby <35 cmH2O). These investigators were able to assess PFT in
iNO improved VFD. Specifically, exposure to iNO appeared to seven patients, finding one with an abnormal diffusion capacity,
decrease the rate of ECMO utilization, suggesting an improve- and a second with exercise-induced hypoxemia.
ment in hypoxemia, thereby reducing total ventilator days and Based on these small case series, the PALICC group recom-
potentially impacting mortality. This is significant, as it implies mended that survivors of PARDS undergo screening for PFT
a connection between improvement in hypoxemia and better abnormalities within 1 year of discharge (54). The small sample
outcomes in PARDS, a connection which is not consistently cor- size of these existing studies, antiquated ventilator management,
roborated in adult ARDS trials (44). For certain trials of salvage and variable follow-up time precludes any real assessment of the
therapy, such as methylprednisolone, iNO, prone positioning, prevalence of pulmonary dysfunction in PARDS survivors. Larger
and HFOV, the use of ECMO/death as a primary outcome may scale, multicenter follow-up is sorely needed, potentially exploit-
be rational. However, as in the example above, there is little ing the infrastructure of existing pediatric critical care research
information added by this specific reporting that was not also networks and in collaboration with pediatric pulmonologists and
captured by the more conventional short-term outcome of VFD rehabilitation providers.
at 28 days. Additionally, as ECMO is not an outcome per se but Studies within this framework are becoming more common
simply an additional mode of supportive care, with subjective in pediatric critical care. The out-of-hospital arm of Therapeutic
thresholds for its utilization among different centers and prac- Hypothermia after Pediatric Cardia Arrest (THAPCA) trial (55)
titioners, the composite outcome of ECMO/death is difficult to was powered for a primary outcome of a dichotomized (good
standardize. Finally, the component variables of ECMO/death versus bad) version of the Vineland Adaptive Behavior Scale,
are not of equal importance to the patient, thus calling into second edition (VABS-II). Ebrahim et al. (56) reported on the
question its validity as a patient-centered, clinically meaningful 1-month post-PICU admission outcome of 65 urgently admitted
composite outcome. survivors using VABS-II, pediatric cerebral performance category

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TABLE 3 | Potential outcomes for PARDS studies.

Outcome Timeframe Advantages Disadvantages

Mortality Short term Easy to obtain Impractical given low baseline mortality
28 or 60 days Fixed time-point
PICU Related to acute process
Hospital Patient-centered
Medium and long term Potentially captures longer period of risk for unfavorable Similarly low rate
90 days outcomes Harder to obtain follow-up
1 year More related to underlying comorbidities

VFD 28 days Easy to obtain Imbalance in components of the composite outcome

Increases power to detect clinically meaningful Only increases power if intervention benefits both
improvements related to shortened ventilation mortality and ventilator days

Ventilator days 28 days Easy to obtain Needs non-invasive support explicitly defined
PICU LOS Related to pulmonary nature of PARDS Unclear if patient-centered

ECMO/death Short term Increases power to detect efficacy of pre-ECMO Subjective use of ECMO
“salvage therapies” Imbalance in components of the composite outcome
Unclear if patient-centered

Neurocognitive Medium and long term Rapid (POCP/PCPC) More thorough cognitive function requires longer testing
and functional 90 days Patient-centered
(POPC/PCPC) 1 year Potentially completed over telephone Changes with developmental age and with comorbidities
Pre-return to school Potentially more practical, as it is a prevalent outcome

Pulmonary Medium and long term Patient-centered Requires infrastructure (expertise and equipment) for
outcomes 90 days Related to pulmonary nature of PARDS in-person follow-up
1 year
Pre-return to school

Biometric Medium and long term Patient-centered Requires development, testing and validation
outcomes 90 days Does not require return to clinic Requires expertise
1 year Potentially improved response rate HIPAA concerns
Pre-return to school Ownership concerns (who owns the data and how will it
be used?)

Psychiatric Long term Patient-centered Requires infrastructure (expertise) for in-person follow-up
Potentially completed over telephone

Health care Medium and long term Patient-centered Difficult to obtain

utilization 90 days and 1 year Does not require inpatient follow-up Sensitive to local practices
re-hospitalization Related to pulmonary nature of PARDS Potentially more related to underlying comorbidities than
Addresses cost to patient/family to PARDS

ECMO, extracorporeal membrane oxygenation; LOS, length of stay; PARDS, pediatric acute respiratory distress syndrome; PCPC, pediatric cerebral performance category; POPC,
pediatric overall performance category; PICU, pediatric intensive care unit; VFD, ventilator-free days.

