Expert Review of Respiratory Medicine

ISSN: 1747-6348 (Print) 1747-6356 (Online) Journal homepage: https://www.tandfonline.com/loi/ierx20

Emerging approaches in pediatric mechanical

ventilation

Duane C Williams & Ira M Cheifetz

To cite this article: Duane C Williams & Ira M Cheifetz (2019): Emerging approaches
in pediatric mechanical ventilation, Expert Review of Respiratory Medicine, DOI:
10.1080/17476348.2019.1586536

To link to this article: https://doi.org/10.1080/17476348.2019.1586536

Accepted author version posted online: 26

Feb 2019.

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Emerging approaches in pediatric mechanical ventilation

Duane C Williams1* and Ira M Cheifetz2

1
Division of Pediatric Critical Care Medicine, Department of Pediatrics, Penn State Hershey Children’s Hospital,
Hershey, PA, USA

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Division of Pediatric Critical Care Medicine, Department of Pediatrics, Duke Children’s Hospital, Durham, NC, USA

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*Corresponding author:

Duane Williams
1
Division of Pediatric Critical Care Medicine, Department of Pediatrics, Penn State Hershey Children’s Hospital,

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Hershey, PA, USA
dwilliams3@pennstatehealth.psu.edu

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Emerging approaches in pediatric mechanical ventilation

Duane C Williams1* and Ira M Cheifetz2

1
Division of Pediatric Critical Care Medicine, Department of Pediatrics, Penn State Hershey Children’s Hospital,
Hershey, PA, USA

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2
Division of Pediatric Critical Care Medicine, Department of Pediatrics, Duke Children’s Hospital, Durham, NC, USA

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*Corresponding author:

Duane Williams
1
Division of Pediatric Critical Care Medicine, Department of Pediatrics, Penn State Hershey Children’s Hospital,

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Hershey, PA, USA
dwilliams3@pennstatehealth.psu.edu

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ABSTRACT
Introduction: The use of mechanical ventilation is an invaluable tool in caring for critically ill patients.
Enhancing our capabilities in mechanical ventilation has been instrumental in the ability to support
clinical conditions and diseases which were once associated with a high mortality.

Areas covered: Within this manuscript, we will look to discuss emerging approaches to improving the
care of pediatric patients who require mechanical ventilation. After an extensive literature search we
will provide a brief review of the history and pathophysiology of acute respiratory distress syndrome, an
assessment of several ventilator settings, a discussion on assisted ventilation, review of therapy used to

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rescue in severe respiratory failure, methods of monitoring the effects of mechanical ventilation, and

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nutrition.

Expert Opinion: As we have advanced in our care, we are seeing children survive illnesses that would

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have once claimed their lives. Given this knowledge, we must continue to advance the research in
pediatric critical care to understand the means in which we can tailor the therapy to the patient in
efforts to efficiently liberate them from mechanical ventilation once their illness has resolved.

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KEYWORDS:
Acute respiratory distress syndrome
Assisted Ventilation
Driving Pressure
Electrical Impedance Tomography
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Esophageal Pressure Monitoring
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Extracorporeal membrane oxygenation
High frequency ventilation
Lung Biomarkers
Non-invasive Monitoring
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1. INTRODUCTION

Mechanical ventilation is essential in patients with respiratory failure to ensure gas exchange needed for
the function of their vital organs. Greater than 60% of all patients admitted to an intensive care unit
require invasive support during their stay with over 10% of intensive care admissions carrying the
diagnosis of acute respiratory distress syndrome (ARDS) [1,2,3]. Infants and children (0 to 18 years of
age) compared to adults are particularly prone to develop respiratory failure given their ineffective

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cough clearance during illness, greater chest wall compliance (specifically in infants making it more

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difficult to generate significant negative intrathoracic pressure in time of illness), weaker cartilaginous

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airway support leading to dynamic airway compression, higher baseline airway resistance, and decrease
in diaphragmatic efficiency [4]. Thus, having a solid understanding of the use and means to manipulate

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mechanical ventilation is one of the most imperative foundational skills that a pediatric intensivist
should possess. When the decision is made to move to invasive mechanical ventilation, the clinician
must take into account the need to balance adequate oxygenation and effective ventilation with
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preventing ventilator induced lung injury. The choice of ventilator, mode of ventilation, peak pressure /
tidal volume limit, and degree of monitoring during mechanical ventilation differs amongst providers
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and institutions. Given the lack of prospective randomized control pediatric trials, pediatric providers
have extrapolated clinical practice from adult studies and consensus statements [4,5]. However, one
should question whether extrapolation from adult-based studies is a wise practice decision given the
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pathophysiologic (i.e., presence of pre-existing co-morbidities) and anatomic differences between

