Trauma 2007; 9: 255266

Prevention and treatment of post-traumatic acute

respiratory distress syndrome
Rodd Benfield, Joseph DuBose and Demetrios Demetriades

Post-Traumatic Acute Respiratory Distress Syndrome (ARDS) is a major cause of

morbidity and mortality in the acutely injured patient. The American-European
Consensus Conference Report established the most widely accepted definition of
ARDS in 1994. In recent years it appears the incidence and impact of the disease are
on the decline. This article reviews strategies to prevent and treat post-traumatic
ARDS. Well-accepted, proven strategies include lung protective ventilation strategies,
as well as conservative transfusion and crystalloid resuscitation policies and the
adoption of leukoreduction techniques. Other modalities including hypertonic saline
resuscitation, use of albumin and diuretics, positive end expiratory pressure, highfrequency ventilation, prone positioning, recruitment maneuvers, extracorporeal
membrane oxygenation, corticosteroids, exogenous surfactant, and inhaled nitric
oxide are also reviewed.
Key words: Acute Respiratory Distress Syndrome (ARDS); Acute Lung Injury
(ALI); trauma; mechanical ventilation; blood transfusion; resuscitation; critical care,
prevention

Introduction
The Acute Respiratory Distress syndrome (ARDS)
remains a major cause of morbidity, mortality,
and financial burden in the care of the critically
ill and injured patient. This article reviews
the current status of the disease with particular
emphasis on methods to reduce its incidence
and overall impact.

of ARDS and made research in this field difficult.

The AmericanEuropean Consensus Conference
(AECC) Report, published in 1994, defined ARDS
as a non-cardiogenic pulmonary edema and respiratory failure that follows a relatively predictable
clinical course (Bernard et al., 1994). Today, the
AECCs definition and diagnostic criteria are the
most contemporary and widely accepted.

Incidence
Definition
ARDS has been variously defined since its first
description. This heterogeneity in the identification
of patients with ARDS led to wide variations in the
literature pertaining to the incidence and outcomes
University of Southern California, 1200 North State Street,
Room #9900, Los Angeles, CA, USA 90033-4525.
Address for correspondence: Rodd J Benfield, University of
Southern California, 1200 North State Street, Room #9900,
Los Angeles, CA, USA 90033-4525.
E-mail: rjbenfield@mac.com

The range of reported incidence of ARDS is broad

with values ranging 882%. This disparity may be
a function of different definitions of ARDS,
differences in patient demographics over time, the
etiology of the syndrome, differences in diagnostic
and management approaches, and differences in data
collection methods. Hudson and his coworkers
prospectively identified 695 ICU patients with
known risk factors for ARDS between 1983 and
1985 and found an overall incidence of 26%. The
highest incidence of ARDS was found in septic
patients (43%) and those requiring 414 units of
blood transfusion in 24 h (40%). Patients with

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R Benfield et al.

multiple trauma had a 25% incidence of ARDS

(Hudson et al., 1995). In a 1996 review of 83 articles
dealing with ARDS, Garber et al. (1996) reported an
incidence of ARDS ranging 1.55.3 cases/105/year
with trauma as the second leading cause behind
sepsis.
Recent evidence suggests a lower incidence of
ARDS in trauma patients. Hoyt et al. (1993)
reported their experience with 3289 trauma patients
in 1993 with an incidence of ARDS of 1.2%.
In 2004, Treggiari et al. (2004) reported a 12%
incidence of ARDS in 1296 patients and in a more
recent report Salim et al. (2006) found an incidence
of 10.6% among 2042 ICU trauma patients. In a
retrospective review of ARDS patients reported by
Rocco et al. (2001) half of patients developing
ARDS from 1990 to 1998 were victims of trauma,
with an overall incidence of 11%. When Rocco and
colleagues (2001) compared patients from 1990 to
1994 to those from 1995 to 1998, they were unable,
however, to demonstrate a significant change in
incidence (11% versus 11.5%).
More recent reports suggest the incidence of
ARDS is on the decline. Navarette-Navarro et al.
(2001) looked at two groups of trauma patients
admitted from 1985 to 1987 and 1993 to 1995
and found a decrease in ARDS from 8.5 to 4.3%.
A weakness of this study, however, was a lower
Injury Severity Score (ISS) noted in the later patient
group. Martin et al. (2005) looked at 1913 ICU
trauma patients from 2000 to 2004 and found an
overall incidence of ARDS of 14%. They noted
a significant decrease in incidence of ARDS from
23% in 2000 to 8.4% in 2003. Plurad et al. (2007)
reported on a series of 2346 ICU trauma patients
between 2000 and 2005 and found a similar decline in
patients with late post-traumatic ARDS (developed
448 h after admission) from 14.9% in 2000 to 3.8%
in 2005. This decline was associated with a decrease
in blood product transfusions, peak inspiratory
ventilatory pressures and number of patients
ventilated with a tidal volume of 410 mL/kg.

