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Many ARDS pharmacotherapies, including corticosteroids, nitric oxide, surfactant,
ketoconazole, lysofylline, xacetylcysteine, and fish oil, have initially shown efficacy in animal
models but have not had clinical success. This review explores the pharmacological treatments
studied clinically, proposed reasons for their lack of success, and new concepts emerging in
ARDS therapy.

 


 Because ARDS is initiated by excessive inflammation, corticosteroids were the

earliest treatment evaluated. Corticosteroids inhibit production of inflammatory cytokines, such
as TNF , IL
, IL, and IL. In addition, corticosteroids may have a role in decreasing
collagen deposition by accelerating fibroblast procollagen messenger RNA degradation. In the

s, several trials of early shortterm, highdose methylprednisolone treatment every  hours
for 24 to 4 hours showed no decrease in mortality. The trial consisted of 24 patients who had
been receiving mechanical ventilation for more than 7 days and were randomized to receive daily
methylprednisolone at 2 mg/kg for 32 days. There was a marked reduction in hospital mortality
in the methylprednisolonetreated group (
2%) vs the placebo group (2%) (cr.4). No increase
in infectious complications occurred. Limitations of this study include the small number of
patients, unequal groups with
 patients in the treatment group and  patients in the placebo
group, and a crossover of 4 placebo patients into the methylprednisolone group. Nonetheless,
these positive results have prompted a large, ongoing ARDS Network trial called the Late
Steroid Rescue Study.

c   The interest in prostaglandin E
(PGE
) as a treatment option for ARDS is based
on its function as an antiinflammatory mediator and vasodilator.In an early, singlecenter
randomized controlled trial performed with trauma patients, nebulized PGE
showed improved
survival of 7
% at 3 days vs 35% survival in the placebo group. However, in a subsequent
randomized multicenter study of patients with ARDS from trauma or sepsis, improved mortality
could not be shown, and PGE
administration was complicated by systemic hypotension. The
systemic effects of PGE
can be partly overcome by using liposomes to deliver the drug in a
lungtargeted manner, but even with this advancement, there has been no survival benefit or
reduction in ventilation time.



  ! " Nitric oxide is a natural free radical gas produced in the lungs by nitric
oxide synthase from Larginine, reduced nicotinamide adenine denucleotide phosphate, and
oxygen. Nitric oxide relaxes pulmonary vascular smooth muscle and thus has important
regulatory effects on regional lung ventilation and perfusion ratios. Inducible nitric oxide
synthase is upregulated by many cytokines and endotoxin. Using a murine endotoxininduced
lung injury model, Ullrich showed that during inflammation nitric oxide synthasederived nitric
oxide blocks normal hypoxic pulmonary vasoconstriction and contributes to the intrapulmonary
shunt characteristic of ARDS. This study suggests that inhibition of nitric oxide synthase should
maintain hypoxic vasoconstriction during ARDS and lessen shunting. Although endogenous
nitric oxide, produced from nitric oxide synthase, impairs gas exchange during ARDS,
exogenous inhaled nitric oxide relaxes vascular smooth muscle that supplies ventilated alveoli

Inhaled nitric oxide reduced pulmonary artery pressures and increased arterial oxygenation
without producing systemic vasodilation. Despite its beneficial effect on Pao2, several large
multicenter trials have shown no survival benefit with inhaled nitric oxide.Additionally, adverse
effects of inhaled nitric oxide have been noted, including methemoglobinemia, production of
toxic compounds such as nitrogen dioxide and peroxynitrate ion, increased pulmonary edema,
and rebound pulmonary hypertension. Interestingly, recent trials using inhaled nitric oxide for
preterm infants with respiratory failure have shown conflicting results. One study showed that
death or chronic lung disease occurred in 4% of infants treated with nitric oxide vs 5% in the
placebo group (cr.3), whereas the other showed that treatment with inhaled nitric oxide
resulted in no overall survival benefit. The differing results are thought to be due to differences
in patient demographics, severity of illness, and study design. Further trials are under way to
resolve these discrepancies in infants, but the results in adults have been consistently negative.

c  Prostacyclin is an endotheliumderived vascular smooth muscle relaxant that also

inhibits platelet aggregation and neutrophil adhesion. Thus far, studies have shown fairly
comparable results between inhaled nitric oxide and prostacyclin in terms of decreased
pulmonary vascular resistance, decreased pulmonary artery pressures, and improved arterial
oxygenation and shunt fraction. Prostacyclin may have some benefits over nitric oxide in that it
is relatively simple to administer and has harmless metabolites, but it is more expensive and has
also not shown any clear survival benefit in clinical trials.

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The rationale for surfactant treatment of ARDS is based on several observations. Normal
surfactant, a mix of phospholipids and 4 proteins (A, B, C, D), lowers surface tension and thus
prevents alveolar collapse. Surfactant proteins A and D are important for generating an innate
immune response, and surfactant also has antiinflammatory and antimicrobial properties. ARDS
surfactant is abnormal because of decreased production by injured type 2 alveolar cells,
increased removal, and altered composition with an increased proportion of relatively inactive
forms. Surfactant obtained by BAL from ARDS patients is dysfunctional, with decreased surface
tensionlowering activity compared with that from healthy patients. Although exogenous
surfactant replacement improves survival in premature infants with hyaline membrane disease, it
has not been proved effective in treating ARDS.

