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No treatment for acute respiratory distress syndrome (ARDS) is definitive. The cornerstone of management
is impeccable intensive care. Early anticipatory management may avoid late complications and poor
outcome. Treat the primary cause (eg, sepsis, pneumonia) if possible. As much as possible, minimizing the
risk of multiple organ dysfunction syndrome (MODS) and ventilator-induced lung injury (VILI) is essential.
Critical aspects are maintaining nutrition and being cognizant of the risk of numerous complications in
critically ill children, including sepsis, fluid overload, inappropriate levels of sedation, and neuromuscular
blocking agents.
Many of the therapies and strategies proposed for ARDS are founded on rational physiologic and
pathologic principles, but they have not been shown to have unequivocal benefits. Reasons include an
incomplete understanding of the pathophysiology of ARDS, the lack of a standardized diagnostic test, and
the heterogeneity of the illness and the patient population.
Furthermore, an inability to adequately control for other therapies, specifically ventilation modalities, and
the fact that most patients die from MODS or their precipitating illness confound the analysis and
interpretation of data from many trials.
Although they have shown promise in animal and small-scale human studies, many pharmaceutical agents
have not demonstrated an unequivocal benefit in large trials. These agents include systemic pulmonary
vasodilators, pentoxifylline, various antioxidants, ketoconazole, anticytokines, and antiproteases. Their use
is not discussed further.
Go to Acute Respiratory Distress Syndrome and Barotrauma and Mechanical Ventilation for complete
information on these topics.
Initial Considerations
Since the eventual severity of ARDS relates to the severity of the inciting event, prehospital care is likely to
have the most impact by early recognition of associated risk factors and aggressive treatment to reversing
respiratory and circulatory failure, potentially averting the onset of ARDS.
Children who ultimately develop ARDS more typically present in the emergency department (ED) without
many of the signs and symptoms that fulfill the diagnostic criteria for acute lung injury (ALI) or ARDS.
However, early recognition of these signs and symptoms as well as recognition of the more common risk
factors for developing ALI/ARDS can influence the decision to initiate varying treatments for respiratory
distress.
When patients present in the ED with increased work of breathing secondary to worsening lung
compliance, increasing mean airway pressure and instituting other alveoli-recruiting maneuvers may offer
the most benefit in addition to administering supplemental oxygen. This can be achieved either invasively
(ie, with tracheal intubation and mechanical ventilation) or noninvasively.
If the patient continues to have good respiratory effort and adequate oxygenation, noninvasive positive
airway pressure support may be all that is required in the ED setting.
If intrahospital transfer from the ED to the pediatric intensive care unit (PICU) is indicated, the patient must
be accompanied by providers who are competent to secure and manage the airway. This team often
includes a physician, a nurse, and a respiratory therapist.
Interhospital transfer may be indicated. Transfer to a center skilled in pediatric intensive care should be
mandatory for any patient at risk of developing ARDS or any patient with full-blown ARDS. Ideally, a
dedicated team with expertise in the transport of critically ill children should perform the transfer via ground,
rotor, or fixed wing transport. In critically ill children, transporting them to a facility that offers pediatric
extracorporeal membrane oxygenation (ECMO) capabilities is preferable.
Ventilation
Ventilation is the cornerstone of treating the patient with ARDS. [17] Noninvasive positive pressure ventilation
and/or endotracheal intubation with mechanical ventilation is usually required in patients with clinical and
radiographic evidence suggestive of worsening lung disease with a fraction of inspired oxygen (FiO 2) of
greater than 50%. Striking a balance between the level of ventilator support necessary to provide a
reasonable ventilation and oxygenation while minimizing VILI is one of the most active areas of research in
critical care.
Noninvasive ventilation has been used early in ALI and ARDS to avoid endotracheal intubation. [18] Published
experience has largely been limited to the adults, and most patients with ARDS require endotracheal
intubation for airway control and invasive mechanical ventilation.
Continuous positive airway pressure (CPAP) and bilevel positive airway pressure (BiPAP) therapies via
nasal mask or face mask have been successful in maintaining adequate oxygenation and ventilation in
some patients who present with impending acute respiratory failure and who otherwise would require
tracheal intubation.
The main benefits of CPAP and BiPAP include improvement of oxygenation and work of breathing without
the expense of inducing and maintaining sedation for intubation, since CPAP and BiPAP are relatively well
tolerated by patients. Patients are also able to continue regulating their own minute ventilation.
More recently, Vapotherm (Vapotherm; Stevensville, MD) has become an option for delivering positive
airway pressure and supplemental oxygen noninvasively, especially as a substitute for nasal CPAP in
infants. Very few studies have been performed using this device.