Impact
ARDS represents a significant burden on
the modern healthcare system. It is associated
with increased ICU length of stay, hospital
length of stay, length of mechanical ventilation

and hospital charges. Tregiarri et al. (2004) found

that one third of all disease complications in
trauma patients were related to the pulmonary
system with ALI/ARDS representing 34% of
total yearly costs of ICU trauma patient care. In
their study of 1296 ICU patients adjusted for age,
ISS and APACHE score; average ICU length of
stay for patients without ALI/ARDS was 2 days,
with ALI was 8 days, and with ARDS was 11 days.
In this same study, ALI/ARDS resulted in
an average increased hospital cost from $24 700
to $59 633 per patient Tregiarri et al. (2004). Salim
et al. (2006) found that of 2042 ICU patients from
January 2000 to December 2003, hospital length
of stay and ICU length of stay were increased
from 17.9 and 8.4 days in patients without ARDS
to 32.2 and 22.1 days in patients with ARDS
and that the average hospital cost in patients
with ARDS was $267 037 compared to $136 680
in those patients without ARDS. They also found
the incidence of complications (defined as
pneumonia, deep venous thrombosis, pulmonary
embolism, acute renal failure and disseminated
intravascular coagulopathy) in ARDS patients
to be 43% versus 9.5% in those without ARDS.
Martin et al. (2005) found that ARDS was
associated with increased days of mechanical
ventilation (12.1 versus 9.1 days), increased
ICU length of stay (13.6 versus 10.6 days)
and increased hospital length of stay (17.1 versus
11.9 days).
Although ARDS is associated with significant
mortality, survivors are frequently victims of
subsequent morbidity and disability. ARDS has
been shown to be associated with worse neurologic
outcomes, decreased long-term pulmonary function
and diminished overall quality of life. Holland et al.
(2003) demonstrated worse neurologic outcomes
as measured by Glasgow Outcomes Scores at 3
and 12 months in patients with ALI and severe
traumatic brain injury (TBI) versus those with
severe TBI without ALI. Cooper et al. (1999)
showed that 12 years after onset of their illness,
survivors of ALI have reductions in pulmonary
function testing, quality of life and exercise tolerance similar to those seen in patients with chronic
disease. A limited ventilation strategy was not
shown to augment pulmonary function or quality
of life in these patients. Davidson (1999) similarly
showed that ARDS survivors had a clinically

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Prevention and treatment of post-traumatic ARDS

significant reduction in health related quality of life
that appeared to be caused exclusively by ARDS
and its sequelae. These reductions were noted
mainly in the areas of physical functioning and
pulmonary disease.
Mortality related to ALI/ARDS has traditionally
been high. Krafft et al. (1996) reviewed 101 studies
published between 1967 and 1994 dealing with
ARDS from any cause and found an overall
mortality of 53% /
22% with no increasing
or decreasing trend in mortality rates over this
time period. Hudson et al. (1995) prospectively
analysed 695 ICU patients from 1983 to 1985
and noted a three-fold higher mortality when
ARDS was present (62%) than among patients
with clinical risks who did not develop
ARDS (19%; p50.05). This difference in mortality
with ARDS was particularly noted in trauma
patients (56% versus 13%) and less so in patients
with sepsis (69% versus 49%).
More recent reports, however, suggest a
downward trend in mortality associated with
ARDS. Rocco et al. (2001) retrospectively reviewed
980 ventilated patients with ARDS between
January 1990 and December 1998 and found an
overall mortality of 52%. When patients were
grouped for years 19901994 and 19951998 the
mortality rate was noted to drop from 72% in
the earlier group to 39% in the later group.
They found predictors of death in ARDS to be
age 475, multiple organ dysfunction score (MODS)
48 and lung injury score (LIS) 43. Rocco
and colleagues postulated that this decrease was
due to the use of lung protective ventilation
strategies used in the later group of patients.
Navarrete-Navarro et al. (2001) demonstrated
a lower incidence of mortality in traumatic
ARDS from 1993 to 1995 versus 1985 to1987
(21.4% versus 29.2%; p50.04). They also surmised
that this reduction resulted from the use of
new approaches to mechanical ventilation as well
as renal replacement therapy and vasoactive
drug therapy.
Several studies suggest ARDS may not independently lead to mortality. Tregiarri et al. (2004)
found no additional mortality associated with
ALI/ARDS after adjusting for age, ISS and
APACHE score. Salim et al. (2006) retrospectively
reviewed 216 trauma patients who met criteria for
ARDS and matched them to similarly injured

257

control patients based on gender, age, mechanism

of injury, ISS and chest AIS and found no increase
in overall mortality with ARDS. Martin et al. (2005)
similarly found no increase in mortality in trauma
patients with ARDS after adjusting for age and
injury severity (p 0.57). These studies suggest that
ARDS may merely serve as a marker of more severe
injury rather than a direct cause of mortality.