children and adults who suffer from ARDS. The work by experts of the Pediatric Acute Lung Injury and
Sepsis Investigators (PALISI) Network and the Pediatric Acute Lung Injury Consensus Conference
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(PALICC) group have generated specific recommendations for pediatric acute respiratory distress
syndrome (PARDS) [6]. The PALICC definition of PARDS has several key differences from the adult ARDS
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definition (Table 1). The most poignant are the use of oxygenation index (or oxygenation saturation
index) rather than PaO2/FiO2 ratio and the allowance for defining PARDS with unilateral disease. Such
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efforts have sparked others to pursue additional means to improve the care we deliver to children.
What developments are on the horizon to further advance clinical practice? In this paper, we discuss
emerging approaches to improving the care of pediatric patients who require mechanical ventilation
with a focus on the assessment of several ventilator settings, discussion on assisted ventilation, review
of therapies used to rescue in severe respiratory failure, methods of monitoring the effects of
mechanical ventilation, and nutrition.
2. HISTORY AND PATHOPHYSIOLOGY OF ARDS
In 1994 during the American-European Consensus Conference a panel of healthcare providers looked to
define a unique aspect of pulmonary disease characterized by hypoxia, tachypnea, and poor pulmonary
compliance. Their discussion led to the designation of a mild and severe disease process titled acute
lung injury and adult respiratory distress syndrome, respectively; the latter was later renamed acute
respiratory distress syndrome [7]. Characterized as an acute non-cardiogenic pulmonary edema with

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bilateral pulmonary infiltrates on chest radiograph; the difference in the mild versus severe form was

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denoted by a PaO2/FiO2 ratio of < 200 torr versus < 100 torr, respectively [7]. With further
understanding of this disease, the ARDSnet Task Force developed the Berlin criteria which looked to

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ascribe mild, moderate, and severe distinctions for ARDS to those with a PaO2/FiO2 ratio of 200-300,
100-200, and < 100 torr, respectively (see Table 1). Subsequently, pediatric specific denotations for

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ARDS were developed by the PALICC investigators in 2015 leaning more on oxygenation index rather
than PaO2/FiO2 ratio to denote disease levels or severity (see Table 1).
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The primary diagnoses reported with pediatric ARDS by Flori et al were pneumonia (35%), aspiration
(15%), sepsis (13%), near-drowning (9%), concomitant cardiac disease (7%), and other entities (21%).
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Infectious causes, including sepsis and pneumonia, represented approximately half of all clinical
disorders associated with ALI [8].
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Historically, ARDS is characterized as progressive transitioning from an acute phase (with some who do
not progress to the later stages), to a fibrotic stage, and then, hopefully, to recovery. During the acute
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phase, we observe hypoxemia refectory to supplemental oxygen secondary to the influx of protein-rich
edema fluid into the airspaces disrupting the alveolar epithelium (composed of type I and type II cells).
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Progressive inflammation is felt to lead to diffuse alveolar damage with the influx of neutrophils and
macrophages which worsen the alveolar epithelial injury [9,10]. Of note, an autopsy study reported that
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diffuse alveolar damage was not universal in those with ARDS but was seen in a high percentage in those
with severe ARDS [12]. Damage to the epithelium promotes alveolar flooding as the damage to type II
cells impairs removal of fluid from the alveolar space [18]. We should note that damage to type II cells,
which impairs surfactant production, has led providers to use supplementary surfactant as a therapy.
However, the use of exogenous surfactant has not shown direct benefit to support routine use [13,14].
Unfortunately, for some, ARDS progress to a fibrosing alveolitis phase in which the alveolar space
becomes filled with mesenchymal cells, collagen, and fibronectin [15]. This corresponds to worsening of
alveolar dead space and pulmonary compliance. At this time providers may note the development of
airspace disease, such as pneumothorax or pneumomediastinum.

During the recovery phase, gradual improvement in hypoxemia and fibrosis leads to improvement in

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compliance and the ability to wean respiratory support. With that, mortality from pediatric ARDS has

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been described to be less than for the adult population. Yet, specific populations secondary to their co-
morbidities have a mortality rate that is quite significant [8]. Specifically, pediatric patients who are

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immunocompromised (e.g., bone marrow transplant recipients) are uniquely vulnerable to poor
outcomes from ARDS in that this group develops bronchitis obliterans with organizing pneumonia to a

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higher degree [16,17].

3. BASIC SETTINGS

3.1 Tidal Volume

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The optimal tidal volume for the pediatric patient continues to be debated. Following the ARDS
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Network report of increased mortality for those receiving 12 ml/kg versus 6 ml/kg, tidal volume has
been viewed as causality for volume induced lung injury [6,23]. This practice has been extrapolated to
pediatrics with the PALICC recommendation to set tidal volume at 3-6 ml/kg for those with poor
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compliance and 5-8 ml/kg for those with better compliance [6]. Albuali and colleagues reported findings
supporting decreased mortality with this route of care [19]. Yet, Panico et al failed to demonstrate an
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association between tidal volume and mortality while there was an association with high inspiratory
pressure and mortality [20]. Erickson et al and Khemani et al demonstrated a significant association
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with PEEP, mean airway pressure, and peak inspiratory pressure with mortality. However, there was an
inverse relationship between tidal volume and mortality in their cohort. They speculated this finding
was secondary to the use of a pressure controlled mode where higher tidal volume may be related to
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better lung compliance (i.e., association between higher tidal volume and survival rather than a cause-
and-effect relationship) [21,22]. Providers must be mindful of their choice in tidal volume and the
potential benefit and harm they are providing.

