Article

PDF
Access to the PDF text
Service d'aide à la décision clinique
Advertising


Free Article !

La Presse Médicale
Volume 40, n° 12P2
pages e543-e560 (décembre 2011)
Doi : 10.1016/j.lpm.2011.04.023
Quarterly Medical Review

Pathophysiology of acute respiratory distress syndrome. Glucocorticoid receptor-mediated regulation of inflammation and response to prolonged glucocorticoid treatment
 

Gianfranco Umberto Meduri 1, , William Bell 1, Scott Sinclair 1, Djillali Annane 2
1 University of Tennessee Health Science Center and Memphis Veterans Affairs Medical Center, Critical Care and Sleep Medicine, Division of Pulmonary, Departments of Medicine, Memphis, 38104 TN, United States 
2 Université de Versailles SQY (UniverSud Paris), 92380 Garches, France 

Gianfranco Umberto Meduri, Memphis Veterans Affairs Medical Center, University of Tennessee Health Science Center, Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, 1030 Jefferson Avenue, Suite #CW444, Memphis, 38104 TN, United States.
Summary

Based on molecular mechanisms and physiologic data, a strong association has been established between dysregulated systemic inflammation and progression of ARDS. In ARDS patients, glucocorticoid receptor-mediated down-regulation of systemic inflammation is essential to restore homeostasis, decrease morbidity and improve survival and can be significantly enhanced with prolonged low-to-moderate dose glucocorticoid treatment. A large body of evidence supports a strong association between prolonged glucocorticoid treatment-induced down-regulation of the inflammatory response and improvement in pulmonary and extrapulmonary physiology. The balance of the available data from controlled trials provides consistent strong level of evidence (grade 1B) for improving patient-centered outcomes. The sizable increase in mechanical ventilation-free days (weighted mean difference, 6.58 days; 95% CI, 2.93 –10.23; P <0.001) and ICU-free days (weighted mean difference, 7.02 days; 95% CI, 3.20–10.85; P <0.001) by day 28 is superior to any investigated intervention in ARDS. The largest meta-analysis on the subject concluded that treatment was associated with a significant risk reduction (RR=0.62, 95% CI: 0.43–0.91; P =0.01) in mortality and that the in-hospital number needed to treat to save one life was 4 (95% CI 2.4–10). The balance of the available data, however, originates from small controlled trials with a moderate degree of heterogeneity and provides weak evidence (grade 2B) for a survival benefit. Treatment decisions involve a tradeoff between benefits and risks, as well as costs. This low cost highly effective therapy is familiar to every physician and has a low risk profile when secondary prevention measures are implemented.

In this issue

Does my patient really have ARDS?
L. Brochard, Geneva, Switzerland.
Mechanical ventilation during acute lung injury: current recommendations and new concepts
L. Del Sorbo et al., Torino, Italy
Prone positioning in acute respiratory distress syndrome: When and How?
F. Roche-Campo et al., Barcelona, Spain
Pathophysiology of acute respiratory distress syndrome. Glucocorticoid receptor-mediated regulation of inflammation and response to prolonged glucocorticoid treatment
G. Umberto Meduri et al., Memphis, USA
Virus-induced acute respiratory distress syndrome: epidemiology, management and outcome
C.-E. Luyt et al., Paris, France
Lung function and quality of life in survivors of the acute respiratory distress syndrome (ARDS)
M. Elizabeth Wilcox and Margaret S. Herridge, Toronto, Canada

The full text of this article is available in PDF format.