Pathophysiology
Risk factors for ARDS include many conditions
frequently found in critically ill patients. Sepsis and
severe trauma are the two most significant risk
factors for ARDS along with pneumonia,
DIC, multiple blood product transfusions, shock,
extremity long bone fractures, pulmonary contusion
and aspiration (Garber et al., 1996). Hudson et al.
(1995) identified sepsis, transfusion 415 units and
multiple trauma as the leading three risk factors for
ARDS. Rocco et al. (2001) classified risk factors for
ARDS into two separate categories, direct and
indirect. Direct risk factors include those conditions
with direct injury to the pulmonary system such as
aspiration, pneumonia, pulmonary contusion and
inhalation injury. Indirect risk factors exhibit their
effect through activation of the host inflammatory
response. These risk factors include sepsis, long
bone fractures, pancreatitis and multiple blood
transfusions. Croce et al. (1999) suggested the
existence of two forms of post-traumatic ARDS,
early and late. They identified 178 patients over a
5.5-year period with post-traumatic ARDS and
found 46% who developed ARDS within 48 h of
admission and 54% who developed ARDS greater
than 48 h after admission. The early ARDS group
was characterised by profound haemorrhagic shock
and penetrating injury while the late ARDS
group was significantly older and more commonly
associated
with
generalised
injury
(90%
blunt injury), systemic inflammatory response and
pneumonia. Dicker et al. (2004) also found a
disparity in trauma patients who developed early
versus late onset ARDS. They found that the early
ARDS group was characterised by earlier onset,
fewer ventilator days, less severe derangements in
lung mechanics and faster recovery. They also
found that the late ARDS group had higher SIRS
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R Benfield et al.

scores, incidence of sepsis and incidence of multiple

organ failure.
ARDS is a sequelae of the inflammatory response
characterised by an intense neutrophil infiltrate
within the lungs (Pallister et al., 2002). A myriad
of conditions that lead to the release of proinflammatory mediators have been shown to be
associated with ARDS including pneumonia, sepsis,
mechanical ventilation, crystalloid infusion,
DIC, multiple blood product transfusions, shock,
extremity long bone fractures, pulmonary contusion, aspiration and trauma (Garber et al., 1996;
Dreyfuss and Saumon, 1998). Trauma activates the
inflammatory response and thereby may independently act as a risk factor for ARDS (Moore et al.,
1993; International Consensus Conferences in
Intensive Care Medicine, 1999; Khadaroo and
Marshall, 2002; Nast-Kolb et al., 2001; Pallister
et al., 2002).
Transfusions, and the amount of transfusion, are
known to be associated with ARDS (Miller et al.,
2002; Gong et al., 2005; Silverboard et al., 2005;
Toy et al., 2005). Transfusion related acute lung
injury (TRALI) is a well-described condition in
which acute lung injury occurs within 6 h of
allogenic blood transfusion. It is thought that
during transfusion the recipient is exposed
to
human
antileukocyte
antibodies
that
activate neutrophils that have been primed by
transfused cytokines and lipids (Looney et al., 2004;
Toy et al., 2005).
Liberal crystalloid resuscitation has been
associated with development of ARDS (Mitchell
et al., 1992; Martin et al., 2002; Wiedemann et al.,
2006) presumably by its contribution to capillary
leak and neutrophil activation (Fu et al., 1992;
Rhee et al., 1998). Eberhard et al. (2000) found
ALI patients had received larger volumes of
crystalloid over the first 24 h of admission versus
those without ALI (11.9 L versus 7.3 L).
Mechanical ventilation has been associated with
ALI/ARDS (International Consensus Conferences
in Intensive Care Medicine, 1999; Morrison and
Bidani, 2002; Gajic et al., 2004). Mechanical
shear forces are induced by repeated opening and
closing of the alveoli which is not only directly
toxic to the alveoli but also leads to the release
of proinflammatory mediators (Webb and Tierney,
1974; Dreyfuss et al., 1988; Dreyfuss and Saumon,
1998) Gagic et al. (2005) demonstrated that

