Elmer ress

Review J Clin Med Res • 2012;4(1):7-16

Acute Respiratory Distress Syndrome: Pathophysiology and

Therapeutic Options

Charalampos Pierrakosa, Menelaos Karanikolasb, Sabino Scollettac, Vasilios Karamouzosd,

Dimitrios Velissarise, f

oxygenation methods are very useful as rescue therapy in patients

Abstract with intractable hypoxemia, even though a survival benefit has not,
to this date been demonstrated. Despite intense ongoing research
Acute Respiratory Distress Syndrome (ARDS) is a common entity on the pathophysiology and treatment of ARDS, mortality remains
in critical care. ARDS is associated with many diagnoses, including high. Many pharmacologic and supportive strategies have shown
trauma and sepsis, can lead to multiple organ failure and has high promising results, but data from large randomized clinical trials are
mortality. The present article is a narrative review of the literature needed to fully evaluate the true effectiveness of these therapies.
on ARDS, including ARDS pathophysiology and therapeutic op-
tions currently being evaluated or in use in clinical practice. The
literature review covers relevant publications until January 2011. Keywords: ARDS; Pathophysiology; Treatment
Recent developments in the therapeutic approach to ARDS in-
clude refinements of mechanical ventilatory support with emphasis
on protective lung ventilation using low tidal volumes, increased
PEEP with use of recruitment maneuvers to promote reopening of Introduction
collapsed lung alveoli, prone position as rescue therapy for severe
hypoxemia, and high frequency ventilation. Supportive measures In 1821, Laennec described a new syndrome characterized
in the management of ARDS include attention to fluid balance, re- by pulmonary edema without heart failure [1]. Subsequently,
strictive transfusion strategies, and minimization of sedatives and
several terms, such as “double pneumonia”, “shock lung”
neuromuscular blocking agents. Inhaled bronchodilators such as
inhaled nitric oxide and prostaglandins confer short term improve-
and “post traumatic lung” have been used to describe this
ment without proven effect on survival, but are currently used in syndrome. The term “Acute Respiratory Distress Syndrome”
many centers. Use of corticosteroids is also important, and appro- was first used in 1967 to describe a distinct clinical entity
priate timely use may reduce mortality. Finally, extra corporeal characterized by acute abnormality of both lungs [2].
In 1994, the American-European Consensus Conference
on ARDS established criteria for the diagnosis of ARDS.
These criteria include acute onset, bilateral lung infiltrates,
no evidence of elevated left atrial pressure and arterial oxy-
gen tension to inspired oxygen fraction (PaO2/FiO2) less
than 200. The diagnosis of ARDS requires all these features.
However, as these clinical criteria do not always correlate
Manuscript accepted for publication December 1, 2011
well with diffuse alveolar damage, which is the typical patho-
a
Intensive Care Department, Brugmann University Hospital, Brussels logic ARDS feature, ARDS remains a syndrome associated
1030, Belgium with multiple diagnoses [3], rather than a disease in itself.
b
Department of Anesthesiology, Washington University School of Despite substantial progress in understanding ARDS
Medicine, St. Louis, Missouri, USA pathophysiology, ARDS remains a major clinical problem,
c
Department of Surgery and Bioengineering, Unit of Cardiothoracic
and mortality is still as high as 40 - 46%. The incidence of
Anesthesia and Intensive Care, University of Siena, Italy
d
Department of Internal Medicine, University Hospital of Patras, Rio, ARDS in the Intensive Care Unit (ICU) ranges between 4%
Greece to 9% depending on patient age and study population [4].
e
Department of Anesthesiology and Critical Care Medicine, University
Hospital of Patras, Rio, Greece
f
Corresponding author: Dimitrios Velissaris.
Pathophysiology
Email: [email protected]

doi:10.4021/jocmr761w Increased capillary permeability is the hallmark of ARDS.

