第 16 卷 第 5 期 中国当代儿科杂志 Vol.16 No.

5
2014 年 5 月 Chin J Contemp Pediatr May 2014

o 10. 4 . .100 0.2014.05.001

Acute respiratory distress syndrome in the pediatric age:

an update on advanced treatment
Giuseppe A. Marraro1,2, Chengshui Chen2, Maria Antonella Piga1,
Yan Qian3, Claudio Spada1,2, Umberto Genovese1
(1. Healthcare Accountability Lab, Departmental Section of Legal Medicine, University of Milan, Italy;
2. Department of Respiratory Diseases, First Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
3. Department of Pediatrics, First Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China)

Abstract: Acute respiratory distress syndrome (ARDS) is a heterogeneous syndrome that lacks definitive
treatment. The cornerstone of management is sound intensive care treatment and early anticipatory ventilation support. A
mechanical ventilation strategy aiming at optimal alveolar recruitment, judicious use of positive end-respiratory pressure
(PEEP) and low tidal volumes (VT) remains the mainstay for managing this lung disease. Several treatments have been

for routine care. Non-invasive ventilation (NIV) is suggested with a cautious approach and a strict selection of

severe ARDS. The extra-corporeal carbon dioxide removal (ECCO2 R), used as an integrated tool with conventional
ventilation, is playing a new role in adjusting respiratory acidosis and CO2 2 R over

related side effects and technical complications, as well as lower costs. The advantages and disadvantages of inhaled
nitric oxide (iNO) are better recognized today and iNO is not recommended for ARDS and acute lung injury (ALI) in
children and adults because iNO results in a transient improvement in oxygenation but does not reduce mortality, and

patients with ARDS. However, studies which are still controversial have shown that surfactant supplementation can

in different modes and doses, also in neonatal respiratory distress syndrome (RDS) of preemies. Management of ARDS
remains supportive, aimed at improving gas exchange and preventing complications. Progress in the treatment of ARDS

predict the treatment outcome, also with the perspective to develop predictive and personalized medicine that highlights

legal implication. [Chin J Contemp Pediatr, 2014, 16(5): 437-447]

Key words: Acute respiratory distress syndrome; Protective lung strategy; Recruiting maneuver; Non-invasive
ventilation; High-frequency oscillatory ventilation; Extra-corporeal carbon dioxide removal; Inhaled nitric oxide;
Surfactant; Child

Acute respiratory distress syndrome (ARDS) is fraction of inspired oxygen (FiO2) and tidal volumes
a heterogeneous syndrome with a complex pathology (VT) in the last decade has made of ARDS a rarely
and mechanisms of disease that still remains without seen condition in today’s modern pediatric ICUs.
a definitive and efficacious treatment. ARDS is less The cornerstone of management is correct
frequent in infants and children than in adults and the i nt e ns i v e ca r e tr ea tm en t . E ar l y an t ic ip at ory
severity of respiratory failure is lower. The judicious management may improve outcomes, avoid side
use of positive end-respiratory pressure (PEEP), effects and complications, and increase survival.

期 201 12 2 期 2014 02 20
Giuseppe A. Marraro, MD.( male), Adjunct Professor. Healthcare Accountability Lab, Departmental Section of Legal Medicine,
University of Milan, Italy. Email: [email protected].

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Treating the primary cause (e.g., sepsis, pneumonia), of the volume/pressure curve) for keeping terminal
minimizing the risk of multiple organ failure (MOF) bronchioles patent and improving functional residual
and dysfunction and ventilator-induced lung injury capacity (FRC) and a high respiratory rate according
(VILI) are essential. to minute volume (if possible by maintaining PaCO2
Recently, ARDS was given a new definition
under the Berlin Definition of ARDS Statement and adult patients.
has been classified into three exclusive categories The risk of low VT ventilation is that of reducing
on the basis of the degree of hypoxemia, thereby tidal volume, hypoventilation and that only dead
eliminating the acute lung injury (ALI) terminology: space ventilation can be produced while the increased
Mild (200 mm Hg < PaO 2 /FiO 2 respiratory rate is not able to normalize minute volume
Moderate (100 mm Hg < PaO2/FiO2 and eliminate CO 2 (hypercapnia development).
[1]
and Severe (PaO2/FiO2 . Increase in PaCO 2 (permissive hypercapnia) is
Four ancillary variables [severity of chest acceptable - instead of increasing tidal volume or
2 O, compliance of the peak inspiratory pressure (PIP) - but PaCO2 should
respiratory system (Crs 2 O, corrected
expired volume per minute (VEcorr ventilation can be reduced by lower tidal volumes
addition to the oxygenation index (OI) are suggested as long as PaCO2 is balanced by serum bicarbonate
for the evaluation of severe ARDS, even though levels to determine a pH above 7.20. A safe pH level
these variables do not contribute to the prognostic for in the pediatric age remains one unresolved issue and,
[2]
survival . crucially, in the premature neonate and infant setting
The Berlin Definition is not a prognostic tool where an increased risk of brain hemorrhage exists[8-9].
but can be of help, despite several limitations, in that Acidosis may be protective, by reducing cellular