large tidal volumes and elevated ventilatory

pressures are independently related to the
development of ALI and ARDS (Gajic et al.,
2004, 2005). Parsons et al. (2005) showed that in
patients with ALI, low tidal volume ventilation
was associated with a more rapid attenuation of
the inflammatory response, manifest as greater
decrease in interleukin-6 and interleukin-8 levels
compared to patients receiving the traditional,
higher tidal volume ventilation strategy. The landmark ARDSNet group trial published in 2000
clearly demonstrated a survival advantage in
ARDS patients treated with lower tidal volume
ventilation leading to widespread adoption of these
conservative modes of ventilation (ARDS
Network, 2000).

Diagnosis
In 1992, the American European Consensus
Conference (AECC) (Bernard et al., 1994)
developed a standardised definition for ARDS to
better facilitate clinical and epidemiologic research
of this syndrome. Based upon the recommendations
of the AECC a new designation, acute lung
injury (ALI), was adopted. As recommended by
the AECC, ALI is defined as a syndrome of
inflammation and increased permeability that
cannot be explained by, but may coexist with, left
atrial or pulmonary capillary hypertension. The
AECC further documented that ALI is associated
most often with sepsis syndrome, aspiration,
primary pneumonia or multiple trauma and less
commonly with cardiopulmonary bypass, multiple
transfusions, fat embolism, pancreatitis and others.
They then substituted the term acute for adult
in outlining acute respiratory distress syndrome
(ARDS) as a subset of ALI with a more
severe oxygenation defect. Per the AECC, ALI
and ARDS are both processes marked by acute
onset of a persistent pulmonary pathology. The
current AECC diagnostic criteria for ALI includes
acute onset of respiratory failure with a PaO2/FiO2
5300 mmHg (5200 mmHg for ARDS) and presence
of bilateral radiographic pulmonary infiltrates with
a pulmonary wedge pressure (PCWP) below
18 mmHg or no clinical or radiologic evidence of
elevated pressure in the left atrium.

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Prevention and treatment of post-traumatic ARDS

Decreasing the impact of

ARDS prevention and
management strategies
Reasons for both the decreasing incidence
and diminished attributable morbidity and
mortality due to post-traumatic ALI/ARDS are
likely multi-factorial. Factors proposed as
contributors to the decreasing incidence have
included advances in the critical care management
of this patient population, ranging from changes
in transfusion policies to ventilation strategies.
Improvement in our understanding of the management of ALI/ARDS, incorporating both
non-pharmacologic and pharmacologic methodologies, have likely contributed to improved
outcomes after onset of ALI/ARDS. While it is
difficult to clearly discern the individual impact
of each of these advances on the incidence and
outcome of ALI/ARDS, expanded experience with
these methodologies provides evidence to
delineate their potential respective influences on
this changing paradigm.

Non-pharmacologic methodologies
Fluid and transfusion management strategies
Increasing awareness has developed regarding
the potential association between the clinical
manifestations of ARDS and iatrogenic causes.
The association between ARDS and transfusion, in
particular, has gained increasing recognition for
the reasons described above. The utilisation of
transfusion strategies incorporating leukoreduction
techniques has been shown to reduce the occurrence
of TRALI (Hebert et al., 2003; Vamvakas 2003;
Toy et al., 2005) and organ failure (van Hilten et al.,
2004; Blajchman, 2006), illustrating the pivotal role
that neutrophil activation plays in the development
of pulmonary failure and ARDS. Plurad et al.
(2007) recently published a report showing
a decrease in the incidence of late post-traumatic
ARDS during a 6-year period in an urban level
I trauma centre and postulated that these
results could be explained by initiation of a
conservative transfusion practice and protective
ventilation strategies.