Damage of the capillary endothelium and alveolar epitheli-

Articles © The authors | Journal compilation © J Clin Med Res and Elmer Press™ | www.jocmr.org 7
Pierrakos et al J Clin Med Res • 2012;4(1):7-16

um in correlation to impaired fluid remove from the alveolar vances in technology have introduced new treatments and
space result in accumulation of protein-rich fluid inside the improved therapeutic strategies. The following paragraphs
alveoli, thereby producing diffuse alveolar damage, with re- discuss recent developments in the therapeutic approach to
lease of pro-inflammatory cytokines, such as Tumor Necro- ARDS.
sis Factor (TNF), IL-1 and IL-6 [5]. Neutrophils are recruited
to the lungs by cytokines, become activated and release toxic Low tidal volume ventilation
mediators, such as reactive oxygen species and proteases [6].
Extensive free radical production overwhelms endogenous The concept of “baby lung” was introduced in 1980s by
anti-oxidants and causes oxidative cell damage [7]. Gattinoni et al and generated interest in the use of low tidal
Inflammation due to neutrophil activation is key in the volume ventilation as therapeutic strategy in ARDS. Several
pathogenesis of ARDS. Fundamental transcription abnor- animal studies showed that ventilation with large tidal vol-
malities, involving NF-kappa B that is required for tran- umes and high inspiratory pressures resulted in development
scription of genes for many pro-inflammatory mediators, of hyaline membranes and inflammatory infiltrates in the
are present in the lungs of ARDS patients [8]. In addition, lungs, and development of respiratory failure [17].
other factors such as endothelin-1, angiotensin-2 and phos- In the late 1990s four randomized controlled trials
pholipase A-2 increase vascular permeability and destroy (RCTs) evaluated the potential benefit of low tidal volume
micro-vascular architecture, enhancing inflammation and ventilation in ARDS [18-21]. Although all four studies had
lung damage. In conclusion, as several different pathways limited power, one study by Amato et al [21] demonstrated
are involved in ARDS development, no single biomarker can that the low tidal volume group had higher survival, higher
predict outcome in ARDS patients [9]. rate of weaning from mechanical ventilation and reduced
Computed Tomography studies in the 1980s helped us rate of barotrauma.
understand the pathophysiologic alterations in the lungs of Because of conflicting results from these studies, the
ARDS patients [10]. In addition, as lung compliance corre- National Heart Lung and Blood Institute ARDS Network
lates with the degree of the normally ventilated tissue, lung conducted a multicenter RCT on 861 ARDS patients [22],
compliance decreases in ARDS because of decreased lung comparing two group of patients ventilated with low vs. high
size, rather than because of lung stiffness, and this hypoth- tidal volumes. In-hospital mortality was significantly lower
esis introduced the concept of ”baby lung” in ARDS [11]. and the number of days without mechanical ventilation was
Pulmonary hypertension (PH) is widely recognized as significantly higher in the low tidal volume group. Although
a characteristic feature of ARDS [12]. PH etiology includes this study has been criticized for the high difference of tidal
parenchymal destruction and airway collapse, hypoxic pul- volume between groups, it demonstrated that high tidal vol-
monary vasoconstriction, presence of other pulmonary vaso- umes should be avoided, and underlined the importance of
constrictors and vascular compression [13]. maintaining low plateau pressures, with 30 cm H2O as an
The initial phase of fluid accumulation is followed by a acceptable cut-off.
proliferation phase characterized by resolution of pulmonary Low tidal volume ventilation is generally well tolerated
edema, proliferation of type II alveolar cells, fibroblasts and and it has not been associated with clinically important ad-
myofibroblasts, and new matrix deposition. This phase starts verse outcomes, except for hypercapnic respiratory acidosis
early (within 72 h) in ARDS, and lasts for more than 7 days. in some patients. In conclusion, hypercapnia and respiratory
Factors influencing the progression to fibro-proliferation vs. acidosis are expected consequences of low tidal volume ven-
resolution and reconstitution of normal pulmonary paren- tilation. However, there is no evidence that hypercapnia is
chymal architecture are poorly understood [14], but patients harmful in ARDS patients, and it may in fact confer some
who develop pulmonary fibrosis exhibit deterioration of pul- protection against ventilator-associated lung injury.
monary compliance, progressive hypoxia and ventilator de-
pendence, and increased mortality (> 57%) [15]. PEEP
Multiple Organ Failure (MOF) is the leading cause
of death in ARDS, but the pathophysiologic link between PEEP is an essential component of mechanical ventilation
ARDS and MOF is not well defined [16]. However, based for patients with ARDS, as it was early observed that PEEP
on existing data it is not clear whether ARDS is the mani- greatly improves oxygenation in ARDS patients. High PEEP
festation of a disease, or it is a disease that causes the MOF levels may open collapsed alveoli and decrease intrapulmo-
syndrome. nary shunt. Additionally, ventilation-induced alveolar injury
is reduced by decreasing alveolar over-distention, because
the volume of each subsequent tidal breath is shared by more
Treatment open alveoli [23]. On the other hand, high PEEP levels may
decrease repetitive alveolar opening and closing during the
Improved understanding of ARDS pathophysiology and ad- respiratory cycle, thereby promoting lung injury [24].

