Several primary pulmonary and systemic disorders injure alveolar epithelium and increase permeability of the alveolar-capillary barrier. Primary lung disorders that cause ARDS include pneumonia, aspiration, inhalation injuries, near-drowning and contusions from trauma. Sepsis, shock, burns, and pancreatitis are systemic disorders that can cause ARDS. Exudation of protein-rich fluid into alveolar spaces follows with decrease in aerated lung and lung compliance. Injury to type II pneumocytes decreases alveolar fluid clearance, impairs surfactant production and turnover. Inactivation of surfactant by alveolar fluid and inflammatory mediators exacerbates alveolar instability.

The acute phase of ARDS is followed either by resolution of lung injury or by fibrosing alveolitis and chronic lung disease. The clinical correlate of the fibrotic phase is nonresolving ARDS beyond 7 days(5).

Mechanical ventilation merely supports gas exchange while the disease process runs its course. However, mechanical ventilation can contribute to lung injury(6,7). The goal of mechanical ventilation should be to maintain adequate rather than "normal" gas exchange while minimizing lung injury. This is the premise on which permissive hypoxemia and hypercarbia are based. Adequate oxygen delivery should be maintained by optimizing cardiac output and hemoglobin concentration in addition to arterial oxygen saturation.

There is a limited role for the use of non invasive ventilation (NIV) in a select population of pediatric ARDS. There are no large randomized controlled trials (RCTs) examining NIV in pediatric ARDS. NIV through face mask or helmet was used in a series of 23 immunocompromised children with ARDS. Early and sustained improvements in oxygenation were noted in 82% and 74%, respectively. 54.5% avoided intubation, and responders to NIV had a significantly lower mortality and shorter ICU stay than non-responders(8). NIV is more likely to be successful in avoiding the need for intubation in children with acute respiratory failure (ARF) due to hypoventilation rather than due to ventilation-perfusion (V/Q) mismatch. Higher Pediatric Risk of Mortality (PRISM) score(9), and failure of the fractional inspired concentration of oxygen (FiO2) to decrease after the initiation of NIV(10) were predictive of failure of NIV in pediatric ARF. While a short trial of NIV may be acceptable and feasible in alert, hemodynamically stable children with ARDS, improvement in gas exchange and respiratory mechanics should be monitored to avoid a delay in intubation.

Modest to severe hypercapnia often develops in the setting of ventilation with reduced TV. Hypercapnia, especially that which develops over time is well tolerated by most children(19). There is some evidence that hypercapnia should be limited to a degree that allows arterial pH to be >7.2(18). Permissive hypercapnia is contraindicated in patients with intracranial hypertension, pulmonary hypertension, and severe cardiac dysfunction.

In adult patients without ARDS who were ventilated for over 48 hours, high TV and high peak inspiratory pressure (PIP) were both significantly associated with the development of ARDS(20).This highlights the importance of lung protective ventilation in all children, regardless of the presence or absence of lung injury.

Prone positioning improves VQ matching and secretion clearance. Dependent lung units are better ventilated in the prone position. These have been proposed as mechanisms by which prone positioning might improve oxygenation. In a RCT on 102 child-ren with ARDS, no benefit in mortality or duration of ventilation was demonstrated in the group that was placed prone early in the course of their illness and for a significant portion of the day (20 hours) despite the fact the patients in the prone group did show an improvement in oxygenation(26). Prone positioning was well tolerated. Similar findings were shown in 18 of 23 children with ARDS studied prospectively by Casado-Flores and colleagues(27). Prone posi-tioning cannot be recommended routinely, but may be considered in the patient with severe ARDS and refractory hypoxemia(28).

Inhaled nitric oxide (iNO) is a selective pulmonary vasodilator with minimal systemic effects. Theoretically, iNO selectively increases perfusion of ventilated lung units, reducing V/Q mismatch. A RCT on 108 children with ARF of iNO 10ppm versus conventional ventilation alone showed an improvement in oxygenation without reduced mortality in the study group. The effect was more sustained among immunocompromised children and those with entry oxygenation index (OI) >25(29). Further improvement has been shown in combination with HFOV due to better lung recruitment(30). A meta-analysis of multiple trials in adults and children with ARDS showed that iNO improves oxygenation in patients with ARDS without changing mortality(31). There is insufficient data to support the routine use of iNO in children with ARDS.

Secondary surfactant deficiency contributes to the pathogenesis of ARDS. Additionally, in ARDS, surfactant is inactivated and its function inhibited by inflammatory mediators, plasma proteins that have exuded into the alveolar space, and cellular debris(32). This has posed some unique challenges in successful surfactant replacement therapy in adults with ARDS and potentially explains un-successful trials of surfactant in adult ARDS. These trials used synthetic, semi-synthetic or recombinant surfactant preparations(33,34). There has been speculation that surfactant may be more efficacious in patients with direct lung injury(35).