259

An additional association between neutrophil

mediated capillary leak and pulmonary dysfunction
in the setting of overzealous crystalloid resuscitation
has been cited as a contributing factor in the
development of ARDS. Based on observational
data from several randomised clinical trials
(Mitchell et al., 1992; Martin et al., 2002;
Wiedemann et al., 2006), many researchers have
suggested a relationship between conservative
crystalloid administration strategies and lower
incidence of ARDS. Martin et al. (2002) showed a
decrease in the incidence of post-traumatic ARDS
and suggested this may be a result of more
conservative crystalloid administration as well as
lower mean ventilatory tidal volumes and lower
mean ventilatory peak inspiratory pressures in ICU
patients. In 2006, the ARDSNet group reported
their results of a randomised trial comparing
restrictive fluid administration by protocolised
resuscitation guided by pulmonary artery catheterisation (PAC) versus a more liberal policy without
utilisation of PAC guided therapy. They found that
the restrictive strategy resulted in better lung injury
scores and oxygenation indexes, as well as
lower plateau pressures and positive end-expiratory
pressure. They also noted a trend in the PaO2:
FiO2 ratio in the conservatively managed group,
although this did not reach statistical significance.
Unfortunately, although they found no increase
in non-pulmonary organ failure during this study,
they were unable to demonstrate a significant
difference in 60-day mortality (Wiedemann et al.,
2006). Although ARDS and lung failure were not
the primary endpoints examined by this study
design, this data is compelling and has led to
the adoption of conservative fluid resuscitation
strategies by many groups.
Hypertonic saline resuscitation of haemorrhagic
shock has been shown experimentally to attenuate
neutrophil mediated organ damage and has
therefore been proposed for the treatment and
prevention of ARDS in trauma patients. Animal
studies of haemorrhagic shock resuscitated with
hypertonic saline have demonstrated attenuation of
alveolar macrophage priming and lung neutrophil
accumulation in haemorrhagic shock (Pascual et al.,
2003; Powers et al., 2003). Although encouraging,
human data demonstrating significant benefit
to resuscitation with hypertonic saline in regards
to the prevention or treatment of ARDS is lacking.
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R Benfield et al.

The role of albumin combined with furosemide in

hypoproteinemic patients with ALI has been
investigated with several clinical trials. These studies
have demonstrated improved oxygenation, fluid
balance and haemodynamic stability in patients
with ALI (Martin et al., 2002, 2005). Randomised
clinical trials are necessary to determine the effect
on important clinical outcomes such as duration of
mechanical ventilation and mortality rates.
Albumin has been shown to have immunomodulatory effects that may prove useful in the treatment
and prevention of ARDS in trauma patients.
Animal models of haemorrhagic shock resuscitated
with 25% albumin have shown reduced lung
leukosequestration as well as decreased expression
of inflammatory markers (Powers et al., 2002;
Chen et al., 2006). Clinical evidence supporting
the use of albumin in the resuscitation of trauma
patients in order to treat and/or prevent ARDS is
currently lacking.

Ventilatory strategies
Tidal volume manipulation
Following the landmark ARDSNet group trial
(ARDS Network, 2000) showing a survival
advantage for ARDS patients managed with lower
tidal volume ventilation, this practice has become
widely accepted for the treatment of ARDS. In their
large multi-centre, randomised trial the ARDSNet
investigators demonstrated that patients with acute
lung injury ventilated with low tidal volume
ventilation (LTVV), defined as an initial tidal
volume of 6 mL/kg of predicted body weight and a
plateau pressure of 30 cm of water or less, had
improved mortality and increased number of
ventilator-free days than counterparts undergoing
ventilation with initial volumes of 12 mL/kg of ideal
body weight. Motivated by the findings of this and
other studies on the topic, many groups have
additionally advocated the adoption of LTVV as a
part of lung protective manoeuvers for prophylaxis
against ALI and ARDS. Gagic et al. (2004, 2005) in
two studies, has shown that LTVV and elevated
ventilatory pressures were independently related to
later development of ALI and ARDS. These
findings support the contention that LTVV may
have a role as not only a therapeutic, but also a
prophylactic intervention for ALI and ARDS.

Subsequently, it has been suggested that the

mitigation of airway pressures as part of LTVV
strategies, including manipulation of positive
end-expiratory pressure (PEEP), may prove
instrumental in the avoidance of alveolar injury
and subsequent ALI or ARDS. Indeed, as part of
their landmark trial supporting the use of LTVV in
patients with ALI and ARDS (ARDS Network,
2000), the ARDSNet investigators assigned an
initial plateau pressure of 30 cm or less to the
LTVV group and accepted higher end-inspiratory
thresholds of 50 cm or less in the higher tidal volume
ventilation arm. While the interplay between
pressurevolume relationship in the ventilatory
management of patients with ALI and ARDS is
apparent, it warrants emphasis that the
effective implementation of lung protective
LTVV strategies may prove difficult in many
patients
without
mitigation
of
elevated
airway pressures via ventilator mode adaptations
and appropriate manipulation of the pressure
volume curve.
Positive end-expiratory pressure
Positive end-expiratory pressure (PEEP) has been
examined by several groups as a factor in the
treatment of ALI and ARDS. Early investigations
well established the ability of positive pressure
maintained throughout the respiratory cycle to
improve oxygenation in patients with ARDS.
In preventing alveolar de-recruitment, the use
of PEEP allows for the reduction of oxygen
requirements and improves compliance. By stenting
the alveoli in the open position, it also serves to
decrease the repetitive opening and closing motions
associated with alveolar unit damage and
inflammatory response.
Although the effective manipulation of PEEP
is widely accepted as a useful adjunct in the
ventilatory support of patients with ALI, the
pressure levels required to accomplish optimal
benefit and minimal complications are not well
established. The ARDSNet group reported their
results of a large multi-centre, randomised trial
comparing lower versus higher PEEP strategies for
ALI patients in 2004 (Brower et al., 2004). In a
study design utilising the 6 mL/kg projected body
weight protocol standard to ARDSNet, they
randomised patients to several stratified levels of
PEEP at various levels of FIO2. The group