8 Articles © The authors | Journal compilation © J Clin Med Res and Elmer Press™ | www.jocmr.org
Acute Respiratory Distress Syndrome J Clin Med Res • 2012;4(1):7-16

Three RCTs have evaluated modest vs. high levels of of alveoli, more homogeneous ventilation due to decreased
PEEP in patients with ARDS. The NHLB ARDS Network ventilation-perfusion inequalities and reduced ventilator in-
conducted the ALVEOLI trial (Assessment of Low tidal Vol- duced lung injury [36].
ume and Elevated end expiratory pressure to Obviate Lung Four RCTs have investigated the effect of prone posi-
Injury) [25]. This study showed improved PaO2/FiO2 ratio tioning on outcome. The first trial by the Prone-Supine Study
but no benefits with regards to survival or duration of me- group randomized 304 patients with a wide range of severity
chanical ventilation in the high PEEP group. Several years of acute lung injury [37].Patients remained prone for 7 h/
later, the Canadian Critical Care Trials Group performed a day on average, for up to 10 days, but there was no effect on
similar study to determine whether the combination of low survival. Three years later, Guerin et al conducted a similar
tidal volume ventilation with high PEEP could improve mor- multicenter study [38]: patients remained prone for about 8
tality to a greater extent compared to low tidal ventilation h/day, and prone positioning continued until clinical criteria
alone [26]. Results of this study showed reduced need for for improvement were met, but this study also did not show
other rescue therapies such as prone position or NO, but did a reduction in mortality. Two subsequent RCTs attempted to
not show any benefit in survival. correct some shortcomings of the earlier study: they only in-
In conclusion, based on published data, high levels of cluded patients with ARDS, and patients remained prone for
PEEP do not seem to confer any benefit with regards to mor- most of the day (about 20 h). The first RCT by Mancebo et
tality in ARDS. Because ARDS patients are a heterogeneous al was terminated prematurely, after only including 142 pa-
population, the apparent absence of benefit from high levels tients, because of problems with patient recruitment [39]. A
of PEEP could be due to the beneficial effects of high PEEP more recent multicenter RCT by Taccone et al, included 344
in some ARDS patients being offset by detrimental effects in patients [40], and showed significantly increased frequency
other patients [27]. However, data from the RCTs mentioned of adverse events (airway obstruction, hypotension, vom-
above suggest that high PEEP levels improve lungs function iting, accidental extubation) in patients treated with prone
without any adverse effect on mortality [28]. position. Neither of the last two studies showed any surviv-
al benefit using the prone position in patients with severe
Recruitment maneuvers ARDS.
In conclusion, existing data do not support routine use of
A recruitment maneuver is a transient increase of trans-pul- the prone position in ARDS. However, because all published
monary pressure intended to promote reopening of collapsed studies have shown improved oxygenation, prone position-
alveoli [29]. Techniques described for recruitment maneu- ing is an attractive rescue treatment for ARDS patients with
vers include sustained high-pressure inflation and increased severe hypoxemia, even though a survival benefit has never
PEEP, with concurrent reduction of tidal volume [30], but been demonstrated.
it is not clear if any maneuver is superior to others. Several
studies have shown improved gas exchange with recruitment High-frequency ventilation
maneuvers, but no RCT has shown benefit on ARDS mor-
tality [31] and a recent systematic review by Fan et al [32] The idea of high frequency ventilation (HFV) is to provide
showed that hypotension and decreased saturation occur in tidal volumes below that of anatomic dead space at high fre-
12% and 8% of patients respectively during or after such ma- quency (> 60 breaths per minute). Compared to conventional
neuvers. Based on currently available data, although routine mechanical ventilation, mean airway pressure is higher [41].
recruitment maneuvers are not recommended in ARDS, such Two studies, by Hamilton and Chan, showed reduced risk for
maneuvers can dramatically improve oxygenation in certain barotrauma and lung over-distention, after performing high
patients, and should be considered as rescue therapy in pa- frequency ventilation [42, 43]. High frequency ventilation
tients with life-threatening refractory hypoxia [33]. can be applied by different modes, such as high-frequency
percussive ventilation, high-frequency jet ventilation and
Prone position high-frequency oscillatory ventilation (HFOV) [44]. In the
absence of studies showing superiority of one method over
Prone positioning has been used in ARDS for over 30 years. another, HFOV is the HFV method used more often in adult
In 1976 Piehl et al. reported improved oxygenation in ARDS critical care [43].
patients when they were turned to the prone position [34]. In HFOV very small tidal volumes (1 - 4 ml/kg) are de-
Since then, several observational studies on ARDS have livered at high frequency (3 - 15 Hz) by an oscillatory pump
found similar results, and improvement in oxygenation can [45]. However, the use of HFOV as rescue therapy in pa-
sometimes be dramatic [35]. Mechanisms proposed to ex- tients with refractory hypoxia remains controversial. There
plain the observed beneficial effects of prone positioning are two RCTs comparing HFOV with conventional mechani-
include increased chest wall elastance decreased compres- cal ventilation. The first RCT by Derdak et al found a trend
sion of lung tissue in the dependent regions and recruitment for decreasing 30-day mortality [46] even though relatively