Acute respiratory distress syndrome (ARDS) is a disease of multifactorial etiology characterized by a specific morphologic lesion termed “diffuse alveolar damage” (DAD) [1]. This chapter will emphasize the inflammatory nature of ARDS, the regulatory role of the glucocorticoid receptor and how, similar to all inflammatory lung diseases [2], prolonged glucocorticoid treatment is an important therapeutic option. Clinicians assess the progression of ARDS with daily measurements of variables incorporated into the lung injury score (LIS) [3]. Patients with a 1-point or greater reduction in LIS in the first week of mechanical ventilation (resolving ARDS), in contrast to (unresolving ARDS), in contrast to patients with unresolving ARDS, have improved short and long-term outcomes [4]. Experimental and clinical evidence has demonstrated a strong cause and effect relationship between persistence vs. reduction in systemic and pulmonary inflammation and progression (unresolving) vs. resolution (resolving) of ARDS, respectively [4]. In this chapter, the cellular mechanisms involved in activating and regulating inflammation are contrasted between patients with resolving and unresolving ARDS. At the cellular level, patients with unresolving ARDS have deficient glucocorticoid-mediated down-regulation of inflammatory cytokine and chemokine transcription despite elevated levels of circulating cortisol, a condition defined as systemic inflammation-associated acquired glucocorticoid resistance [4]. These patients, contrary to those with resolving ARDS, have persistent elevation over time in both systemic and bronchoalveolar lavage (BAL) levels of inflammatory cytokines and chemokines, markers of alveolar-capillary membrane permeability and fibrogenesis [4]. At the tissue level, the continued production of inflammatory mediators leads to tissue injury, intra- and extravascular coagulation and proliferation of mesenchymal cells, all resulting in maladaptive lung repair and progression of extrapulmonary organ dysfunction [4]. High levels, contrary to low-moderate levels, of inflammatory cytokines also promote bacterial growth and increase susceptibility to nosocomial infections [5].

In ARDS, down-regulation of systemic inflammation is essential to restoring homeostasis, decreasing organ dysfunction and morbidity and improving survival. Prolonged low-moderate dose glucocorticoid therapy promotes down-regulation of inflammatory cytokine transcription at the cellular level by enhancing activated glucocorticoid receptor ⍺ (GC-GR⍺)-mediated down-regulation of transcription factor nuclear factor-κB (NF-κB) [4]. Eight controlled studies have consistently reported a significant reduction in markers of systemic inflammation, pulmonary and extrapulmonary organ dysfunction scores, duration of mechanical ventilation and intensive care unit length of stay [6]. In the aggregate (N=628), reduction in mortality was substantial for all patients (RR=0.75, 95% CI: 0.63 to 0.89; P <0.001; I2 43%) and for those treated before day 14 (RR=0.71, 95% CI: 0.59 to 0.85; P <0.001; I2 40%). Despite the lack of financial incentives to educate intensivists [7], this treatment is now used in 50% of patients with ARDS [8]. Much of this chapter was previously published in a recent review [4].

Systemic inflammation and tissue host defense response

Systemic inflammation is a highly organized response to infectious and noninfectious threats to homeostasis that includes the activation of at least five major programs:

(1)
tissue host defense response [9];
(2)
acute-phase reaction;
(3)
sickness syndrome (including sickness behavior) [10];
(4)
pain program mediated by the afferent sensory and autonomic systems and;
(5)
the stress program mediated by the hypothalamic-pituitary-adrenal (HPA) axis and the locus ceruleus-norepinephrine/sympathetic nervous system [11].

The main effectors of systemic inflammation are inflammatory cytokines, such as tumor necrosis factor-⍺ (TNF-⍺), interleukin-1β (IL-1β) and IL-6; chemokines and other mediators of inflammation; the acute-phase reactants, mostly of hepatic origin, such as C-reactive protein (CRP), fibrinogen and plasminogen activator inhibitor-1; the effectors of the sensory afferent system, such as substance P and of the stress system, namely hypothalamic corticotropin releasing hormone (CRH) and vasopressin, cortisol, the catecholamines norepinephrine and epinephrine and peripheral neuronal CRH (reviewed in reference [11]). Excessive release of inflammatory mediators into the circulation induces tissue changes in vital organs leading to multiple-organ dysfunction syndrome (MODS) [12, 13].

The host defense response (HDR) is a tissue-protective response, which serves to destroy, dilute, or contain injurious agents and to repair any resulting damage. The HDR consists of an integrated network of three simultaneously activated pathways ((Box 1)) [4] – inflammation, coagulation and tissue repair – which account for the observed histological and physiological changes with progression or resolution of ARDS and MODS. Whereas appropriately regulated inflammation – tailored to stimulus and time [11] – is beneficial, excessive or persistent systemic inflammation incites tissue destruction and disease progression [14]. It is the lack of regulation (dysregulated systemic inflammation) of this vital response that is central to the pathogenesis of organ dysfunction in patients with sepsis and ARDS [15, 16]. Improved understanding of the critical role played by the neuroendocrine response in critical illness and the cellular mechanisms that initiate, propagate and limit inflammation [17] have provided a new understanding of the role endogenous and exogenous glucocorticoids play in life-threatening systemic inflammation.