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Prevention and treatment of post-traumatic ARDS

administered higher PEEP (mean of 14 cm of water)
demonstrated a clear improvement in oxygenation
efficiency as measured by PaO2/FIO2 ratio as well
as improved lung compliance. Despite this improvement, however, the higher PEEP group failed to
manifest any improvement in survival, ventilatorfree days or non-pulmonary organ failure rates.
Additionally, no benefit of higher PEEP was
observed among patients with direct versus indirect
injury, nor by severity of initial gas exchange
abnormality. The authors were left to conclude
that, over the range of values examined, higher
levels of PEEP are either not harmful or there are
off-setting risks and benefits (Brower et al., 2004).
Defining the optimal PEEP level for use in
patients with ALI likely requires significant
individualisation for appropriate identification of
that level which optimises oxygenation without
compromising haemodynamics via increases in
intra-thoracic pressure.
High-frequency ventilation
The use of high-frequency ventilation (HFV)
represents an emerging approach to the ventilatory
management of ALI and ARDS. Through the
manipulation of oscillation pressure amplitude,
frequency, endotracheal tube cuff leak and mean
airway pressure; HFV provides smaller tidal
volumes and more complete lung recruitment
than conventional modes of ventilation. Decreased
systemic haemodynamics and high transpulmonary
pressures associated with the use of HFV may,
however, limit its application in some patients.
The use of HFV in clinical trials has shown some
early promise. In a small, prospective, multi-centre
study, Ferguson et al. (2005) found that the use
of HFV, combined with recruitment manoeuvers,
was well tolerated and resulted in a rapid and
sustained improvement in oxygenation. The role of
HFV in the management of ALI and ARDS is as of
yet ill-defined and warrants further examination.
Recruitment manoeuvers
Recruitment manoeuvers (RM), or the temporary
but sustained elevation of airway pressures to
expand alveolar units has been included by various
groups in their treatment of ALI and ARDS.
In the ARDSNet PEEP trial, the authors
examined the effects of recruitment manoeuvers,
in a subset of ALI patients (Brower et al., 2004).

261

Randomised patients received either a 30 s period

of 3540 cm H20 of continuous positive airway
pressure (CPAP) or a sham RM. They found
that the administration of RMs produced only
modest effects on oxygenation that lasted 51 h.
Additionally, the investigation was limited due to
the onset of safety concerns resulting from the onset
of hypotension in several patients in whom these
manoeuvers were performed.
The aggressive use of RMs should be considered
carefully, as several adverse sequelae associated
with their use have been observed. Haemodynamic
effects associated with these interventions,
although typically transient, can prove significantly
detrimental to critically ill patients. In an animal
study examining the effects of recruitment
manoeuvers in three different animal models of
lung injury, Lim and colleagues (2004) noted
significant decreases in cardiac output following
these interventions, particularly with sustained
inflation. In the ARDSNet PEEP (Brower et al.,
2004) trial, similar effects witnessed in the
RM treatment arm resulted in the discontinuation
of this aspect of the study at only 10%
recruitment. Additionally, repeated RMs are
believed to attenuate de-recruitment associated
lung injury through both mechanical forces and
cytokine response.
Prone positioning
Prone positioning, alone or in conjunction with
other recruitment manoeuvers, has long been
proposed as a treatment modality for ALI and
ARDS patients. The rationale for the use of
positional alterations surrounds the ability of these
manoeuvers to improve gravity-directed blood
distribution to areas of the lung with improved
alveolar recruitment, thereby improving ventilationperfusion matching. To date, however, the use of
prone positioning remains an unproven entity.
More study is required to establish the optimal
modality of ventilation to coincide with these
positional changes, the duration and frequency of
positioning and standardisation of the manoeuver
for further clinical application.
The use of prone positioning, alone or in
conjunction with high PEEP or other recruitment
manoeuvers, may prove useful as a rescue therapy
in patients with severe hypoxemia, but all of
these methods of ventilation do not appear to
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R Benfield et al.