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Pierrakos et al J Clin Med Res • 2012;4(1):7-16

high tidal volume was used in the control group. The second relaxation may also improve chest wall compliance. NMBAs
RCT by Bollen et al was terminated prematurely because may also have anti-inflammatory effects that could decrease
of slow enrollment, but found an opposite trend in mortal- the inflammation associated with ARDS. However, because
ity [47]. Two meta-analyses also had conflicting results. The there is evidence that NMBAs increase the risk of acquired
first one included only 2 RCTs comparing HFOV vs. con- neuromuscular weakness, thereby making weaning from
ventional ventilation, and did not find any mortality reduc- mechanical ventilation more difficult, and may even increase
tion or improvement of oxygenation [48]. However, a more mortality [56].
recent study by Sud et al included 8 RCTs and found reduced
30-day mortality with HFOV compared to conventional ven- Nutrition
tilation [49]. In conclusion, the role of HFOV in ARDS is
not well defined, and deserves further study from well de- Two RCTs [57, 58] and a meta-analysis by Puntes-Arruda
signed RCTs. et al [59] showed that administration of enteral nutrition
containing high concentrations of eicosapentanoic acid and
Supportive treatment of ARDS γ-linoleic acid and ω-3 fatty acids increased oxygenation and
decreased ICU stay and 28-day mortality in ARDS.
Fluid management
Pharmacologic agents
Early data indicate that increased fluid administration is
correlated with worse outcome in ARDS, whereas negative Vasodilators
fluid balance was associated with better outcome [50]. The
ARDS network conducted a RCT with 1000 patients ran- Because diffuse pulmonary vasoconstriction is part of ARDS
domized to receive conservative or liberal fluid administra- pathophysiology, selective vasodilatation of well ventilated
tion. The conservative strategy group showed improved lung areas seems an attractive method to improve gas exchange in
function and shortened duration of mechanical ventilation, ARDS patients.
but there was no difference in non pulmonary organ failures Inhaled nitric oxide (iNO) causes vasodilation of venti-
and 60-day mortality. lated lung units and redistribution of pulmonary blood flow
away from non-ventilated lung areas, without adverse sys-
Transfusions temic hemodynamic effects. Four RCTs evaluated the effects
of iNO and showed transient improvement in oxygenation
Allogenic blood transfusion is associated with detrimental [60-63], but no improvement in mortality. Similarly, one
immuno-modulatory effects that may result in ARDS [51]. meta-analysis found transient oxygenation improvement but
Consequently, conservative transfusion strategies may de- no survival benefit with iNO [64]. Consequently, iNO may
crease the incidence of ARDS. be useful as short-term rescue therapy in patients with severe
hypoxemic respiratory failure.
Sedation Inhaled prostacycline is another selective pulmonary
vasodilator. Importantly, liposomal PGE1 influences neu-
Several studies have shown that newer ventilation strate- trophil function and decreases neutrophil accumulation
gies using low tidal volume and high levels of PEEP do not and lung leak. Although inhaled prostacycline improves
require high doses of sedation [52]. Furthermore, evidence oxygenation, it has not been shown to reduce duration of
suggests that use of sedatives may increase duration of me- mechanical ventilation or mortality in ARDS patients [65].
chanical ventilation and ICU length of stay and may even be Despite the lack of sufficient data supporting the use of
associated with higher mortality [53]. In addition, there is prostacycline as alternative to iNO, prostacycline is increas-
evidence that spontaneously breathing ARDS patients have ingly used as pulmonary vasodilator, because of the high
improved cardiopulmonary function, presumably by recruit- cost of iNO [66].
ing non ventilated lung units [54]. Therefore, based on cur-
rent evidence, avoidance or minimization of sedation and Vasoconstrictors
paralysis is preferred in ARDS.
Vasoconstrictors can improve oxygenation in ARDS patients
Neuromuscular blocking agents by decreasing intrapulmonary shunt. Phenylephrine [67] and
almitrine [68] have been used in small studies, mainly as
Administration of neuromuscular blocking agents (NMBA) adjuncts during administration of NO. B-blockers have also
in addition to sedation can result in improvement in severe been shown to increase arterial oxygenation in patients with
hypoxemia, because paralysis improves patient-ventilator ARDS [69]. However, the role of these agents in ARDS has
synchronism and reduces oxygen consumption [55]. Muscle not been adequately evaluated, and deserves further study.