3.2 Driving Pressure

With the findings of the ARDS Network, the move to lower tidal volume, higher PEEP, and avoidance of
elevated plateau pressures has been an almost universal adaptation of respiratory care [5,11,23]. The
use of higher PEEP is felt to augment lung recruitment which enhances the redistribution of tidal volume
from overdistended alveoli to newly recruited lung, thus, improving ventilation and oxygenation [24].
Understanding that diseased lung may have an increased closing capacity (lung volume at which the
bronchioles collapse), successful recruitment may potentially reduce the peak pressures needed for
proper ventilation. However, is there another measure that would correlate to improved outcomes?
Amato and colleagues in an adult study investigated driving pressure (pressure exerted on the functional

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lung; equal to the tidal volume (VT) divided by the respiratory system compliance (CRS), ΔP = VT/ CRS) and

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found that irrespective of tidal volume and/or plateau pressure those with lower driving pressure
(limited to 14 cm H2O) yielded better outcomes [23]. In patients with ARDS the proportion of lung

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available for ventilation is decreased as reflected by lower respiratory-system compliance (CRS) [23,25].

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Therefore, to understand the potential long-lasting trauma that can affect the lung parenchyma, it may
yield greater insight to assess the pressure exerted on the functional lung than the tidal volume or

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plateau pressure alone. Unfortunately, data are lacking in the pediatric population.

When a patient is not generating spontaneous inspiratory effort, ΔP can be calculated by the plateau
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pressure minus the positive end expiratory pressure (PEEP). Looking at this marker, Amato and
colleagues noted that increasing the PEEP was not associated with improved survival, if there was not
subsequent reduction in the driving pressure. These finding warrant further investigation for the
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pediatric population as the driving pressure target may be the same or lower in our efforts to assess
what aspect of ventilation truly negatively affects patient survival.
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3.3 Fraction of Inspired Oxygen

Hypoxemia leads to poor oxygen delivery and impairs healing in those who are critically ill. Hence, the
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use of mechanical ventilation to support hypoxemia is vital to reducing mortality. However, hyperoxia
can produces extraordinary amounts of reactive O2 species that overwhelms natural antioxidant
defenses and destroys cellular structures through several pathways which in turn can negatively affect
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outcomes [26]. Therefore, published recommendations from groups such as the PALICC investigators
are to maintain a FiO2 to sustain SpO2 88%-97% [6].

4. ASSISTED VENTILATION

In an attempt to decrease peak pressures, improve carbon dioxide clearance, and improve patient-
ventilator synchrony, ‘assist ventilation’ has been utilized as a modality of care. Modes such as pressure
support ventilation allow the patient to control their own respiratory rate and inspiratory time.
Providers set a PEEP and level of pressure support to assist the patient who triggers each breath.
However, with changes in lung compliance the generated tidal volume will vary. Therefore, with
worsening airway disease the provider may need to increase the set pressure support to allow for an
appropriate tidal volume and, thus, adequate minute ventilation and oxygenation. Alternative support
modes, such as volume support (in which providers set a set volume for the patient), prevent loss of a

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desired tidal volume but may lead to elevated peak pressures in the presence of worsening lung disease.

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Proportional assist ventilation (PAV) is a form of synchronized partial ventilatory assistance in which the

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ventilator generates pressure in proportion to the patient’s instantaneous effort which lowers alveolar
pressure (this allows for increased air flow into the lungs by allowing the mean airway pressure to