Based on personal experience, the advantages of using the Vapotherm device or a similar high-flow,
humidified nasal cannula device include easy set-up, easy access to the patients mouth, and better
visualization of the patients face. The disadvantages include not being able to titrate, regulate, and
measure pressures as precisely as with CPAP and BiPAP.
In the event that a patient requires intubation for ALI, it may be prudent to use a cuffed endotracheal tube
regardless of the age of the patient. Traditionally, children younger than 8 years are intubated with uncuffed
tubes. However, various lung conditions, such as ALI/ARDS, worsen lung compliance. Therefore, cuffed
tubes are often required to effectively inflate the lungs. Otherwise, excessive air may leak around the
endotracheal tube resulting in inadequate oxygenation and ventilation.
No gas exchange occurs in collapsed or fluid-filled alveoli. A nearly linear increase in functional residual
capacity (FRC) develops as positive end-expiratory pressure (PEEP) is increased over a range from 0-15
mm Hg with recruitment of terminal airways and alveoli and improved oxygenation.
Traditional ventilatory strategies maintained normal arterial blood gas (ABG)values, often at the cost of high
tidal volumes and pressures and high morbidity and mortality rates. The strategy of open lung ventilation is
based on the recognition that repetitive opening and closing of alveoli exacerbates lung injury and that
there is often little harm associated with a high arterial carbon dioxide tension. This approach, termed the
permissive hypercapnic strategy, may allow reductions in rate and peak inspiratory pressure (PIP), thereby
limiting further barotrauma/volutrauma.
The twin goals of permissive hypercapnia and open lung maintenance are achieved by optimizing PEEP
and minimizing delivered tidal volumes. PEEP is optimized by keeping it above the lower inflection point on
a pressure-volume curve (ie, Pflex) and below the upper inflection point where overdistention occurs (see
the image below). This general approach has been assessed in a number of studies.
Hickling et al gave one of the original descriptions of permissive hypercapnia, reporting an almost 80%
reduction in mortality rates, though subsequent trials showed no benefit in reducing tidal volumes. [19] Amato
et al reported that their strategy of ventilating at a low tidal volume with an elevated carbon dioxide level
and preventing alveolar closure by optimizing PEEP decreased the mortality rate (38% versus 71%). [3]
The study by Amato et al was criticized for the high mortality rate in the control arm, but its results were
confirmed by a multicenter study sponsored by theNational Institutes of Health (NIH).[20]
In this NIH study, the control group was ventilated with a tidal volume of 12 mL/kg adjusted to maintain a
plateau pressure of 45-50 cm water. In the study group, tidal volume was reduced to 6 mL/kg and then as
low as 4 mL/kg to maintain a plateau pressure less than 30 cm water. The trial was prematurely terminated
when an interim analysis showed a markedly reduced mortality rate in the group receiving low tidal volume
(31% vs 39.8%).
Mercat et al reported that a strategy of using PEEP to maximize alveolar recruitment in the adult population
reduced the duration of organ failure and mechanical ventilation. [21]
Ranieri et al provided additional information to suggest that low tidal volume may be beneficial, reporting
reported lowered levels of cytokines in bronchoalveolar lavage (BAL) fluid and plasma in patients treated
with low tidal volume.[22] The authors postulated that decreased levels of cytokines reflect reduced
inflammation in organs other than the lungs, leading to a possible survival benefit.
Numerous ventilator modes are available; however, there are few if any data to indicate that any of these
modes is superior to any other.
Prophylactic application of PEEP has not been shown to improve outcome. [23] As PEEP is increased,
cardiac output may fall, and volume expansion or inotropic/pressor agents may be required.
Another technique that has been studied is high-frequency ventilation (HFV). Two modes of HFV are highfrequency oscillatory ventilation (HFOV) and high-frequency jet ventilation (HFJV). HFJV is rarely used in
pediatric practice and therefore will not be discussed further.
HFOV may be thought of as the ultimate in high-PEEP low-tidal-volume strategy. Because of the extremely
small tidal volumes used, HFOV minimizes repetitive opening and closing and possibly reduces VILI, if the
lung is sufficiently recruited.
Because of the extremely high respiratory rates, carbon dioxide can be maintained at satisfactory levels.
Randomized controlled trials have compared HFOV with conventional mechanical ventilation in pediatric
and neonatal practice, with generally encouraging results. Although initial studies in neonates show no
benefit, the strategy was less than optimal.
Recruiting (or opening) the atelectatic areas of the lung is critical to maintaining lung volume at the FRC.
Optimal lung volume is gauged with clinical assessment, monitoring of arterial oxygen saturation, ABG
measurements, and lung inflation on chest radiography.
Airway pressurerelease ventilation (APRV) is a relatively new mode of ventilation that allows spontaneous
ventilation with mean airway pressures similar to that achieved with HFOV. Case studies report the
successful use of APRV in ARDS; however, data are insufficient to compare it with conventional ventilation
or HFOV.