10 Articles © The authors | Journal compilation © J Clin Med Res and Elmer Press™ | www.jocmr.org
Acute Respiratory Distress Syndrome J Clin Med Res • 2012;4(1):7-16

Anti inflammatory agents [87] have been evaluated, but none of them has been shown
to be effective for treatment of ARDS.
The interaction between nuclear factor-kappa B (NF-kB)
and glucocorticoid receptor alpha (GRa) is a key mechanism Extracorporeal techniques
regulating the progression of systemic and pulmonary in-
flammation in ARDS [70]. The ability of GC-GRa to down- Extracorporeal membrane oxygenation (ECMO) has been
regulate NF-kB activation is critical for the resolution of sys- studied since 1970s as a method for supporting gas exchange
temic and pulmonary inflammation in ARDS [71]. Although in patients failing conventional ventilation [88]. A RCT con-
several studies showed that corticosteroids confer no benefit ducted in 1979 showed that ECMO use had no effect on long-
and may even cause harm [72], corticosteroids are still used term survival of ARDS patients [89]. Nowadays, ECMO is
in clinical practice. used to support oxygenation of patients with severe ARDS,
Timing of corticosteroid administration and duration of thereby allowing use of decreased ventilator settings (tidal
therapy may be important, and should be taken into consid- volume, respiratory rate, FiO2), in an attempt to minimize
eration. A RCT conducted by the ARDS Network, random- ventilator induced lung injury.
ized 180 patients with persistent (> 7 days) ARDS, to receive In a more recent study 180 patients with severe ARDS
methylprednisolone (2 mg/kg/d) or placebo for 21 days, and were randomized to support by ECMO vs. conventional
showed improved oxygenation and more ventilator-free days treatments. This study showed significantly improved sur-
in the methylprednisolone group, but no significant improve- vival (63% vs. 47%, P = 0.03) at 6 months in the ECMO
ment in mortality [73]. Another RCT evaluated early cortico- group [90]. Although no definite conclusions can be drawn
steroid administration, and showed that methylprednisolone from this study [91], the results of this study suggest that
administration (1mg/kg/d) [74] less than 72 after the onset of ECMO can be used as a rescue therapy in cases of very se-
ARDS reduced mortality. However, these results should be vere ARDS.
interpreted with caution, because this study included a large Extracorporeal CO2 removal (ECCO2R) is an alter-
number of patients with septic shock. native device that uses veno-venous circuit for removal of
Conflicting data exist concerning the correlation be- CO2 at much lower extracorporeal flow rates compared to
tween corticosteroids and ICU neuromyopathy. A sub-analy- ECMO. A RCT conducted before the year 2000 used EC-
sis of study survivors did not show any association between CO2R and showed no effect on mortality [92]. In another
randomization to corticosteroids and increased risk of neuro- study ECCO2R was combined with low frequency positive
myopathy [75]. In conclusion, the relationship between cor- pressure ventilation (2 - 3 b/min), and showed improvement
ticosteroids and ICU neuromyopathy is an important issue in lung mechanics [93]. Overall, extracorporeal support
that deserves further study [76]. technologies produce significant temporary improvement in
Several other anti-inflammatory factors like Ibuprofen ARDS patients with severe respiratory dysfunction, but this
[77], ketoconazole [78], neutrophil elastase inhibitors (ONO improvement does not seem to affect outcome. New, well
5046) [79], NF-KB inhibitors [80], recombinant soluble conducted clinical studies are needed to better evaluate the
complement receptor-1 [81], and liposomal prostaglandin E1 role of ECMO and ECCO2R on survival in ARDS.
[82] have been evaluated in ARDS patients without success.