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exceed alveolar pressure) [32]. Therefore, PAV looks to normalize the neuro-ventilatory coupling by
making the ventilator an extension of the patient’s respiratory muscles easing work of breathing as the
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patient has complete control of all aspects of breathing [33]. In this scenario, the patient receives
support without any preselected volume, pressure, or flow. This mode has been shown in both invasive
and non-invasive mechanical ventilation to improve arterial blood gas tensions, alveolar ventilation, as
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well as unloading the respiratory muscles in both acute and chronic patients [32, 34-36]. Additionally,
compared to pressure assist control ventilation and synchronized intermittent mechanical ventilation,
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PAV has been noted to maintain similar gas exchange with lower airway pressure, transpulmonary
pressure, and calculated oxygenation index [37,38]. A group in King’s College Hospital in London looked
at this modality in the neonatal bronchopulmonary dysplasia population [39]. In their study with the
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understanding that PAV can provide inflation pressure in phase with the tidal volume change to reduce
the compliance load (i.e., the load due to the stiffness of infant’s lungs) and in phase with the flow
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change to reduce the resistance load (i.e., the load due to airflow obstruction), termed elastic and
resistive unloading respectively, that their infants would have superior oxygenation index after four
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hours of PAV as compared to those on assist control ventilation [39,40]. While maintaining an oxygen
saturation of 92-96% they looked to enroll 18 neonatal subjects to test this theory. The enrollment was
stopped at eight patients as all eight showed a statistically significant fall in oxygenation index. One
should note that the PAV group did have a higher (although not statistically significant) tidal volume.
Although specifically in the neonatal population, this raises the possibility of future study in other
pediatric populations as a modality of care. It should be noted that there are no definitive studies which
show PAV has an effect on overall outcome.
Neurally adjusted ventilator assist (NAVA) provides proportional pressure support based on
measurements of the electrical activity of the diaphragm, which serves as a proxy for the neuronal
output of the respiratory center [41]. NAVA has been shown to increase ventilator free days and lower
peak pressures in children. Piastra et al reported in children less than one who were weaning from
HFOV and transitioned to either NAVA or Pressure Support Ventilation showed that those on NAVA had
a higher PaO2/FiO2 ratio, lower peak pressure, and higher minute ventilation. Further the COMFORT

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score (pain assessment tool) was improved with the NAVA group [42,43]. The use of NAVA has
increased due to its ability to assist with patient asynchrony and discomfort which are, unfortunately,

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frequently treated with sedation or muscle relaxation which prolong mechanical ventilation [44,45].

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The success seen with invasive NAVA has led to non-invasive use of this device. Vignaux et al preformed
a prospective randomized cross-over study in six children undergoing non-invasive ventilation in a PICU

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and showed that the trigger delay was lower in neutrally adjusted ventilatory assist compared to
pressure support [46]. This was supported by a study of eighteen children requiring non-invasive
support for mild early pediatric acute respiratory distress by Chidini et al [47]. These investigators also
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showed a decrease in peak pressure, mean airway pressure, and oxygenation index. With the increase
in the number of interface options for infants and children over the past 5 years or so the incorporation
with non-invasive NAVA may be an area of needed exploration. Unfortunately, to date, definitive
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outcome data are lacking.

5. RESCUE THERAPY
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5.1 High Frequency Oscillatory Ventilation

Even with adjustments in ventilator settings and modes of ventilation, ventilator-induced lung injury
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(baro-, atelec-, and volu-trauma) may exist. As ARDS is a heterogeneous disease, areas of lung
parenchyma may transition between hyperinflation, normal aeration, and collapse; thus, careful
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adjustment of ventilator settings and modes as lung condition changes is vital to achieving the best
outcomes [48,49]. At elevated levels of peak inspiratory, plateau and/or mean airway pressure,
providers may consider high frequency oscillatory ventilation (HFOV) to decrease the pressure swings
potentially associated with alveolar trauma. The theoretical advantage of HFOV is the maintenance of an
open lung model with the use of a higher mean airway pressure but low phasic volume and pressure
changes to maintain the alveoli open between the lower and upper inflection points [50]. Such an
approach may limit lung trauma (atelectrauma) caused by the opening and closing of the lung to deliver
a tidal volume and lung overdistention (volutrauma), especially in the presence of poor compliance [51].

To date, there are no clear pediatric data demonstrating that HFOV is better than conventional
ventilation. An adult study (OSCILLATE trial) randomized patients with moderate to severe ARDS to
HFOV or CMV. This study did not show a reduction, and raised concern for a potential increase, in

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hospital mortally with HFOV [52]. An additional adult study (OSCAR trial) randomized patients to receive

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HFOV or usual ventilatory care. Their results revealed no difference in 30 day mortality [53]. It could be
speculated that these findings may be the result of poor lung recruitment prior to the initiation of HFOV

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[54]. Gupta et al performed a post hoc analysis of the virtual PICU system database, and after
propensity matching, length of mechanical ventilation and mortality were significantly lower in the CMV

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vs the HFOV group [55]. However, when assessing those whom utilized early transition to HFOV (first 24
hour of symptoms); those patients in that early group were noted to have a shorter length of
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mechanical ventilation and shorter ICU length of stay. This was supported by another single center
study involving 26 children [56]. Interestingly, these findings are contrary to what Bateman et al.
reported [57]. Given the range of findings and clinical thoughts, it is not surprising that the PALICC
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group has a weak agreement towards the use of HFOV in children.
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5.2 Prone Positioning

Prone positioning has been used in ARDS to improve ventilation-perfusion matching, recruitment of
dependent lung regions, and to optimize chest wall mechanics [58-60]. Yet, in the pediatric population,
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we have not seen improvement in clinical outcomes. In 2005 Curley et al performed a randomized
control trial of 102 pediatric patients with ARDS to either supine or prone. This study was stopped
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secondary to futility with no difference noted in ventilator free days between the two groups [62]. In
2013, the PROSEVA study group showed that patients with severe ARDS who underwent early
application of prolonged prone-positioning had a statistical significant reduction in 28 and 90 day
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mortality [64]. Additionally an adult study that looked at those with low tidal volume demonstrated that
when stratified for low tidal volume prone positioning was associated with a significant decrease in the
relative risk of death [65]. With this, there may be a specific population in which prone positioning may
impact outcomes.