Box 1

Components of the tissue host defense response

Reproduced with permission from reference [4].
Inflammation
Vasodilatation and stasis
Increased expression of adhesion molecules
Increased permeability of the microvasculature with exudative edema
Leukocyte extravasation*
Release of leukocyte products potentially causing tissue damage
Coagulation
Activation of coagulation
Inhibition of fibrinolysis
Intravascular clotting
Extravascular fibrin deposition
Tissue repair
Angiogenesis
Epithelial growth
Fibroblast migration and proliferation
Deposition of extracellular matrix and remodeling
*Initially polymorph nuclear cells and later monocytes

Progression of acute respiratory distress syndrome: resolving vs. unresolving

ARDS is a disease of multifactorial etiology characterized by a specific morphologic lesion termed “diffuse alveolar damage” (DAD) [1]. ARDS develops rapidly, in most patients within 12–48h of exposure to infectious or noninfectious insults that can affect the lung directly (via the alveolar compartment) or indirectly (via the vascular compartment) [18]. At presentation, ARDS manifests with severe, diffuse and spatially inhomogeneous HDR of the pulmonary lobules leading to a breakdown in the barrier integrity and gas exchange function of the lung. Every anatomical component of the pulmonary lobule (epithelium, endothelium and interstitium) is involved including the respiratory bronchioles, alveolar ducts and alveoli, as well as arteries and veins. Diffuse injury to the alveolar-capillary membrane (ACM) causes edema of the airspaces and interstitium with a protein-rich neutrophilic exudate, resulting in severe gas exchange and lung compliance abnormalities [19]. Although the term “syndrome” was applied in its original description, [20] ARDS meets all the constitutive elements of a disease process [21]. Translational clinical research has constructed – through a “holistic” level of inquiry – a pathophysiological model of ARDS that fits pathogenesis (biology) with morphological (pathology) and clinical (physiology) findings observed during the longitudinal course of the disease [21].

The LIS quantifies the physiologic respiratory impairment in ARDS through the use of a four-point score based on the level of positive end-expiratory pressure (PEEP), ratio of Pa O2 to fraction of inspired oxygen (FI O2 ) (Pa O2 :FI O2 ), the static lung compliance and the degree of infiltration present on chest radiograph (one point per quadrant of lung fields involved) [3]. On simple physiological criteria, the evolution of ARDS can be divided into resolving and unresolving based on achieving a 1-point reduction in LIS by day 7 (Table I) [4]. Even though, at the onset of ARDS, the two groups may appear similar, daily measurement of lung injury and MODS scores and C-reactive protein levels allow early identification of nonimprovers. Patients failing to improve LIS in the first week of mechanical ventilation (unresolving ARDS) have, significantly higher levels of inflammatory cytokines at the onset of the disease (Figure 1) [22, 23]. Moreover, nonimprovers have persistent elevation over time in circulating and bronchoalveolar lavage (BAL) levels of inflammatory cytokines (Figure 1) [22, 23, 24, 25, 26, 27, 28, 29, 30, 31] and chemokines [32], markers of ACM permeability [27, 33, 34] and fibrogenesis compared to improvers [35]. Patients with unresolving ARDS develop fever (systemic inflammatory response syndrome) in the absence of infection [29, 36, 37] and are also at increased risk for developing nosocomial infections (Figure 2) [5, 29]. Elevated levels of systemic cytokines are also involved in the pathogenesis of morbidity frequently encountered in patients with sepsis and ARDS including hyperglycemia [38], short- and long-term neurological dysfunction (delirium [39], neuromuscular weakness [39] and posttraumatic stress disorder [40] and sudden cardiac events in those with underlying atherosclerosis (Figure 2) [4, 41].



Figure 1


Figure 1. 