Several randomized controlled studies have been performed using various preparations, doses,
and methods of surfactant administration, and none have shown a mortality benefit.However,
one study showed a decrease in Fio2 requirement. A recent multicenter randomized controlled
trial was conducted in 44 adult ARDS patients who received recombinant protein Cbased
surfactant. Surfactanttreated patients had improved gas exchange and oxygenation, but no
difference occurred in the number of ventilatorfree days or 2day mortality. A recently
published multicenter trial of infants, children, and adolescents with ARDS using calfactant, a
natural surfactant with high surfactant protein B levels, showed a mortality benefit in treated
patients. However, this study had only
53 patients, and infants made up 2% of the population.
Surfactant studies have been criticized for a variety of reasons, including use of proteinfree
surfactant preparations; use of aerosolized surfactant, which delivers less than 5% of the
compound to distal alveoli; and short treatment periods. Thus, although a clear mortality benefit
has not been shown for surfactant administration in adults with ARDS, investigation of different
surfactant preparations and dosing regimens is ongoing.

c
  &

Circulating free fatty acids levels are elevated in patients with ARDS. Inflammatory cytokines
such as TNF and IL
activate phospholipase A2 and acyltransferase enzymes, converting
these fatty acids into proinflammatory mediators. Lisofylline is a xanthine derivative that inhibits
lysophosphatidic acyltransferase and decreases release of cell membranederived free fatty acids.
In addition to its effect on free fatty acids, lisofylline lowers TNF , IL
, and IL levels. The
ARDS Network conducted a multicenter randomized doubleblind, placebocontrolled trial of
lisofylline vs placebo administered to 235 patients with ARDS. The treatment group received
lisofylline at 3 mg/kg up to 3 mg intravenously every  hours for 2 days. The study was
stopped early for failure to show differences in prespecified outcomes, including resolution of
organ failure, ventilatorfree days, and infectionrelated deaths. Mortality in the lisofylline group
at 2 days was 3
.% vs 24.7% in the placebo group. At this point, lisofylline does not appear to
have a role in treating ARDS.

&"      '"   &

Pulmonary vascular smooth muscle cells, endothelial cells, platelets, and neutrophils release
arachidonic metabolites, including thromboxanes and leukotrienes. Thromboxanes increase
platelet aggregation, vascular tone, and lung permeability, whereas leukotrienes cause
bronchoconstriction and act as a potent neutrophil chemokine.Ketoconazole is a synthetic
imidazole antifungal that inhibits thromboxane and leukotriene synthesis via inhibition of 5
lipoxygenase. It does not inhibit cyclooxygenase and thus does not affect prostacyclins or
prostaglandins.

Three major clinical trials have administered ketoconazole prophylactically to prevent ARDS in
highrisk, critically ill patients, with one of these reporting lower mortality with the use of
ketoconazole.The ARDS Network thus initiated a multicenter randomized, doubleblind,
placebocontrolled trial of 234 patients with ARDS who received placebo vs enteral
ketoconazole, 4 mg/d, for treatment up to 2
days. The study was unable to show a statistically
significant difference between the 2 groups in markers of gas exchange, ventilatorfree days, or
mortality. Interestingly, urinary thromboxane B2 levels were not decreased in the ketoconazole
group, suggesting that the ketoconazole dose used was insufficient to decrease thromboxane
synthesis.

" 

Reactive oxygen species, such as superoxide anion, hydroxyl radical, hydrogen peroxide, and
hydrochlorous acid, are produced by neutrophils, alveolar macrophages, and pulmonary
endothelial cells during ARDS. Indices of oxidative damage, including lipid peroxidation,
protein degradation, and further neutrophil recruitment, are higher in patients who die of ARDS.
Healthy lungs contain antioxidants, such as glutathione, superoxide dismutase, and catalase,
which provide defense against these radical oxygen species and their harmful effects, and
glutathione has been shown to be depleted in the lungs of patients with ARDS. Thus, agents such
as xacetylcysteine and procysteine, which increase glutathione levels in the lungs, have been
used to treat ARDS. The results of animal studies of xacetylcysteine were favorable, but human
trials were not as successful. One randomized, doubleblind, placebocontrolled trial of 
patients with ARDS compared xacetylcysteine treatment at
5 mg/kg hourly for  days vs
placebo. No improvement occurred in oxygenation or survival in the xacetylcysteinetreated
group. Another study administered xacetylcysteine, procysteine, and placebo to 3 groups in a
randomized, doubleblind, placebocontrolled trial of 4 patients with ARDS. The 2 treatment
groups had increased glutathione stores and improved lung function, with the largest benefit
being seen in the procysteinetreated group, but no significant difference in survival occurred.
Another study of 
patients with acute lung injury randomized treatment with xacetylcysteine,
4 mg/kg daily intravenously, vs placebo for 3 days. The xacetylcysteinetreated group had
better oxygenation and less ventilatory support but did not have reduced mortality. Currently, no
clear evidence exists that xacetylcysteine or procysteine improves ARDS mortality.

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Supplying appropriate nutrition to intensive care unit patients has become an area of increasing
interest, and manipulating diet composition to decrease endogenous inflammatory mediator
release has been investigated as another method to treat ARDS. In animal models, fish oil or
eicosapentaenoic acidenriched diets reduce lung inflammation. Fish oil and borage oilenriched
enteral feeding was administered to 5
patients with ARDS. Compared with standard nutrition
controls, the patients consuming fish oil diets had fewer BAL neutrophils at days 4 and 7,
improved oxygenation, and fewer ventilator days, but no effect on mortality was seen. A meta
analysis of
2 randomized controlled trials comparing standard enteral nutrition with antioxidant
nutrition found decreased rates of infection but again no effect on mortality. Other dietary
components, including ascorbic acid, tocopherol, and flavonoids, which scavenge reactive
oxygen species, are also currently being tried in patients with ARDS.