(PCPC), pediatric overall performance category (POPC), and ADULT ARDS INVESTIGATIONS OF
overall pediatric quality of life inventory, fourth edition. They ALTERNATIVE OUTCOMES
demonstrated an overall poor quality of life for these patients at
1-month post-PICU admission. A recent review article identified Seminal work in adult ARDS long-term outcome (6, 7) has paved
potentially useful health-related quality of life (HRQL) metrics the way for potentially comparable studies in PARDS. In 2002,
for pediatric critical care (57). This review identified substantial adult survivors of moderate and severe ARDS were followed
morbidity for PICU survivors, some of which were associated with at 3, 6, and 12 months, with a primary outcome of 6-min walk
treatments received during their PICU stay, suggesting possible distance (6). The authors found that survivors of ARDS (median
modifiable risk factors. Additionally, a recent review has also sug- age 45 years) had persistent physical limitations at all time-
gested significant psychiatric morbidity in PICU survivors (58), points tested, primarily due to muscle wasting and weakness.
including post-traumatic stress disorder (PTSD), depression, and At 12 months, only 49% of patients had returned to work. In
behavioral disorders, with prevalence of post-traumatic stress multivariable regression, use of corticosteroids and duration of
symptoms potentially as high as 62% (59). Finally, the ongoing mechanical ventilation both negatively affected 6-min walk dis-
multicenter Life after Pediatric Sepsis Evaluation (LAPSE) study tance, suggesting a possible relationship between modifiable risk
is a prospective observational study collecting information on factors and medium-term functional outcome. In the subsequent
quality of life, family dynamics and stress, and health care utiliza- 5-year follow-up study, the median 6-min walk distance remained
tion in survivors of pediatric severe sepsis. below predicted values (7). However, pulmonary function had

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Yehya and Thomas Outcomes in Pediatric ARDS

returned to near normal, and persistent exercise limitations the ARDSNet recommended PaO2 ranges of 55–80, suggesting
were attributed to continuing weakness and neuropsychological that existing, arbitrary guidelines may be too permissive, and
impairments. Health-care costs continued to be substantial for that this level of mild hypoxemia may be associated with long-
survivors up to 5 years after discharge, especially in those with term neurologic sequelae. Additionally, the conclusions of the
pre-existing comorbidities. FACTT trial that conservative fluid management resulted in 2.5
For PARDS investigators, this experience is instructive. The additional VFD without additional organ failures are now called
major strengths of these studies are the well-characterized, into question, as 12-month neurologic function clearly suggests
multicenter cohort, the longitudinal study design, the high rates potential sub-clinical neurologic dysfunction, leading to long-
of follow-up, and the in-person data collection. The granularity term functional impairment. To date, no study in children with
of the data allowed significant associations to be made regarding PARDS has investigated any sort of long-term outcome, and the
ICU exposures (e.g., corticosteroids) and subsequent medium- efficacy of our interventions on long-term function in growing
and long-term outcomes. While these observations remain and developing children remains a mystery.
hypothesis-generating, these are still essential initial steps toward
determining how to design future prospective trials with clini- BIOMETRIC OUTCOMES
cally meaningful, patient-centered outcomes.
An earlier study employing an alternative design is also One of the disadvantages of the existing framework for evaluat-
worth considering (60). A prospective case control interview/ ing long-term outcomes is the expense and expertise necessary
questionnaire study was performed of adult ARDS survivors to bring back patients to a follow-up clinic and conduct PFT
matched with non-ARDS survivors with similar severity of ill- and neuromuscular testing. An alternative strategy has been
ness at a median of 23 months after discharge. ARDS survivors demonstrated by cardiologists with the embrace of remote
demonstrated worse HRQL in nearly all domains tested, includ- telemonitoring (RTM) technology. These have taken the form
ing respiratory-specific domains. The most profound reduc- of devices, which record heart rate, cardiac rhythm, pulse oxi-
tions in ARDS survivors were in the domains assessing either metry, and blood pressure, with wireless transmission to a data
physical limitations or on the impact of pulmonary symptoms collection center (63). Devices can be modified to also include
on activities of daily living. This was the first study to assess the brief questionnaires, adding additional data regarding subjective
HRQL in ARDS survivors matched to similarly ill non-ARDS experiencing of symptoms by the patient. Home spirometry
patients, thus minimizing the possibility that observations were adapted with an automated modem for data transmission has
simply reflections of severity of illness; rather, this study design been used in a trial for management of children with asthma
increased the plausibly that these associations were either actu- (64). Device modifications exist, which can additionally measure
ally caused by having ARDS specifically, or conversely, by the grip strength, as well as assess flexibility and reaction time using
treatments used for it. game-playing scenarios (65), which may be able to address
The significance of long-term, patient-centered outcomes is certain neurocognitive and neuromuscular outcomes in PARDS
elegantly made when considering the neuropsychological func- survivors. RTM devices have already been incorporated as inter-
tion in adult ARDS survivors of the fluid and catheter treatment ventions in clinical trials in adult heart failure (66, 67). The use of
trial (FACTT). The initial trial used a 2 × 2 factorial design to RTM for patients with pacemakers and implantable cardioverter
test (separately) the utility of pulmonary-artery catheters versus defibrillators by pediatric cardiologists was associated with fewer
central-venous catheters, and the effects of a conservative ver- clinic visits (68), providing proof of concept for RTM to allow
sus a liberal fluid management strategy on hemodynamically follow-up for patients at lower cost.
stable ARDS patients (61, 62). The trial failed to demonstrate Remote telemonitoring remains unexplored in pediatric
superiority of either fluid strategy in its primary outcome of critical illness research, although it possesses significant poten-
60-day mortality (25.5% mortality in fluid conservative, 28.4% tial. Some of the limitations regarding patient loss to follow-up
in fluid liberal, p = 0.30). However, the conservative arm resulted are nicely addressed by RTM. Platforms which may only require
in 2.5 more VFD (p < 0.001) and 2.2 additional ICU-free days smartphones and appropriate adaptors, or which utilize gaming,
(p < 0.001) (61) without additional increase in non-pulmonary are intuitively appealing to a pediatric population, and may
organ failures. Based on these findings, the FACTT investigators improve compliance. However, expertise in development and
recommended a conservative fluid strategy in hemodynamically interpretation are still necessary, and validation will be required
stable ARDS patients. prior to implementation.
The follow-up ARDS cognitive outcome study (ACOS)
conducted telephone interviews of FACTT survivors at 2 and CONCLUSION
12 months post-discharge (8). Similar to prior investigations
(6, 60), the investigators found that most survivors (55–60%, Mortality in PARDS is decreasing, and while it remains clinically
depending on metric used) experienced long-term cognitive relevant and patient-centered, it is impractical for most purposes,
impairment. Interestingly, lower PaO2 (p = 0.015) and allocation and its use should likely be limited to trials aimed at enrolling
to the conservative fluid arm (p = 0.005) were independently pre-determined higher risk groups. VFD is likely to remain the
associated with long-term cognitive impairment. The PaO2 dur- most common primary endpoint for clinical trials in the foresee-
ing ARDS reported in ACOS survivors with cognitive impair- able future, but advocates should be aware of its limitations, and
ment was median 71 (interquartile range 67–80), well within should ensure that the power of this composite outcome rests