not only severity and patient prognosis, but also injury (i.e. MOF). Hypercapnic acidosis may also
to facilitate the definition of therapeutic strategies down-regulate inflammatory cell activity and inhibit
predicated on severity. xanthine oxidase, thus reducing oxidant stress[10].
The most important change in the management Permissive hypercapnia is suggested as a
of adult ARDS has been the adoption of lower VT
strategies and suitable PEEP levels to prevent VILI cardiac output improvement, reduction of the artery-
[3-5]
and improve survival . venous difference and of lactate production remain
A similar body of literature does not exist in
infants and children and ventilation strategies in
these age groups are predicated on the experience 1 Atelectasis
matured in adults. An attempt to carry out a similar
study in children has failed and revealed inconsistent
mechanical ventilation practices and the use of to atelectasis in normal lung during anesthesia is not
[6-7]
adjunctive therapies in patients with ALI . recent. Several studies have shown that 85%-90% of
Similarly, a low VT strategy can be considered patients with normal lung develop atelectasis during
a milestone in the study of ventilation for ARDS
and acute respiratory failure in the pediatric age. A conventional chest X-ray imaging[11].
The development and origin of atelectasis have
2-3 cm H 2O over the upper lower inflection point not been fully investigated among mechanically

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ventilated children undergoing intensive care. The PEEP is useful for keeping the recruited lung open[11, 15].
experience gained from anesthesia can be used In neonates, infants and small children, no
in evaluating atelectasis appearance, especially if study has so far indicated the most appropriate
the child remains in the supine position, sedated recruitment method to be applied without creating
and paralyzed. Atelectasis formation has been lung barotrauma. It is reasonable to suggest a 5-8 cm
demonstrated in dependent lung areas after 15 minutes H2O increase over preset PIP and sustained distention
of anesthesia, muscle paralysis and intermittent for 8-10 seconds[15]. In case of lung pathology with
positive pressure ventilation in children[12]. unilateral prevalence, selective bronchial intubation
Several complications have been linked to and recruitment of the pathologic lung may be used
atelectasis. A reduction in functional residual capacity with the aim of re-opening the atelectasis/consolidated
(FRC), the development of hypoxemia and the need lung and protecting the less pathologic lung from
to increase FiO 2 (increase in oxygen toxicity risk) over-distension[19].
and surfactant inhibition that can lead to alveolar Bedside monitoring of alveolar recruitment
instability and increased permeability. Atelectasis can (or derecruitment) has entered the clinical area and
increase macrophages activity in producing IL-1 and should improve in the close future the ventilatory
[13]
. management of patients with ARDS. Because it is
Moreover, atelectasis and pneumonia may be noninvasive and easily repeatable, bedside trans-
considered together because the changes associated thoracic lung ultrasound appears as the most
with atelectasis may predispose to pneumonia . promising semi-quantitative technique for evaluating
Recruiting maneuvers have been proposed to the recruited lung areas and which have maintained
resolve atelectasis, improve oxygenation and re- patency[20].
opening of non-ventilating lung areas[15-16]. Lung recruitment must be followed by adequate
Various types of recruiting maneuvers have ventilation strategies to prevent collapse of re-opened
been described: the application of sigh during lung lung. The suggested treatment is the application of
protective strategy, with three consecutive sighs per PEEP level to maintain the alveoli open (keeping
2 O of plateau pressure for one
hour in patients ventilated with a protective strategy, volume curve, i.e. Pflex), improve oxygenation and
oxygen transport and avoid provoking hemodynamic
However, there is a need for large-size, controlled complications. PEEP optimization may lead to
lung protection via mechanisms other than alveolar
effects. The method used to apply the recruitment recruitment, e.g. by avoiding surfactant depletion
maneuver may influence both their efficacy and and disruption occurring at low end-expiratory lung
potential for complications. Although recruitment volumes[21].
maneuvers compromise respiratory and hemodynamic We do not have a clear idea about which level
conditions transiently, serious long-term complications of PEEP is “best”, but surely any level that can avoid
seem to be rare [17] . The long-lasting effects of repeated lung collapse and maintain alveolar patency
recruiting maneuvers on arterial blood gases are is clearly desirable[22]. The follow-up of ARDS NET
contradictory[18]. demonstrated that survival was similar with high and
Several questions remain unresolved regarding low PEEP, and that improvement in outcome was
performing recruitment: (1) which peak pressure level strictly connected to “low tidal volume strategy”[23].
Setting PEEP still remains a “compromise”
maintained at the end of inspiration, (3) which level of that allows improvement in oxygenation and oxygen