5.3 Extracorporeal Support

When conventional methods fail, extracorporeal support has been influential in providing support for
the most critically ill of patients. However, does the use of ECMO improve survival in the pediatric
population? Barbaro and the RESTORE Study Investigators looked at mortality, ventilator free days, and
length of stay in patients who received ECMO versus those who did not for PARDS [67]. Their data
showed no difference in mortality or ventilator free days but did show that the ECMO group had a
longer length of stay. The difference in severity of illness between these groups should be

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acknowledged. Given these findings, understanding if there are unique characteristics of a patient that

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lead to poor outcomes would be insightful. Zabrocki et al. reviewed the ELSO database to assess for
predictors of mortality with ECMO. In their review they noted that children with comorbidities (renal

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failure, cardiac arrest, cancer, and hepatic failure), those older than 10 years, those ventilated for
greater than 14 days, and those presenting with a pH less than 7.19 had an increase likelihood of

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mortality [68]. That leads providers to question whether one could generate a system to evaluate a
patient to assess if they would benefit from the use of ECMO? Furthermore, given that those noted by
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Zabrocki et al who were ventilated for greater than 14 days had an increased likelihood of mortality,
would early intervention with ECMO be beneficial? Schmidt et al developed a scoring system (RESP –
Respiratory ECMO Survival Prediction Score) for adults which they validated internally (c = 0.74; 95%
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confidence interval, 0.72-0.76) and externally (c = 0.92; 95% confidence interval, 0.89-0.97) [69]. In their
study taking into account such factors as age, length of mechanical ventilation prior to initiation of
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ECMO, and etiology of illness (to name a few) they showed that those patients with a higher RESP score
showed increase likelihood of survival. The development of such a scoring system for pediatrics may
allow providers the means to predict those who will be optimal candidates for early cannulation.
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6. MONITORING
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6.1 End tidal CO2 (ETCO2) and Volumetric Capnography (VCO2)

After setting the ventilator parameters, providers utilize non-invasive monitoring to gain insight to
adequate gas exchange. Measuring ETCO2 and VCO2 possess the capability to non-invasively assist in the
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care of critically ill patients without the need for frequent blood gas analysis. The measurement of
ETCO2 is dependent on adequate pulmonary capillary flow of CO2 rich blood to the alveoli. The normal
ETCO2 in a healthy subject generally differs by 4-6 mmHg from the corresponding PaCO2 (representing
normal anatomic dead space of the upper airway). Although capnography is routinely utilized as
standard of care to confirm endotracheal tube placement, its use is less consistent in those mechanically
ventilated for respiratory failure. A widening ETCO2- PaCO2 gradient can alert providers to an increase in
alveolar dead space seen in states such as low cardiac output, pulmonary embolism, and worsening V/Q
mismatch [27,28]. This is of central importance as an increase in alveolar dead space has been linked to
an increased mortality in ARDS [70].

Volumetric capnography is the measure of carbon dioxide elimination (VCO2) as a function of volume of
gas exhaled (ml/min) rather than a partial pressure (torr). VCO2 relates to the patient’s degree of

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metabolism (i.e., carbon dioxide production), minute ventilation, and pulmonary capillary perfusion.

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Together ETCO2 and VCO2 can provide an understanding into the efficiency of ventilation by providing a
direct measurement of the lung’s current capability for gas exchange, degree of lung collapse, and

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dynamic changes in lung recruitment [27,29,30]. Additionally, the use of VCO2 allows providers to
calculate physiologic dead space (VD/VT) by subtracting the mixed-expired partial pressure of carbon

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dioxide (PĒCO2) from the PaCO2, then dividing by the PaCO2.

VD/VT = (PaCO2 - PĒCO2)/ PaCO2 an

This modification of Bohr’s original formula by Enghoff allows for the calculation of physiologic dead
space ventilation as a bedside tool. Providers have used VD/VT as a means to predict extubation failure.
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Specifically a VD/VT < 0.5 was associated with successful extubation as compared to a VD/VT of > 0.65
[17]. With that, the use of this bedside technology allows for real time assessment of these parameters
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and may improve efficiency in care.