Frontiers in Pediatrics | [Link] 7 May 2016 | Volume 4 | Article 51

Yehya and Thomas Outcomes in Pediatric ARDS

on whether the tested intervention improve both mortality and AUTHOR CONTRIBUTIONS
duration of ventilation in survivors. Finally, given the prevalence
of long-term neuropsychiatric morbidity and functional impair- NY and NT researched the topic, reviewed the relevant source
ment in adult ARDS survivors, it is imperative that these param- articles, and wrote the manuscript together.
eters are defined for children. After a better understanding of the
burden of surviving PARDS on patients and families is obtained, FUNDING
studies can be designed to demonstrate a return to pre-morbid
functioning, which is fundamentally most important to the child NY received grants from National Institutes of Health
and family. (K12HL109009).

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66. Bekelman DB, Plomondon ME, Carey EP, Sullivan MD, Nelson KM, Hattler B, Conflict of Interest Statement: Dr. NT reports personal fees from Discovery Labs
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et al. Effectiveness of remote patient monitoring after discharge of hospitalized
patients with heart failure: the Better Effectiveness After Transition-Heart Copyright © 2016 Yehya and Thomas. This is an open-access article distributed under
Failure (BEAT-HF) randomized clinical Trial. JAMA Intern Med (2016) the terms of the Creative Commons Attribution License (CC BY). The use, distribu-
176(3):310–8. doi:10.1001/jamainternmed.2015.7712 tion or reproduction in other forums is permitted, provided the original author(s)
68. Boyer SL, Silka MJ, Bar-Cohen Y. Current practices in the monitoring of or licensor are credited and that the original publication in this journal is cited, in
cardiac rhythm devices in pediatrics and congenital heart disease. Pediatr accordance with accepted academic practice. No use, distribution or reproduction is
Cardiol (2015) 36(4):821–6. doi:10.1007/s00246-014-1090-4 permitted which does not comply with these terms.

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