improve survival for the wide population of patients

with ARDS.
Extracorporeal membrane oxygenation
Extracorporeal membrane oxygenation (ECMO)
was one of the first non-pharmacologic manoeuvers
for the treatment of ARDS. Based on the concept
that ECMO support of respiration would allow the
lungs to rest and heal, Zapol and colleagues (1979)
conducted a randomised study in 90 adult patients
with what, in the era prior to the AECC definition
of ALI and ARDS, was termed severe acute
respiratory failure. While they noted an improvement in respiratory gas exchange with the utilisation
of ECMO, they failed to demonstrate any benefit in
terms of survival or other parameters. Enticing as
the concept of ECMO remains, this and later trials
have failed to prove that outcomes are altered with
the utilisation of this technique in patients with
ARDS outside of the early pediatric population.
It has, nevertheless, been successfully employed
in extreme cases as a salvage strategy following
failure of other manipulations in severe ARDS.

Pharmacologic interventions
Only a relative few pharmacologic modalities for
the treatment of ARDS have been carefully studied.
Therapies examined have consisted primarily of
either those designed to modulate the inflammatory
response associated with ARDS or treatments
intended to facilitate improvements in gas exchange
in this setting. Despite the introduction of several
innovative modalities in this effort, none have
convincingly proven efficacious in combating
ARDS. Nevertheless, these therapies warrant
review; as the controversies surrounding their
utility, particularly that of steroid utilisation,
remain contentious.

Corticosteroids
Perhaps no single therapy for ARDS remains as
controversial as that of corticosteroids. The attraction for this therapeutic modality is intuitive, as the
anti-inflammatory effects of corticosteroids make
them inherently attractive as potential agents in
the treatment of ARDS. As far back as 1967,
Ashbaugh and colleagues proposed their utilisation

in this setting. Despite significant enthusiasm for the

use of corticosteroids, they have traditionally failed
to demonstrate significant benefit; particularly in the
early setting of the disease process. In one rigorous
human clinical trial, Bernard and colleagues (1987)
conducted a prospective, randomised, double blind,
placebo-controlled study of methylprednisolone
therapy in 99 patients with early ARDS. They
found no difference between the treatment and
placebo arms in terms of 45-day mortality or
ARDS reversal, leaving them to conclude that
high-dose methylprednisolone does not significantly
affect outcome in this setting of early ARDS. The
results of Bernard and other authors (Luce, 2002;
Koontz et al., 2006) have continued to demonstrate
an absence of survival benefit following the utilisation of corticosteroids in this setting.
The role of corticosteroids for early ARDS,
however, has recently been revisited in light of the
experiences documented by recent investigations. In
a recent investigation conducted by Meduri et al.
(2007) a well-designed trial of methylprednisolone
administration for early (5 or 72 h from onset)
ARDS revealed that this treatment facilitated
down-regulation of systemic inflammatory markers
and improvement in both pulmonary and
extra-pulmonary organ dysfunction. Additionally,
steroid use was associated with a reduction in the
duration of mechanical ventilation, decreased ICU
length of stay and ICU mortality. Despite these
promising findings, Meduri et al. were nonetheless
unable to demonstrate an improvement in overall
survival following steroid therapy in this setting. In
light of these findings, however, proponents continue to debate in the medical literature the merits of
steroid use for the treatment of early ARDS.
While interest in the role of steroids for the
treatment of early ARDS has recently remerged, the
debate regarding their use as a salvage therapy in
late ARDS has remained a contentious topic
for many years. Several early case series have
documented both modification of the inflammatory
response and improvement in clinical course
following sustained therapy with moderate to high
dose glucocorticoids during the later, fibroproliferative stage, of ARDS. In contrast, a subsequent
small, prospective randomised trial of eight patients
with ARDS persisting more than 7 days, failed to
demonstrate a survival benefit with steroid use
(Meduri et al., 1998). In a recently completed large,

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Prevention and treatment of post-traumatic ARDS

randomised, blinded trial of methylprednisolone
versus placebo for patients with ARDS of at least
7 days duration, the ARDSNet investigators
discovered that methylprednisolone use was
associated with an increase in the number of
ventilator and shock free days during the first 28
days of therapy. They also noted an improvement
in oxygenation, fewer days of vasopressor therapy
and improved respiratory system compliance and
blood pressure associated with steroid treatment.
They were not, however, able to demonstrate any
significant improvement in hospital mortality rate
at intervals of 60 or 180 days. In fact, they found
that the initiation of steroid therapy more than
2 weeks after the onset of ARDS was associated
with a significantly increased mortality at the same
time intervals (Steinberg et al., 2006).
The debate regarding steroid use in the treatment
of ARDS is likely to continue. In the absence
of consensus agreement, the use of steroids should
be considered carefully in this setting. Particular
consideration must be given to the known risks
of infection, neuromuscular weakness, and
severe persistent functional disability that have
been associated with their use in this setting.
Further research will likely prove paramount in
defining the appropriate role, timing and ideal
patient population for the use of steroids in the
treatment of ARDS.

