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The administration of oxygen, while simple, is not free
from adverse effects. Continuous exposure to high
concentrations of oxygen (FiO
2
> 0.6) is capable of causing
pulmonary injury, even in the absence of a pre-existing
lesion.
7
Pulmonary injury due to oxygen toxicity is the
result of free radicals and reactive oxygen species that are
spontaneously generated in hyperoxic environments or
from the activation of neutrophils and alveolar
macrophages.
8,9
The normal lung deals with oxidative
insults by means of a series of enzymes (superoxide
dismutase, glutathione peroxidase, glutathione reductase,
catalase) or antioxidants (vitamins C and E, albumin, etc.),
and is capable of tolerating elevated oxygen concentrations
for a number of days. However, an injured lung exposed to
moderate concentrations of oxygen (which would not be
harmful to a normal lung) can further aggravate pulmonary
tissue damage even when the exposure is limited to just a
few hours.
8
This phenomenon occurs, presumably, due to
an imbalance between oxidative stimuli and antioxidant
protective mechanisms found in acute lung injury states.
Mechanical ventilation
Mechanical ventilation remains the primary support
technique for ARDS and is indicated in the vast majority of
cases.
10
Nonetheless, the indications for mechanical
ventilation in patients with ARDS are, to a certain extent,
vague, based on clinical findings (dyspnea, tachypnea, use
and fatigue of accessory muscles, diaphoresis, poor
perfusion, etc.), laboratory findings (acidosis, hypoxemia,
hypercapnia) and radiological findings (worsening alveolar
infiltrates). An attempt at making the criteria for the
institution of mechanical ventilation for ARDS more
objective is the so-called “rule of 50s”, in which a PaO
2
< 50
torr and a PaCO
2
> 50 torr with a FiO
2
of 50% characterize
patients likely to require ventilatory support. These criteria,
however, identify patients in extremely severe disease states
with impending respiratory failure. One of the key points in
the treatment of ARDS is the early identification of patients
with respiratory involvement so that mechanical ventilation
can be initiated before they reach an extreme state of
respiratory failure.
The heterogeneous distribution of lung disease in patients
with ARDS makes mechanical ventilation a challenge to the
intensive care specialist. In typical ARDS, gravitationally-
dependent lung regions exhibit dense alveolar and interstitial
inflammatory infiltrates, edema, cellular debris, atelectasis
and consolidation, while non-dependant regions are
relatively spared (Figure 1).
11
In a healthy lung with
homogeneous surface tension, tidal volume is evenly
distributed among the various lung segments. In patients
with ARDS, however, the tidal volume follows the path of
least impediment, with a tendency to overdistend the more
compliant alveoli (non-dependent) while failing to recruit
the less compliant alveoli in the dependent areas. In addition
to being heterogeneous, lung pathology in ARDS is also
dynamic,
12
as areas with relatively adequate compliance
can become poorly compliant in a matter of hours, as the
syndrome evolves rapidly.
Mechanical ventilation for ARDS is much more than a
mere support modality used to buy time until resolution of
the lung disease process. We now know that the choice of
ventilation strategy is capable of influencing the progression
of the lung disease, with more favorable outcomes resulting
from protective strategies. Similarly, non-protective
ventilation strategies are associated with less favorable
physiological outcomes and increased mortality.
5,13-15
Figure 1 - a) Computerized axial tomography of an experimental
ARDS model (swine) showing the heterogeneous
distribution of lung disease. The gravitationally non-
dependent lung region (white arrow) exhibits a
relatively normal aspect, while the dependent lung
region (black arrow) exhibits greater involvement.
Histologic analysis of another animal model of ARDS
(rabbits) also shows the heterogeneous distribution
of this pathology, with less evidence of inflammation
and tissue injury in the non-dependent region (b) in
contrast with the dependent region (c). The use of
an objective pulmonary injury score in this same
model (d) confirms the heterogenous distribution
of tissue injury
Injury
score
Dependent
Non-
dependent
16
14
12
10
8
6
4
2
0
d
c
b
a
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Jornal de Pediatria - Vol.79, Supl.2, 2003
Tidal volume (Vt)
The use of an inadequately high Vt in experimental
models is capable of promoting pulmonary injury even in
healthy lungs.
16
In experimental ARDS models, a Vt that
has traditionally been considered adequate, such as 10 ml/kg,
has been associated with progression and worsening of the
pulmonary injury.
17
This occurs because, in low pulmonary
compliance states, the introduction of moderate or high Vt
can lead to alveolar overdistension, marked by the upper
inflection point on the volume-static pressure relationship
curve (Figure 2), resulting in the so-called “volutrauma”.
Based on this principle, Amato and colleagues have
demonstrated significantly reduced 28-day mortality in
ARDS patients treated with an open lung strategy consisting
of a Vt of less than 6 ml/kg and PEEP set above the lower
inflection point. However, two other studies, employing
reduced Vt only
18,19
failed to show any benefit from this
strategy in patients with ARDS. More recently, a North
American multi-center study involving 861 patients with
ARDS
15
showed a 22% reduction in mortality among
patients treated with reduced Vt (6 ml/kg) in comparison
with traditional Vt (12 ml/kg). The discrepancies between
results of the various multi-center studies are related to
significant methodologic variations, such as different Vt
values employed for the intervention and control groups
(Figure 3). Only studies with a sufficient difference in Vt
between the reduced volume and the control groups
5,15
yielded positive results.
To this date, no clinical studies have tested the hypothesis
that reduced Vt would be beneficial in the pediatric
population. However, considering that the recommendation
to use reduced Vt has a strong physiological, experimental
and clinical support (in adults), pediatric patients with
ARDS should be given mechanical ventilation with a Vt
equal to or less than 6 ml/kg until data specific to this
population become available.
Positive end-expiratory pressure (PEEP)
In ARDS, alveoli in the dependent lung regions exhibit
greatly reduced compliance in comparison with non-
dependent alveoli. As such, during every expiration the
more dependent alveoli reach a critical closing volume,
which results in alveolar collapse. This is followed by
reopening of these collapsed alveoli during inspiration. The
cyclical repetition of alveolar collapse and re-opening
generates shearing forces capable of causing tissue damage
(atelectrauma). The use PEEP is primarily aimed at avoiding
the collapse of the less compliant alveoli at the end of
expiration. Excessive use of PEEP increases the risk of
pneumothorax, generates hyperinflation of certain
pulmonary segments and can cause adverse hemodynamic
effects by increasing intra-thoracic pressure and thus
reducing venous return (pre-load). However, the application
of inadequately low PEEP levels during mechanical
ventilation provokes cyclic alveolar collapse and re-opening,
resulting in atelectrauma.
The use of adequate levels of PEEP that target sufficient
lung volume maintenance during is associated with favorable
physiological outcomes.
13,16,17
As has been mentioned
above, Amato and colleagues
5
have demonstrated a
reduction in 28-day mortality in patients ventilated with a
Vt lower than 6 ml/kg and PEEP level set above the lower
inflection point. It is impossible to discern whether the
observed effects
5
are attributable to the limited Vt, the use
Figure 2 - Static pressure-volume relationship of the respiratory
system in an animal model of ARDS (rabbits). The
arrow indicates the lower inflection point
50
40
30
20
10
0
0
“Safety” zone
Volutrauma zone
Atelectrauma zone
10
20
Pressure (cm H O)
2
Volume
(ml)
30
40
50
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