Prone Positioning
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).
Nitric Oxide
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.
Surfactant
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.
Surveillance and Treatment of Infections
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.
Nutrition
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.
Corticosteroids
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.
Extracorporeal Membrane Oxygenation (ECMO)
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.
Prognostic Factors
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).
Summary
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.
Acknowledgment
Dr Borasino, and Dr N Ambalavanum for critical review
of the manuscript.
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