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transport while avoiding hemodynamic complications. the prone position, as suggested by some studies, may
Decremental PEEP titration to determine the level of induce alterations similar to those connected with the
PEEP required to maintain an open lung after lung supine position. Depending on the early development
recruitment is a suggestive technique but it needs of atelectasis in ventilated patients, prone positioning
further confirmation to be recommended in clinical and mobilization must be started as soon as possible in
practice .
There are children who do not respond to
2 Prone positioning undergoing prone positioning as well as adults do.

Prone positioning has been proposed for of lung pathology they suffer from and delays in their
improving oxygenation, respiratory mechanics, treatment. In these cases, selective lung recruitment
alveolar inflation and ventilation distribution, for before prone positioning must be considered to
homogenizing pleural pressure gradient and limiting

in increasing lung volume, reducing the amount of 3 Non-evidence based treatments

atelectatic lung areas in the dependent lung and in
facilitating the drainage of secretions[26-27]. 3.1 Non-invasive ventilation
With the prone position, pulmonary densities Despite controversial, sometimes far from
redistribute from the dependent lung regions, whereas encouraging, results from large studies which should
in the supine position (proximal to the spine) they have induced clinicians to a prudent attitude and
redistribute to the dependent lung regions (next to a strict selection of patients to treat, non-invasive
the sternum). The prone position reverses alveolar ventilation (NIV) is increasingly used in the ICU
inflation and ventilation distribution, due to the in patients with ALI/ARDS. Published data are
reverse of hydrostatic pressure overlying the lung contradictory and are of difficult evaluation. In
parenchyma, reverses the pressure resulting from general, these studies are case reports or retrospective,
the weight of the heart and changes in chest wall uncontrolled, small size clinical studies with a
shape and mechanical properties. On return to the remarkable quantity of case mixing and an unclear
[30]
supine position, the alveoli in the dorsal regions may .
remain open because of PEEP resulting in a persistent
response[28]. published which attempted to throw light on the real
A recent Cochrane review showed that the prone possibilities of NIV in acute respiratory failure (ARF).
position was significantly superior to the supine All these studies conclude that greater caution should
position in terms of oxygenation. Placing infants be exercised in the use of NIV for those patients
[31]
and children in the prone position may thus improve .
respiratory function. In this review, the benefits of 3.1.1 Continuous positive pressure airway
prone positioning appear to be most relevant to infants ventilation From the time of the earliest report
[29]
because this age group has been more investigated . at the beginning of the 1970s, the application of
T h e i n e ff i c a c y o f t h e p r o n e p o s i t i o n i s continuous positive pressure airway ventilation
probably due to delays in its application (the lung is ( C PA P ) h a s b e e n p r o p o s e d t o o p e n u n d e r -
consolidated and cannot be re-opened) and may also ventilated alveoli and increase functional residual
capacity (FRC), thereby decreasing the right-to-
the prone position. Keeping a patient for 12 hours in left intrapulmonary shunt and improving lung