As an adjunct to ventilator management, prone positioning has been advanced as a means of improving
oxygenation in adults and children with severe ARDS. It is thought that turning patients prone helps
optimize ventilation/perfusion (V/Q) matching by reducing atelectasis in dependent areas of the lung.
Many trials have shown improved oxygenation with prone positioning; however, a multicenter trial of 102
patients demonstrated no significant difference in clinical outcomes, including ventilator-free days. [24] The
study population had a mortality rate of only 8%, suggesting that prone positioning may still have a role in
extremely ill patients with ARDS. Although no consensus regarding how to incorporate prone positioning
into the care of a child with ARDS is available, it should still be attempted in a patient with profound
hypoxemia.
Use of the neuromuscular blocking agent cisatracurium over the initial 48 hours of treatment for adults with
severe ARDSthat is, arterial oxygen tension (PaO2)/FiO2 ratio < 150appears to increase ventilator-free
days, reduce barotrauma, and possibly improve survival without increasing the occurrence of muscle
weakness in this patient population.[25] Care should be used in extrapolating those results to the pediatric
population, given the differences in ARDS mortality rates and the varying causes of ARDS mortality.
Go to Barotrauma and Mechanical Ventilation for complete information on this topic.
Surfactant Therapy
One of the key events in the progression of ARDS is a reduction in both volume and function of surfactant.
In addition, surfactant inhibitors may be present in the alveolus. Based on positive results of many clinical
trials of infant respiratory distress syndrome (IRDS), numerous studies have been conducted to examine
the role of exogenous surfactant in the treatment of ARDS.
Administration of exogenous surfactant has many theoretical benefits, as demonstrated in vitro. These
include the prevention of alveolar collapse, maintenance of pulmonary compliance, optimization of
oxygenation, enhancement of ciliary function, enhancement of bacterial killing, and downregulation of the
inflammatory response.
Studies of various surfactants and different modes of delivery in adults have not yielded a consensus
regarding the efficacy of surfactant in ARDS. In vitro data and extrapolated data from neonatal in vivo
studies suggest that animal-derived surfactant may be superior to synthetic surfactant. In addition,
inhalation may be inefficient as a means of delivery.
A growing body of literature supports the use of surfactant for severe pediatric ARDS. [26] A retrospective
chart review of 19 patients showed improvement in oxygenation index and hypoxemia score but no change
in other outcome measures. Prospective studies from the late 1990s to early 2000 involving porcine or
bovine surfactant showed variable outcomes, ranging from improvement in only oxygenation to shortened
ventilation and PICU stay.[27, 28, 29, 30]
A randomized, controlled multicenter study by Willson et al using a natural exogenous surfactant
(calfactant) demonstrated a significant reduction in mortality, with an absolute risk reduction of 17%. [31] This
reduction was most pronounced in patients younger than 12 months, who had a corresponding absolute
risk reduction of 33%.
Significant improvement was also demonstrated in the oxygenation index, in ventilator-free days, and in
rates of failure with conventional mechanical ventilation. One confounding factor was that the placebo
group had more immunocompromised patients than the treatment group.
Data from a cost-effectiveness study suggested that the use of exogenous surfactant may be cost-effective
in an American healthcare setting. The expense of the surfactant was offset by early PICU discharge.
Mortality benefits and ventilator-free days were not factored into the model. [32]
respiratory failure (oxygenation index >25) or immunocompromise may have benefited from the use of iNO.
However, this analysis has been criticized.[36]
Liquid Ventilation
Perfluorocarbons (PFCs) have numerous attractive properties that facilitate their use in liquid ventilation.
Because PFCs are chemically and biologically inert, with a high vapor pressure that ensures rapid
evaporation when exposed to the atmosphere, both oxygen and carbon dioxide dissolve easily in PFC
liquid.
Perceived advantages of PFCs in the treatment of ARDS include the ability to maintain an open lung and to
minimize repetitive opening and closing of the alveoli. This ability has given rise to the terms liquid PEEP
and PEEP in a bottle.In addition, a lavage effect may clear the alveoli and small airways of debris and
inflammatory mediators, reducing ongoing inflammation. PFCs are also thought to have intrinsic antiinflammatory actions.
By flowing preferentially to dependent areas of the lung where alveolar collapse is maximal, intra-alveolar
pressure is increased; hence, perfusion to these areas is decreased, which may improve V/Q matching.
Two types of liquid ventilation have been described: partial liquid ventilation (PLV), in which a volume of
liquid equal to the FRC is instilled, and total liquid ventilation (TLV). In contrast to PLV, TLV requires that the
lung be filled completely with PFC and that the patient be ventilated with a specially designed liquid
ventilator. For logistical reasons and because no data suggest that TLV is superior to PLV, PLV has been
used more widely than TLV.
