There is no specific drug treatment for ALI/ARDS. Numerous
therapies directed at modulating inflammation have been tried. The
list includes prostaglandin E1, ketoconazole, N-acetylcysteine, and lisophylline.
Corticosteroids have neither decreased the incidence of ARDS when
administered to patients at risk nor decreased mortality from ARDS
when administered early in the course. However, data from small
studies suggest that the administration of corticosteroids to patients
later in the course of ALI may be beneficial. This phase of the
illness is referred to as late ARDS or the fibroproliferative phase
of ARDS, a reflection of the pathological findings. The clinical
diagnosis of late ARDS is usually made when a patient has severe,
persistent hypoxemia on or about Day 7 of their illness. There is
currently a large multicenter, randomized controlled trial of corticosteroids
in late ARDS underway. Until the results of that study are available, most
reviews do not recommend the routine use of corticosteroids in late
Patients with ARDS have severe pulmonary hypertension and lack
of resolution of this hypertension is associated with poor outcomes.
This makes vasodilator therapy an attractive therapeutic option.
Early studies with inhaled nitric oxide (NO) showed improvement
in mortality. However, larger clinical trials did not confirm this
finding, although pulmonary artery pressures were decreased and
oxygenation increased in patients treated with NO. Currently inhaled
NO is not recommended as routine therapy for ALI. Inhaled NO is
used in some patients with refractory severe hypoxia.
Neonates with respiratory distress syndrome have a substantial
improvement in mortality when treated with surfactant replacement
therapy. There is a large body of evidence that suggests that adult
patients with ARDS have significant surfactant dysfunction. These
findings suggested that surfactant replacement therapy could benefit
patients with ARDS. To date, however, no study has shown an improvement
in survival with this therapy in adults. However, studies are ongoing
to both improve the available surfactant preparations and the administration
and delivery of the product.
Although there is no specific pharmacological therapeutic intervention
for ALI/ARDS, there is now an effective intervention for
the most common risk factor for ALI/ARDS, sepsis. The infusion
of activated protein C substantially reduces mortality from severe
sepsis. Although this agent has not been studied as a specific therapeutic
agent for ALI/ARDS, a large percentage of patients in the
sentinal clinical trial had multiple organ failure, required mechanical
ventilation, and/or had the lungs identified as the primary
source of infection.
The majority of patients with ALI require ventilatory support
with endotracheal intubation and mechanical ventilation, although
a small number may be treated with noninvasive ventilation alone.
The appropriate way to manage the ventilator has been debated since
ARDS was first described. Initial debates focused on use of PEEP.
Addition of PEEP in most patients lowers FIO2,
but other potential benefits remain unproven. Initial studies failed
to show that PEEP prevented the development of ARDS, but the debate
on what level of PEEP is best in patients with established ALI/ARDS
The concept that mechanical ventilation could cause or contribute
to acute lung injury has been present for a long time. Animal models
and early patient studies suggested that administration of either
large volumes or extensive pressure to even a normal lung could
cause damage. This has led to an intense search for the most appropriate
way to manage the volumes and pressures delivered by mechanical
ventilators. A group of NIH investigators recently completed a trial
comparing tidal volumes of 12 mL/kg predicted body weight
to 6 mL/kg predicted body weight. For this trial there
was a fixed Fio2/PEEP
algorithm for all patients and plateau pressures were limited. In
the study mortality was 39.8% in the 12 mL/kg
group and 31.3% in the 6 mL/kg group. Although
the study methods were not entirely the same, this confirmed results
from an earlier smaller trial of what is now called lung protective
Most critically ill patients on mechanical ventilation are kept
in the supine position. However, in animal models and in patient
studies, oxygenation has been shown to increase with prone positioning.
This led to a large, recently completed clinical trial that found
oxygenation did increase in patients with ALI/ARDS who
were prone, but there was no change in mortality. Despite the lack of
survival benefit, many experts recommend placing a patient in the
prone position if oxygenation is difficult. The placement of a patient
in the prone position is not without risk. During the change in
position, equipment such as the endotracheal tube and indwelling
lines can become dislodged. Care has to be taken to prevent skin
ulcers in dependent areas. Currently, the optimal timing for initiation
of the prone position and the optimal duration of the prone position
are not known.
Optimal fluid management of patients with ALI is also an area
of controversy. Fluid management needs to balance the need for optimal
organ perfusion with problems of fluid extravasation into the lungs
and tissues that results from severe epithelial and endothelial
injury. The focus is often on maintaining adequate perfusion without
harming oxygenation. Achieving this goal often requires miminizing
fluid resuscitation. Conversely, there was also a focus on increasing
oxygen delivery to decrease the incidence of multiple organ dysfunction
syndrome. Extensive studies have now shown that maximizing oxygen
delivery does not offer a therapeutic benefit. Therefore, the optimal
fluid management in these patients remains unknown. Also unknown
are the indications for insertion of pulmonary artery catheters
(PAC). In early studies of ARDS, diagnosis required measurement
of the pulmonary artery capillary wedge pressure to exclude cardiogenic pulmonary
edema, so many patients had PAC in place. Now that actual measurements
are not needed for diagnosis and there is no evidence that maximizing
oxygen delivery, which also required PAC measurements, improves
outcomes, the indications for PAC insertion are not clear. There
is evidence that the insertion of PAC may be associated with an
increase in mortality in some patient groups, so routine insertion
of PAC is not without problems.
Acute Respiratory Distress Syndrome Network. Ventilation
with lower tidal volumes as compared with traditional tidal volumes
for acute lung injury and the acute respiratory distress syndrome.
N Engl J Med 2000;342:1301.
(The largest trial that has shown the benefit of protective lung
Bernard GR et al: Efficacy and safety of recombinant human activated
protein C for severe sepsis. N Engl J Med 2001;344:699.
(Description of the clinical trial of the only effective
therapeutic intervention in sepsis.)
Brower RG et al: Treatment of ARDS. Chest 2001;120:1347.
(Review of treatments available for ARDS.)
Gattinoni L et al: Effect of prone positioning on the survival
of patients with acute respiratory failure. N Engl J Med 2001;345:568.
(The most recent study of prone positioning
McIntyre RC et al: Thirty years of clinical trials in acute
respiratory distress syndrome. Crit Care Med 2000;28:3314.
(Excellent review of the therapeutic interventions
that have been studied in ARDS. Focuses on how to review the existing
evidence to determine whether a therapy should or should not be