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mechanics[32]. CPAP has been widely used and has A high rate of failure suggests caution in its use
met with considerable success in pediatric setting in ALI/ARDS, including early initiation, intensive
outcomes, chiefly among premature newborns with monitoring, and prompt intubation if signs of failure
or without idiopathic respiratory distress syndrome develop. NIPPV must be used very carefully in
(IRDS) . mixed cases, the timing of ETI must be anticipatively
In patients with mild ARDS, CPAP can increase recognized in order to avoid delayed intubation when
oxygenation, reduce dyspnea, and respiratory muscle needed and must be used selectively[38]. In hypoxic
unloading. CPAP alone improves gas exchange but patients, it is safe not to prolong NIPPV if no rapid
does not unload the respiratory muscles. Non-invasive improvement occurs (the one hour test).
positive pressure ventilation (NIPPV) provides a better NIV must be preferentially applied in ICU or
response in these conditions by unloading the muscles in departments where safe and prompt intubation can
and relieving dyspnea. By lowering left-ventricular be carried out. In moderate ARF, NIV should be used
transmural pressure in patients with congestive left- with caution, depending on patient’s age, work of
heart failure, positive airway pressure may induce left- breathing and onset and severity of symptoms. In the
ventricular afterload reduction without compromising
the cardiac index[35]. because NIPPV increases gas exchange, though not
3.1.2 Non invasive positive pressure ventilation survival[38].
Non invasive positive pressure ventilation (NIPPV) 3.1.3 High-frequency oscillatory ventilation
is frequently applied in patients with clinical and High-frequency oscillatory ventilation (HFOV) has
radiographic evidence of lung disease, supplemented been proposed in the rescue treatment of ARDS when
with a FiO 2 of greater than 50%. The rationale of conventional ventilation has failed in infants and
NIPPV use in adults is the possibility of reducing the children. HFOV may be thought of as the ultimate
work of breathing, improving gas exchange, reducing high-PEEP, low-tidal-volume strategy. Because of the
the need for endotracheal intubation and of infection, extremely small tidal volumes used, HFOV minimizes
[36]
and increasing survival . repetitive opening and closing and possibly reduces
While indicating the possible use of NIV, a
real “chorus” of experts continues to claim that, the extremely high respiratory rates, carbon dioxide
first and foremost, the necessity of immediate or can be maintained at satisfactory levels.
early intubation must be categorically excluded There are at present no sufficient data to
[37-38]
before starting to think of NIPPV . The delay in confirm its advantages in the treatment of ARDS
intubation may expose the patient to the risk of cardiac over conventional ventilation using a protective lung
arrest during intubation - if the patient is severely strategy.
hypoxic and difficult to oxygenate prior to initiate Most of the experience in the use of HFOV is
the maneuver- and to the necessity of applying more derived from uncontrolled studies and case reports in
invasive procedures for treating a worsened pathology. which improvement in oxygenation and safety were
NIPPV can be used early in mild and in early demonstrated. In many of these studies, unfortunately,
moderate forms of ARDS. Published experience has HFOV is compared to large tidal volume, low
largely been limited to the adults where it has been respiratory rate and low PEEP and not to a “low
tidal volume strategy”. One small-size randomized
it has been demonstrated that NIPPV reduces the controlled trials has shown that HFOV is as safe and
need to intubate while failing to decrease mortality effective as conventional mechanical ventilation but
[37]
. does not improved survival[39].