Calfactant is a modified natural surfactant whose ratio of phospholipids to apoprotein surfactant protein B (SP-B) is similar to bovine surfactant. It also resists degradation and inhibition by proteins associated with lung injury. In a RCT of intra-tracheally administered calfactant versus placebo in children with respiratory failure, the primary outcome, which was number of ventilator free days at 28 days, was not different in the two groups. The mortality rate was significantly greater in the placebo group as opposed to the treatment group (27/75 vs 15/77, OR 2.32, 95% CI 1.15-4.85)(36). Infants younger than 12 months in the placebo group had an almost threefold higher mortality than those in the treatment group (9/19 vs 23/21, P = 0.01)(36). However, immunocompromized children were unevenly distributed in the two groups, and there were insufficient numbers for subgroup analysis. Children with respiratory failure from direct lung injury were more likely to benefit from surfactant than those with indirect lung injury such a sepsis. There may be a role for Calfactant in children with ARDS, caused by direct lung injury. There is still uncertainty regarding the role of surfactant in pediatric ARDS. RCTs of Calfactant and a synthetic surfactant Lucinactant are ongoing in children with ALI.

Sepsis and pneumonia have been shown to be the cause of ALI or ARDS in 35-55% of children in different series(37) Tracheal aspirates obtained early in the illness might provide useful information to help guide the choice of antimicrobials. Furthermore, children with ARDS regardless of the cause, are prone to develop nosocomial infections, particularly ventilator associated pneumonia (VAP). While the ideal method of diagnosing VAP remains controversial, the possibility of an infection should always be considered in the event of a new fever with change/increase in secretions from the lower respiratory tract, radiographic changes, and microbio-logic data of respiratory secretions. Non-bacterial etiologies of infection must be considered, particularly in children with risk factors such as neutropenia, immune suppression, or organ/bone marrow transplant recipients. Diagnostic bronchoscopy should be considered in evaluating immune compromised children with ARDS and in immune-competent children where no cause infectious or non infectious cause for the ARDS is evident. Prompt empirical therapy based on knowledge of the local antibiogram should be instituted when an infection is suspected. De-escalation of therapy must occur as soon as feasible.

The permeability of the alveolar capillary barrier is increased in ARDS. In the presence of high central venous pressure (CVP), and pulmonary vascular pressure, the exudation of fluid into the alveolar space is increased. A prospective RCT in adults with ARDS (FACTT Trial) that compared a conservative fluid management strategy to a liberal strategy demonstrated a significant increase in the number of ventilator-free days and ICU free days in the conservative group without an increase in non-pulmonary organ failure, shock, or requirement for renal replacement therapy(38). No association has been found in children between the cumulative fluid balance and duration of mechanical ventilator weaning(39). An association has been noted between mortality and the magnitude of fluid overload in critically ill children(40). In managing the fluid status in children with ARDS, maintenance of negative fluid balance should be attempted only after any accompanying shock has resolved(41).

Hypoproteinemia decreases plasma colloid oncotic pressure. This increases the gradient for fluid movement into the alveoli and is predictive of RDS in adults(42). In a small RCT on 37 adults with ARDS and serum protein concentration of <5 g/L, an intervention group that received albumin with furosemide was compared to a control group who received double placebo. Patients in the intervention group showed improved oxygenation, hemodynamics, and fluid balance. The study was not powered to detect a difference in mortality(43). Effects of combination albumin-diuretic therapy on mortality and duration of ventilation in children remain unknown.

The importance of providing adequate nutrition early to critically ill children is well established. Enteral nutrition is superior to and safer than parenetral nutrition and should be used whenever possible. A RCT of the route of enteral feeding in critically ill children showed that the delivery of food into the intestine resulted in successful delivery of greater nutrition as compared to gastric delivery(44). Despite some evidence that Omega-3 fatty acid supplementation may improve outcomes in adults with ARDS(45), there is no evidence to support specific dietary modifications in children.

The anti-inflammatory and anti-fibritoic properties of corticosteroids suggest that they might have a role in modulating the course of ARDS. The results of numerous trials that have evaluated the role of steroids in the treatment of ARDS have been largely disappointing. A recent meta-analysis of this issue in adults with ARDS suggests that the use of steroids to treat adults with ARDS may increase ventilator free days and reduce mortality(46). No RCT addressing this issue in children has been published although anecdotal reports of improvement exist. Despite complex results from many trials, available evidence argues against the routine use of steroids in ARDS given their doubtful efficacy and their potential for causing serious adverse effects such as infection and steroid myopathy.

There are no RCTs addressing this in children. In a retrospective study of children with hypoxic ARF, including some with ARDS with predicted mortality rate of 50-75%, ECMO reduced mortality(47). ECMO may be lifesaving in critically ill children with ARDS who would otherwise die. The invasive nature of this therapy and the high risk of bleeding require than this be considered only in children in whom all other therapy has failed.

The mortality in children with ARDS and ALI is decreasing. In cohorts of children with ARDS from a variety of causes, mortality rates of 20% – 30% are reported. This is significantly lower than the reported mortality rates in adults, but still very high compared to the overall mortality rates of children admitted to PICUs. The initial severity of the defect in oxygenation, non-pulmonary organ failure, and the presence of neurologic dysfunction were independent predictors of mortality in a prospective evaluation of ALI and ARDS in children. Immune compromised status also correlated positively with increased mortality(3). Sepsis syndrome and multi-organ failure are common causes of death in patients with ARDS(48). Mortality is particularly high in children who have received stem cell transplants who require mechanical ventilation(49).

ARDS results from a variety of pulmonary and non-pulmonary insults. The therapy of ARDS is supportive. Low tidal volume is the only therapy that has consistently shown a mortality benefit and should be implemented in all cases. Mechanical ventilation should be titrated very carefully in order to avoid VILI, and potential multi-organ dysfunction syndrome.

Dr Borasino, and Dr N Ambalavanum for critical review of the manuscript.

Funding: None.

Competing interests: None stated.

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