Little convincing data are available to assess the use of PFC liquid ventilation in ARDS. Investigators from
2 uncontrolled trials (1 in adults and 1 in pediatric patients) described its use in conjunction with
extracorporeal life support (ECLS).[37, 38] A randomized trial in 1998 did not demonstrate a difference in
outcome in a group treated with PLV compared with a group treated with cytomegalovirus (CMV).[39]
indicators include alveolar-arterial (A-a) gradients of more than 450 mm Hg and ventilator peak pressures
of more than 40 cm water.
Exclusion criteria include cerebral hemorrhage, preexisting chronic lung disease, congenital or acquired
immunodeficiency, congenital anomalies, or other organ failure associated with poor outcomes. Ventilation
for more than 10 days before ECMO is a relative contraindication.
Why ECMO may confer a survival benefit is unclear. Possibilities include the ability to rest the lung by
reducing excess stretch (ie, high pressures) and reducing repetitive opening and closing (ie, high ventilator
rates). Oxygen toxicity may be minimized. Fluid balance can be optimized with aggressive diuresis or with
renal replacement therapy.
Steroid Therapy
The use of steroids is reported as a therapy for ARDS. Numerous reported trials demonstrated no benefit
with large doses of steroids administered as a short course in the early phases of ARDS. However, many
investigators contend that ongoing or late-stage ARDS is partly an inflammatory condition. Hence, by virtue
of their anti-inflammatory properties, steroids may be beneficial when used in the fibroproliferative phase.
In a randomized double-blind placebo-controlled trial in adults with ARDS who were not improving, Meduri
et al suggested late use of steroids to attenuate ARDS and improve survival. [45] Patients received
methylprednisolone or placebo for 32 days. Nonresponders were given the alternative treatment on day 10.
Those receiving steroids had reduced lung injury and multiorgan dysfunction scores, were extubated more
frequently, and had significantly lower hospital mortality rates (12% vs 62%). Rates of infection did not differ
between the groups.
Similar data in the pediatric population are not available. Some centers begin steroid therapy on days 7-10
of mechanical ventilation. The use of steroids for the fibroproliferative phase of ARDS in the pediatric
population is extrapolated from this study.
In contrast with the results of Meduri et al, a larger, multicentered randomized controlled trial failed to
demonstrate improved survival.[46] In fact, an increased mortality rate was suggested in subgroups.
A multicenter trial of corticosteroids for persistent ARDS in adults showed increased number of ventilator
and shock-free days but also showed increased 60-day and 180-day mortality rates for patients whose
therapy started 14 or more days after the onset of ARDS. [20]
To the authors knowledge, no study has been performed to examine the potential role of inhaled steroids in
ARDS.
Steroids may be indicated as part of the treatment for the underlying etiology of ARDS (eg, ARDS
secondary to Pneumocystis jiroveci infection).
A subgroup of patients with ARDS with marked eosinophilia in their peripheral blood or bronchoalveolar
fluid may benefit from steroid therapy.
Steroid use may contribute to prolonged weakness after ARDS. Care should be taken to minimize
concomitant neuromuscular blockade.
Many predictors of extubation success have been published; however, clinicians often use clinical judgment
to determine a patients readiness for extubation. To date, no data specifically describe predictive
parameters in children with ARDS. Indices used to predict successful extubation include the rapid, shallow
breathing index (RSBI); the compliance, resistance, oxygenation, and pressure (CROP) index; and ratio of
tidal volume to dead space (Vd/Vt).
Regardless of the method used, all candidates for extubation should have a leak around their endotracheal
tube (ie, at a reasonable airway pressure), and they should be able to maintain their own airway (ie, good
cough and gag reflex). Patients must not be dependent on suctioning through their endotracheal tube. The
level of sedation must not be excessive. If no air leak is present around the endotracheal tube, consider
deferring extubation and administering steroids to reduce airway edema.
Once extubated, patients may require further support of their breathing. Options include CPAP, BiPAP,
supplemental oxygen, heliox, or reintubation.
Activity restriction
In general, the patients activity depends on the severity of the precipitating illness (eg, trauma, sepsis) and
ARDS limits. If the patient recovers, no limitation on activity is usually necessary, except in the few patients
with evidence of extensive pulmonary scarring or fibrosis.
Prevention
Few cases of ARDS can be anticipated before presentation; however, all children with chronic lung disease
should receive influenza and pneumococcal vaccines. Administer respiratory syncytial virus (RSV)specific
vaccines as indicated.
ARDS secondary to aspiration may be prevented by the use of appropriate intubation techniques (eg,
rapid-sequence intubation). Although no evidence is definitive, early intervention with noninvasive
ventilation in patients with respiratory failure may reduce the risk of progression of ARDS.