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In adult patients, the interest in using HFOV that are connected via short tubing to establish an
could decrease in the wake of the publication of arterio-venous shunt into the femoral vessels. The gas
two recent multicenter, randomized trials. The first phase is located inside, while blood passes outside
demonstrated that a HFOV strategy with high mean a hollow-fiber system. Gas exchange takes place
airway pressures led to more deaths than did a alongside a semi- permeable membrane. It is driven
conventional mechanical ventilation strategy that used by the partial pressure gradient of carbon dioxide and
relatively high PEEP levels . The second study did oxygen between blood and the gas phase, which is
connected to an oxygen supply (12-13 L/min). Blood
and conventional mechanical ventilation .
The data obtained from adult studies can raise is solely determined by the difference between arterial
some perplexity and concern regarding the ventilation and venous blood pressure .
of infants and children with HFOV, even though at The proposed advantages of ECCO2 R compared
present we currently have no specific data in these to ECMO are the reduction of artificial surface
patient populations. Future studies are needed to contact, the avoidance of pump-related side effects
assess whether HFOV, used under optimal conditions, and technical complications and reduced operating
with an especial regard for indication and timing using costs .
the best oscillator settings can have a major effect on The methodology appears interesting but
patient outcomes . requires more studies and investigation in the pediatric
3.2 Extracorporeal carbon dioxide removal age . Concerns are connected to the use of large-
Extracorporeal gas exchange, and extracorporeal caliber catheters for maintaining a sufficient flow.
membrane oxygenation (ECMO) in particular, was The positioning of a large catheter could occlude
extensively studied in the 1970s. Enthusiasm for femoral vessels and cause severe peripheral vascular
these methods waned after a large, prospective trial of thrombosis.
ECMO showed no improvement in outcome compared 3.3 Inhaled nitric oxide
with conventional therapy. Some successes have The use of inhaled nitric oxide (iNO) has been
revived interest in ECMO in recent years. Several case proposed in the treatment of severe lung diseases
reports and series have described patients who seemed including ARDS over the past 15 years to reduce
to have survived because ECMO was used after pulmonary hypertension and pulmonary hypoxic
conventional therapy had failed. Nonetheless, ECMO vasoconstriction, as it may improve ventilation of the
is currently used primarily by few centers which have lung and possibly reduce the need for a ventilatory
the necessary resources, expertise, and an interest to support setting and favors oxygenation by reducing
develop the technique further . FiO 2 , thereby limiting the toxicity of high-dose
The extracorporeal carbon dioxide removal oxygen.
(ECCO 2 R) concept, used as an integrated tool After the initial enthusiasm triggered by the use
with conventional ventilation, is playing a new
role in adjusting respiratory acidosis consequent to of this treatment are now better appreciated.
tidal volume reduction in a protective ventilation Improvement in ventilation and reduction of FiO2,
setting .
Pumpless extracorporeal lung assist therapy (i.e. have been questioned in a Cochrane Review which
interventional lung assist, or iLA), makes use of a failed to show a statistically significant effect on
low resistance gas exchange membrane (lung assist the mortality rate and on the transiently improved
device - LAD) is interposed between two cannulas oxygenation in hypoxemic respiratory failure among

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children and adults treated with iNO . adults with ARDS, respectively[53]. Other studies, on
the contrary, found that surfactant supplementation
better understood. Apart from the well-established improves oxygenation and significantly decreases
indications in neonatal persistent pulmonary mortality in pediatric patients .
hypertension (PPHN) and in heart disease (especially The second trial by Willson and colleagues did
for patients prior to cardiac surgery and/or following
cardiac repair), the risks of toxicity both for patients group. In this new study, it was shown that surfactant
and in the immediate environment (including medical supplementation did not improve ALI/ARDS
staff) are well demonstrated, as is the absolute
necessity of vigilant and accurate monitoring to avoid dosage and to the modality of administration of the
severe side effects. Particular attention has been paid surfactant and to the failure to recruit the lung during
to the possibility of inducing iNO dependency with supplementation[57].
prolonged ventilator weaning and of the toxic effects It is unlikely that the use of surfactants
of iNO on exogenous pulmonary surfactant which can as appropriate in premature infants (by bolus
[50]
both negatively impact treatment . administration and in high doses) is the best modality
iNO cannot be recommended for ARDS and of supplementation later in infancy and childhood,
ALI in children and adults. iNO results in a transient
improvement in oxygenation but does not reduce differs in these age groups. In actual fact, surfactant
mortality and may even be harmful[51].
Surfactant supplementation from pneumocyte type II alveolar immaturity while
Multiple surfactant abnormalities have been ARDS in infants and children mainly develops from
[52]
described in patients with ARDS . Alterations in the impaired production and inactivation of surfactant.
surfactant composition and function are believed For these reasons, it may be that other modalities
to result from the actions of a variety of mediators, of supplementation, such as bronchoalveolar lavage
including oxygen radicals, proteases, lipases, bioactive (BAL), could meet with more success as surfactant
lipids, and serum proteins. Abnormal surfactant is supplied when the surfactant inhibitors which
function renders some lung units prone to collapse, are present in the lungs have been mostly removed
which results in much of the inspired tidal volume already[58-60].
being directed toward more compliant, non-atelectatic The supplementation of surfactant remains a
areas of the lung. Uninjured portions of the lung may fascinating tool in the treatment of ARDS in infants
then become over-distended and injured if ventilator
settings are not adjusted accordingly. Alveolar Larger studies are necessary to explore different
instability also may result in cyclical atelectasis (with modalities of surfactant supplementation (such as
reference to lung units that open with inspiration and BAL and aerosol) and assess dosage for various lung
close with exhalation), which may cause shear forces pathologies and in different age groups in pediatrics.
that additionally exacerbate lung injury. Exogenous A big boost to our knowledge of surfactant application
surfactant supplementation could theoretically could materialize when its compassionate use in the
ameliorate many of these problems.
Several randomized trials of adults have found early application becomes routine practice. The high
no clinical benefit of various surfactants at doses cost of this therapy currently represents a real barrier
and with treatment modalities identical to those to research and clinical applications.
administered to premature newborns with RDS and