6.2 Measurement of Lung Biomarkers

Many times it is the adjunct therapies in combination with the technology that promote the best
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outcomes. In that, the ability to target therapy to a specific biomarker may provide an opportunity to
prevent further damage and even repair damage that has been done in respiratory failure. The work
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done in illnesses such as hemophagocytic lymphohistiocytosis and anti NMDA encephalitis have shown
providers the positive effects of targeted immunotherapy [71,72]. The biomarker IL-1b has been
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identified to be present during times of epithelial repair in lung injury [73]. The presence of growth
factors such as hepatocyte growth factor, vascular endothelial growth factor, and epidermal growth
factor obtained from bronchial lavage may correlate to a sign of recovery in acute lung injury (ALI) [74-
77]. Contrarily, biomarkers such as IL-8 and PAI-1 (plasminogen activator inhibitor) if recorded at high
levels is associated with non-survivors [78-80]. Plasma growth factors such as angiopoietin peptides
angiopoietin 1 (Ang-1) and angiopoietin 2 (Ang-2), in particular the ratio of Ang-2/Ang-1 may have
insight into recovery and mortality [78]. A recent study reported that a high Ang-2/Ang-1 ratio was an
independent risk factor for mortality in patients with ALI [81].

In animal models researches have demonstrated that providing a nebulized agonist of the nuclear
transcription factor peroxisome proliferator-activated receptor gamma (PPARγ) promoted lung
maturation and prevented neonatal hyperoxia-induced lung injury in both males and females. It is
postulated that (PPARγ) stimulates alveolar interstitial lipofibroblast maturation which plays a key role in

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physiologic lung development and homeostasis [81]. Additionally, it has also been noted that glutamine
prevents elevation of IL-8 which is correlated with worsening lung injury as described above [83].

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Adapting such therapies to patients may potentially be a therapeutic approach to explore.

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6.3 Esophageal Pressure Monitoring
In wanting to gain an enhanced means to limit the trauma on the lung parenchyma with mechanical
ventilation the use of esophageal pressure (Pes) has been utilized. Pes has been used as a surrogate for
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pleural pressure (PL) to calculate the transpulmonary pressure (pressure felt to drive ventilation of the
lung) by subtracting Pes from the mean airway pressure (Paw) [84,85]. Pes is measured by placing a
catheter into the esophagus via the nose or mouth. These pressure readings are felt to more accurately
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reflect exposure on the lung parenchyma. In the Esophageal Pressure-Directed Ventilation (EPVent)
study Talmor et al tested this capability [86]. In this single center study patients were randomized to a
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control arm (following the ARDS Network protocol) with a tidal volume of 6 ml/kg of predicted body
weight with a PEEP based on the patient’s partial pressure of arterial oxygen (PaO2) and inspired fraction
of oxygen (FiO2) [5]. In the experimental arm, PEEP was titrated to achieve a pleural pressure (as
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estimated by Pes) between 0 and 10 cm H2O at the end of exhalation according a PaO2/FiO2 sliding scale
ratio. Further, tidal volume was limited to keep the Pes less than 25 cm H2O at the end of inhalation.
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They noted at the end of 72 hours the PEEP in the control group was 12 + 5 cm H2O, while in the
experimental group it was 18 + 5 cm H2O. The study was terminated after enrolling 61 patients with
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noting a statistical difference in PaO2/FiO2 ratio of 191 + 71 in the control group and 280 + 126 in the
experimental (Pes) group (p=0.001). Additionally, respiratory compliance was noted to significantly
improve in the experimental group as well. Further, investigators reported a trend towards significance
in 28-day mortality for the experimental group (p=0.055), but noted the study was not powered for
other outcome variables such as ventilator free days, length of stay, nor duration of ventilation. The use
of such a modality in pediatrics, particularly in patients with underlining chronic lung disease, may be
useful in limiting the use of high ventilator settings to support their care.
6.3 Electrical Impedance Tomography
An additional means to evaluate for improvement in ventilation is utilizing electrical impedance
tomography (EIT). First used in 1983 it allows for a non-invasive means to monitor regional changes in
lung volumes, assess for lung overdistention, pneumothorax, and patient asynchrony [87-90]. Via
electrodes distributed around the thorax, EIT generates electrical potentials that allow for the creating
of a cross-sectional image of impedances [91]. Using this modality of care Victorino et al showed

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comparable appreciation of improvement in aeration and lung recruitment as compared to that

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exhibited by computerized tomography scan [92]. In patients with cystic fibrosis Zhao et al

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demonstrated that EIT correlated with spirometry in assessing for airway obstruction. Although a report
in pediatrics has not yet been described, this non-invasive tool warrants consideration in the care of the

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critically ill [93].