Beta agonists Mortality

There are substantial evidences that b2-agonists may play a Conflicting data exist about the evolution ARDS mortality
potential role in the treatment of patients with ARDS. B2 ag- over time. A meta-analysis by Phua et al did not find any
onists have been found to have anti-inflammatory effects by mortality reduction in recent years [94], whereas another
direct influence on neutrophil function and by reducing the meta-analysis by Zambon et al. showed reduced mortality
secretion of several pro-inflammatory cytokines. Addition- in recent years [4]. In the past, several studies evaluated pat-
ally, b2-agonists can reduce the endothelial permeability and terns of ARDS mortality over time within the same institu-
stimulate the fluid clearance from the lungs [83]. In a small tion [95-99], and all studies, except for two [98, 99], found
RCT using the thermodilution method (PiCCO), intravenous decreasing mortality in ARDS. The observed discrepancy
salbutamol (15 μg/kg/h) use for seven days reduced extra- between different studies may be due to different investiga-
vascular lung water compared to placebo [84]. The effects tional methods, but we can conclude that ARDS mortality
of inhaled b-agonists have not, to this date, been adequately remains high (41 - 46%). Regardless of improvements in re-
evaluated, but will be investigated in an ongoing study con- cent years, ARDS mortality is higher in older patients and in
ducted by ARDS network (NCT00434993) medical patients [100]. However, the impact, if any, of newer
Several other pharmacological agents, including gluta- treatment strategies on ARDS mortality has not been evalu-
thione lisofylline [85], N-Acetylcysteine[86], and surfactant ated, because most studies are referred to the period before

Articles © The authors | Journal compilation © J Clin Med Res and Elmer Press™ | www.jocmr.org 11
Pierrakos et al J Clin Med Res • 2012;4(1):7-16

the year 2000. GR, Thompson BT, Brower RG, et al. Prognostic and
pathogenetic value of combining clinical and biochemi-
cal indices in patients with acute lung injury. Chest.
Conflicts of Interest 2010;137(2):288-296.
10. Gattinoni L, Caironi P, Pelosi P, Goodman LR. What has
This work was supported solely by Department funds. All computed tomography taught us about the acute respi-
authors state that they have no conflicts of interest to dis- ratory distress syndrome? Am J Respir Crit Care Med.
close. 2001;164(9):1701-1711.
11. Gattinoni L, Pelosi P, Pesenti A, Brazzi L, Vitale G,
Moretto A, Crespi A, et al. CT scan in ARDS: clini-
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