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3.5 Adjunctive treatments target novel and new treatments in a more personalized
Adjunctive treatments play an important role manner still remains inadequate.
in the treatment of ARDS. Improvements in care Currently, mechanical ventilation strategies
(bronchosuctioning, sedation, muscle paralysis), aiming at optimal alveolar recruitment with the
patient mobilization and secretion removal appear to judicious use of PEEP and low tidal volumes remain
[61]
. the mainstay of the management of respiratory failure
Recently, two interesting studies suggested in children. As in many others areas of pediatric
new ideas in the treatment of severe lung pathology. critical care, clinicians must await new data and trials
Temperature preconditioning in the first of these to use this methodology in on a daily basis in routine
studies and protection from the dissemination through care .
the airways of the lung pathology in the second could The management of ARDS remains supportive,
play an important role in ameliorating treatment and is aimed at improving gas exchange and preventing
improving outcomes in adult patients with severe lung complications while the underlying disease that
pathology.
therapies (new ventilation strategies and drugs) have
appropriate thermoregulation is essential for normal been studied but they have not been hitherto shown
lung cellular functioning. Heat exposure occurring to improve clinical outcomes and thus cannot be
simultaneously with high pressure ventilation recommended for routine care.
accentuates VILI. Suzuki et coll. found that moderate The improvement in survival we are currently
(33-35 °C) hypothermia can attenuate the adverse witnessing is probably due to a better overall treatment
response in models of VILI induced by mechanical of patients and to greater attention being paid to the
[62]
. ventilation method used. There is no single method
of treating all ARDS patients. The treatment must be
ventilated lung easily spreads disease from one area modulated according to the age of the patient and to
to another if treatment is not targeted or adequate. the severity of the lung pathology, taking into account
Ventilatory support over-distends the lungs while that supportive and adjunctive therapies can be
allowing the repetitive opening and closure of the
alveoli and thus facilitates bacterial translocation Patient mobilization (e.g. by prone positioning)
and spread from the alveoli to the blood stream. The in order to recruit dependent lung areas and avoid the
author suggests that greater care should be exercised retention of secretions, the use of methods to naturally
in ventilating these patients in order to avoid these or artificially improve cough to eliminate secretions
[63]
risks . Similar studies are currently lacking form the more easily, the early application of ventilatory
pediatric literature and ought to be investigated. support and the reduction of deep sedation and muscle
paralysis which blunt cough reflexes and allow
Final considerations secretion accumulation in dependent lung areas are
taking on a fundamental role[50,65].
Substantial progress has been made to advance Advances in molecular biology provide new
out understanding of the basic mechanisms of ARDS ground-works for defining pulmonary diseases and
and to optimize clinical management. Despite this
progress, our knowledge of how to predict the useful in the diagnosis of lung pathologies such as
evolution of the disease prior to severe symptoms,
improve disease definition and classification, and the near future similar markers will be developed also

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for ARDS[66-67]. Am, 2006, 12(3): 371-387.

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附中文概要（儿童急性呼吸窘迫综合征的治疗进展）
Giuseppe A. Marraro, Chengshui Chen, Maria Antonella Piga, Yan Qian, Claudio Spada, Umberto Genovese. Healthcare
Accountability Lab, Departmental Section of Legal Medicine, University of Milan, Italy

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