Inflammatory cytokines and chemokines plasma levels in patients with unresolving and resolving acute respiratory distress syndrome (ARDS)

Plasma inflammatory cytokine levels over time in survivors and non-survivors. Plasma TNF-⍺, IL-1β, IL-6 and IL-8 levels from days 1 to 10 of sepsis-induced ARDS. On day 1 of ARDS, non-survivors (n =17) had significantly higher (P <0.001) TNF-⍺, IL-1β, IL 6 and IL-8 levels. Over time, non-survivors had persistent elevation, whereas survivors (n =17) had a rapid decline. Receiver operating curve analysis revealed that at the onset of ARDS, plasma IL-1β (Endogen, Boston, MA), TNF-⍺, IL-6, (Genzyme, Cambridge, MA) and IL-8 (R & D Systems, Minneapolis, MN) greater than 400pg/mL were prognostic of death. When IL-1β values on day 1 of ARDS were categorized as either greater or lower than 400pg/mL, high values of IL-1β were prognostic of death (relative risk=3.75; 95% CI=1.08–13.07) and independent of the presence of sepsis or shock, APACHE II score, cause of ARDS and MODS score. These findings indicate that loss of autoregulation is an early phenomenon.

Zoom



Figure 2


Figure 2. 

Pathophysiological manifestations of dysregulated systemic inflammation in acute respiratory distress syndrome (ARDS)

Dysregulated systemic inflammation leads to changes at the pulmonary and systemic levels [9]. In the lungs, persistent elevation of inflammatory mediators sustains inflammation with resulting tissue injury, alveolar-capillary membrane permeability, intra- and extravascular coagulation in previously spared lobules and proliferation of mesenchymal cells with deposition of extracellular matrix in previously affected lobules, resulting in maladaptive lung repair. This manifests clinically with failure to improve gas exchange and lung mechanics and persistent BAL neutrophilia. Systemic manifestations include: systemic inflammatory response syndrome (SIRS) in the absence of infection, progression of MODS, positive fluid balance and increased rate of nosocomial infections. Additional morbidity attributed to elevated cytokinemia includes hyperglycemia [38], short- and long-term neurological dysfunction (delirium [39], neuromuscular weakness [39] and posttraumatic stress disorder [40] and sudden cardiac events in those with underlying atherosclerosis [41, 128].

Zoom

At the tissue level, the continued production of inflammatory mediators sustains inflammation with resulting tissue injury, intra- and extravascular coagulation (exudation) in previously spared lobules and proliferation of mesenchymal cells (fibroproliferation) with deposition of extracellular matrix in previously affected lobules (intra-alveolar, interstitial and endovascular), resulting in maladaptive lung repair evolving ultimately in fibrosis (Figure 3) [9]. Histologically, these two processes can be seen adjacent to each other [42] and have been described in detail [43]. Persistent endothelial and epithelial injury leads to protracted vascular permeability (“capillary leak”) in the lung and systemically. Intravascular coagulation and fibroproliferation decreases available pulmonary vascular bed, while intra-alveolar fibrin deposition promotes cell-matrix organization by fibroproliferation [44]. Predictors of poor outcome in ARDS are expressions of persistent and exaggerated (dysregulated) systemic inflammation [9].



Figure 3


Figure 3. 

Evolution of acute respiratory distress syndrome (ARDS): adaptive vs. maladaptive response

Top: progression of the host defense response (HDR) in patients with adaptive and maladaptive repair. In the first group, the HDR is initially less severe and diminish over time allowing for restoration of anatomy and function. In the second group, the HDR is initially more severe and continues unrestrained over time leading to repeated inflammatory insults and amplification of intra- and extravascular coagulation and fibroproliferation resulting in maladaptive lung repair. Maladaptive lung repair manifest clinically, with persistent hypoxemia, failure to improve lung mechanics and prolonged mechanical ventilation. Bottom: in patients with adaptive response, with progressive reduction in NF-κB-driven TNF–⍺ and IL–1β levels, previously spared lobules are not subjected to new insults, while previously affected lobules undergo an adaptive repair leading to restoration of anatomy and function. In patients with maladaptive response, with persistent elevation in NF-κB-driven TNF–⍺ and IL–1β levels, previously spared lobules are now subjected to new insults and previously affected lobules undergo a maladaptive repair (unrestrained coagulation and fibroproliferation) leading to fibrosis.