Surfactant
The importance of pulmonary surfactant in
the maintenance of normal lung function, and
expanding knowledge regarding alterations in
endogenous surfactant following the onset of
ALI and ARDS have provided the rationale for
examination of exogenous surfactant in this setting.
The use of surfactant therapy, already known to be
beneficial in the setting of deficient production in
premature infants, has also been examined in
the setting of ARDS. Several small studies
have demonstrated improved pulmonary function,
sustained improvement in oxygenation and a trend
towards improved mortality following exogenous
endobronchial administration. In a larger,
randomised controlled trial of 725 patients treated
with aerosolised surfactant with ARDS, however, a
benefit was not demonstrated (Anzueto et al., 1996).
Results from trials in ARDS have proven variable,

263

due in part to disparity in preparation, dosing

and delivery formats; as well as the types of
patients targeted for use of this therapy. While the
potential promise of surfactant therapy for
post-traumatic ARDS has been demonstrated,
further study is necessary to determine the optimal
utilisation of this therapeutic agent.

Inhaled nitric oxide

Nitric oxide (NO) is a potent endogenous vasodilator that can be exogenously delivered to
the pulmonary vasculature by inhalation. Rapid
inactivation of NO by haemoglobin contact at the
site of administration facilitates the selective
vasodilation of the pulmonary vasculature of
aerated lung units. This activity makes NO ideally
suited for improvement of the intrapulmonary
shunt associated with ALI and ARDS. Numerous
clinical studies of NO use have supported its benefit
in terms of improvement in oxygenation, yet none
to date have been able to demonstrate any
improvement in survival following its use. In a
recently completed large multi-centre phase III trial,
Angus et al. (2006) examined outcomes of 385
previously healthy adults randomised to treatment
with NO or placebo after onset of ARDS. At 1 year,
the investigators were unable to identify any
mortality benefit or improvement in Quality of
Well Being scores among survivors related to NO
use. Despite initial enthusiasm, the use of NO as
treatment for ARDS is not supported by the
literature at this time.

Future
Significant further research on the prevention and
modification of the impact of ALI and ARDS
are needed. While advances in resuscitation and
ventilatory care have improved outcomes, a need to
define the mechanisms responsible for the initiation
of lung injury and alter the course of the subsequent
inflammatory process remains apparent. Further
progress must be made in both prevention
and treatment through non-pharmacologic and
pharmacologic strategies.
As our understanding of resuscitation continues
to evolve, it is likely that we will further elucidate
inciting factors to be avoided in the development of
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264

R Benfield et al.

ARDS. The emergence of non-invasive monitoring

to guide our resuscitative efforts, in particular, may
serve to further this end. Ventilatory strategies
with both potential prophylactic and therapeutic
potential, our understanding of which has already
been furthered significantly by the work of
the ARDSNet investigators and others, will
undoubtedly prove paramount. The refinement of
existing, and development of novel, pharmacologic
strategies are also certain to aid our efforts to
diminish the impact of ARDS. Study of more
refined roles for partial liquid ventilation,
anticoagulation agents and activated protein C are
already ongoing. The emergence of novel therapies
including prostaglandin and complement modification of neutrophil activity, beta-agonist utilisation
to improve alveolar fluid clearance, and GM-CSF
modification of alveolar macrophage function are
other promising developments.

Summary
ARDS represents a significant burden to the health
care system and patient morbidity and mortality.
Based on recent evidence, several proven strategies
have arisen in the prevention and treatment of
post-traumatic ARDS including low tidal volume
ventilation and attenuation of ventilatory pressures
as well as conservative transfusion and
crystalloid resuscitation policies and the adoption
of leukoreduction techniques. Advances in our
understanding of resuscitation, pulmonary function
and immune response modulation have demonstrated significant promise in improving our
ability to decrease the impact of this significant
complication. Substantial additional efforts will
be required, however, if we are to more
effectively
employ
current
strategies
and
incorporate emerging novel approaches in the
prevention and treatment of ARDS.

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