7. EARLY ENTERAL NUTRITION an

In the midst of providing the correct mode of ventilation and optimizing adjunct therapy, providers must
remember that appropriate nutrition is vital to adequate healing during critical illness. As it pertains to
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parenteral nutrition in both the pediatric and adult populations, late initiation is associated with faster
recovery and fewer complications [94,95]. However for enteral feeds, there is a debate. A multicenter
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prospective cohort trial of children 1-18 years of age who required mechanical ventilation for greater
than 48 hours demonstrated a lower 60 day mortality and lower prevalence of acquired infections when
a higher percentage of goal energy intake was enteral [96]. An adult prospective study demonstrated a
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statistical decrease in mortality (34% vs 44%; p< 0.01) with the commencement of enteral feeds within
48 hours of intubation [97]. Retrospectively, Arinian and colleagues showed a decrease in ICU mortality
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(18% vs 21%; p =0.02) and hospital mortality (28% v 34%; p = 0.0005) with early feeding (within 48
hours). We have an opportunity to identify if the commencement of enteral feedings early in illness
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would provide better healing in this vulnerable population.

8. CONCLUSION

The use of mechanical ventilation has transcended the care that we provide to critically ill children.
Building on a strong foundation of existing knowledge we will be able to utilize various modes of
mechanical ventilation in addition to methods of monitoring and caloric support to enhance the care we
provide.
9. EXPERT OPINION

Mechanical ventilation provides a means to care for the most critically ill of children. As we have
advanced in our care we are seeing children survive illnesses that would have once claimed their lives.
Improved understanding of the pathophysiology is allowing management to be tailored not only to the
disease, but to the individual patients affected by the disease. As we develop means for real time

t
individualized assessment of illness, we may be able to adjust respiratory care for patients with

ip
measurements of lung biomarkers IL-1b and PAI-1 with similar efficacy as we have witnessed in sepsis
with urine biomarkers for acute kidney injury [98,99].

cr
As we expand our use of non-invasive means to assess the care we provide, we have the ability to

us
become more efficient in not only implementing the positive but also preventing the negative effects of
ventilation maneuvers. As methods to improve the accuracy in such modalities as esophageal pressure
an
is developed, we will likely have a more authentic measurement of the pressure used to support
critically ill children and, thus, the degree of ventilator induced lung injury that may be occurring.
Additionally, increasing the availability of modalities such as electrical impedance tomography may be
M
the means to guide therapy when it is felt that lung collapse is leading to deterioration in critically ill
patients. As our comfort with non-invasive management increases our patients will reap the benefits.
ed

An emerging concept being proposed by investigators of PALISI is to put forth the prone and oscillation
pediatric clinical trial (PROSpect) [61]. This will look to evaluate if the use of higher frequency (8-15 Hz)
pt

and corresponding high amplitude with or without prone positioning can improve outcomes in severe
pediatric acute respiratory distress. As discussed, the use of prone positioning performed at an early
ce

onset in respiratory failure did not show efficacy in a pediatric study [62]. Yet, when the PaO2/FiO2 ratio
was less than 100, there was an improvement noted. This finding was also noted by Sud and colleagues
Ac

in their meta-analysis [63]. This corresponds with the recommendation of PALICC that prone positioning
cannot be recommended in routine therapy yet may have a role in severe ARDS. Therefore, combining
the open lung model effect of HFOV with the improvement in recruitment and ventilation-perfusion
matching seen with proning may yield improvement in severe PARDS. It will be interesting to see what
the results of this study show as Wong et al in an in vitro model demonstrated a decrease in attenuated
MAP with increasing amplitude [100]. One would speculate that this could lead to worsening
oxygenation.
As we work to improve mortality, we must be mindful of morbidity. It has been noted that infants with
chronic lung disease are prone to frequent respiratory illnesses, feeding difficulties, growth failure, and
re-hospitalization during infancy. This puts a large burden on their families as they struggle with the
financial and psychosocial costs of caring for such children [98]. Newer home ventilator models via cloud
technology allow providers to assess patient interactions and may be a means to adjust settings to

t
prevent excessive pulmonary stretch and subsequent alveolar damage and worsening disease.

ip
Temporary adjustments during illness could augment resolution of disease and potentially avert the
need for admission [101]. As we become more comfortable with our monitoring in the intensive care

cr
setting (i.e., esophageal pressure monitoring) the transition of these methods of care to the home
setting may become as natural as providing home ventilation. Given this knowledge, it is paramount

us
that we continue to advance the research in pediatric critical care to understand the means in which the
therapy we deliver is patient tailored to liberate them rapidly and safely from mechanical ventilation
once their illness has resolved. an
As we look toward the future, there are aspects of care that have been instituted that will likely be
M
expanded and perfected. Furthermore, there are ventures on the horizon that have the potential to
dramatically change our clinical practice. Given the apparent early success with novel modalities such as
non-invasive NAVA and the increased interface options, there is likely to be a continued increase in the
ed

use of non-invasive mechanical ventilation in pediatric medicine. The increase in interphases and
technology such as non-invasive NAVA have provided an opportunity to avoid invasive means of care.
pt

We will likely see the birth of algorithms combining biological markers and scoring systems to guide
providers to what mode of care will provide the best outcomes in patients. Treatment models will
ce

become more specific to the individual patient and their specific illness. Additionally, a patient’s unique
genetic composition may play a larger role in what therapies are chosen. We may be able to identify
Ac

patients in whom continuing to provide conventional mechanical ventilation is not to their advantage as
we aim to prevent ventilator induced lung injury. This may cause an increase in such therapies such as
HFOV and ECMO which are customarily reserved for those with a greater severity of disease. Identifying
patients who at the onset of their illness who would benefit from these therapies once thought to be
the most invasive may be the means to improve mortality and limit subsequent morbidity. The next
step may be the evaluation of a systematic approach to identify those in whom commencing advanced /
adjunct therapies in the early stages of disease would be beneficial.
Nutrition will be seen as even more vital to critical care in those mechanically ventilated. Not only will
attention be paid to the caloric intake and the speed to which we arrive at full enteral feeds, but also to
the protein load delivered [102].

Lastly, we will see greater attention paid to the long-term outcome of pediatric patients. As our care
has improved morbidity, not mortality, will become the most valuable outcome. The resiliency of

t
children is unrivaled. We are observing more children home on therapies once thought to be only

ip
available in a hospital setting. The expansion of home ventilator support alone speaks to this truth.

cr
However, will this population be able to survive without the use of a care provider constantly present?
Will we see a need for less hospital beds and more long-term care facilities to care for these children

us
who may not need the hospital, but are unable to be at home? With medicine pushing the limits in
neonatal and critical care medicine we may see a growth in a more dependent than independent
population.
an
The continued collaborative efforts of physicians such as those of the PALICC and PALISI groups, the
expansion of technology, and the desire to endeavor in research at the cellular level provides us the
M
potential to improve upon care that we provide to the most critical of children.
ed
pt
ce

KEY ISSUES
Ac

• Understanding the physiologic implications of driving pressure on outcome in those with ARDS

may provide greater insight into approaches to improve morbidity rather than focusing on peak /

plateau pressures alone.

 • Bedside non-invasive monitoring technology, such as ETCO2, VCO2, esophageal pressure

monitoring, and electrical impedance tomography may improve efficiency in care and potentially

outcomes.

• There is a possibility that assist ventilation modes may improve patient-ventilator synchrony,

thus minimizing the need for pharmacologic sedation.

t
ip
• The use of high frequency ventilation as well as proning for those with pediatric ARDS requires

further investigation.

cr
• Targeting therapy to specific biomarkers has been the ‘holy grail’. Continued investigation may

us
finally provide additional insight into the pathophysiology of severe ARDS as well as potential

therapeutic management approaches.

•
an
Optimal early nutrition may augment lung healing in those with lung injury.
M
Funding

This paper was not funded.

ed

Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a
pt

financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.
This includes employment, consultancies, honoraria, stock ownership or options, expert testimony,
ce

grants or patents received or pending, or royalties.

Ac

Reviewers Disclosure
Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.
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Table 1. Definition of acute lung injury according to various criteria. PaO2: partial pressure of oxygen.
FiO2:Fraction of inspired oxygen
PEEP: positive end expiratory pressure. CPAP: continuous positive airway pressure. OI: Oxygen Index
[(mean airway pressure x FiO2 x 100)/ PaO2].
OSI: Oxygen Saturation Index [(mean airway pressure x FiO2 x 100)/ SpO2].

AECC Definition (1994) [7] Berlin Definition PALICC Definition

t
(2012) [103] (2015) [6]

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Timing Acute Onset Within one week of Within 7 days of insult
known insult
Chest Imaging Bilateral infiltrates on Bilateral opacities (not Chest imaging with

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chest x-ray explained by new infiltrate
effusions, lobar/lung consistent with acute
collapse, or nodules) pulmonary

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parenchymal disease
Exclusion etiologies Pulmonary wedge <18 Respiratory failure not Children with
mmHg or no clinical explained by cardiac perinatal disease or
evidence of high left atrial failure or fluid congenital lung

Oxygenation
pressure
Hypoxemia independent
an overload
Mild Lung injury:
disease
Mild PARDS:
Distinction of PEEP level 4 ≤ OI 8 5<OSI<7.5
- 200mmHG <
M
PaO2 / FIO2 ≤
300mmHG
with PEEP or
CPAP ≥ 5
ed

cmH2O
Acute Lung Injury: Moderate Lung Injury: Moderate PARDS:
- PaO2/FIO2 < 300 - 100mmHg < 8≤OI<16
pt

PaO2/FIO2 ≤
200 mmHg 7.5<OSI<12.3
with PEEP or
ce

CPAP ≥ 5
cmH2O
Adult Respiratory Distress Severe Lung Injury: Severe PARDS:
Syndrome: - PaO2/FIO2 ≤ OI≥16
Ac

- PaO2/FIO2<200 100mmHg
with PEEP ≥ 5 OSI>12.3
cmH2O