Zoom

Cellular regulation of inflammation – interaction between activated nuclear factor-κB and glucocorticoid receptor ⍺

The body needs mechanisms to keep acute inflammation in check [16] and the GC-activated glucocorticoid receptor ⍺ (GR⍺) complex (GC-GR⍺) is the most important physiologic inhibitor of inflammation [17] affecting thousands of genes involved in stress-related homeostasis with more transactivation than transrepression [45, 46]. In fact, glucocorticoids exert within few hours transrepression activities by physical interaction with NF-kB preventing its migration to the nucleus and downstream reading of genes encoding for most inflammatory mediators. Transactivation occurs within days of exposure to glucocortioids, the GC-GRa complex migrates to the nucleus and activate the reading of a number of genes encoding for proteins involved in the resolution of inflammation. It is now appreciated that the ubiquitously present cytoplasmic transcription factors nuclear factor-κB (NF-κB) – activated by inflammatory signals – and glucocorticoid receptor ⍺ – activated by endogenous or exogenous glucocorticoids – have diametrically opposed functions that counteract each other in regulating transcription of inflammatory genes [47, 48]. NF-κB is recognized as the principal driver of the inflammatory response, responsible for the transcription of greater than 100 genes, including TNF-⍺, IL-1β and IL-6 [49]. NF-κB activation is central to the pathogenesis of sepsis, lung inflammation and acute lung injury [50, 51]. At the molecular level, glucocorticoids also have very rapid (within minutes) non-genomic effects via interaction with membrane sites or the release of chaperone proteins from the glucocorticoid receptor. These effects include mainly a modulation of cellular responses with decrease in cell adhesion, phosphotyrosine kinases and an increase in annexin 1 externalization [52].

The adrenal gland does not store cortisol; increased secretion occurs from increased synthesis under adrenocorticotropic hormone (ACTH) control. During systemic inflammation, peripherally generated TNF-⍺ and IL-1β stimulate the HPA-axis [53, 54] to limit the inflammatory response through the synthesis of cortisol [55]. Cortisol, secreted into the systemic circulation, readily penetrates cell membranes and exerts its anti-inflammatory effects by activating cytoplasmic GR⍺. Once activated, NF-κB and GR⍺ can mutually repress each other through a protein-protein interaction that prevents their binding to and proper interaction with promoter and/or enhancer DNA and subsequent regulation of transcriptional activity. Activation of one transcription factor in excess of the binding (inhibitory) capacity of the other shifts cellular responses toward increased (dysregulated) or decreased (regulated) transcription of inflammatory mediators over time [56]. In sepsis and ARDS, the effect of endogenous cortisol on target tissue is blunted at least partly as a result of decreased GR-mediated activity, allowing an uninhibited increase of NF-κB activation in immune cells over time and, hence, leading to an impaired down-regulation of systemic inflammation [23, 57, 58].

Interaction between activated nuclear factor-κB and glucocorticoid receptor ⍺ in acute respiratory distress syndrome

Using an ex vivo model of systemic inflammation, a recent study investigated the intracellular upstream and downstream events associated with DNA-binding of NF-κB and GR⍺ in naive peripheral blood leukocytes (PBLs) stimulated with longitudinal plasma specimens obtained from 28 ARDS patients (most ARDS caused by sepsis) [23]. Intracellular and extracellular laboratory findings were correlated with physiological progression (resolving vs. unresolving) of ARDS in the first week of mechanical ventilation and after blind randomization to prolonged glucocorticoid treatment vs. placebo on day 9±3 of ARDS (described in the next section) [23, 56]. Exposure of naive cells to longitudinal plasma samples from the patients led to divergent directions in NF-κB and GR⍺ activation that reflected the severity of systemic inflammation (defined by plasma TNF-⍺ and IL-1β levels). Activation of one transcription factor in excess of the other shifted cellular responses toward decreased (GR⍺-driven) or increased (NF-κB-driven) transcription of inflammatory mediators over time [23].

Plasma samples from patients with declining inflammatory cytokine levels (regulated systemic inflammation) over time elicited a progressive increase in all measured aspects of GC-GR⍺-mediated activity (P =0.0001) and a corresponding reduction in NF-κB nuclear binding (P =0.0001) and transcription of TNF-⍺ and IL-1β [23]. In contrast, plasma samples from patients with sustained elevation in inflammatory cytokine levels elicited only modest longitudinal increases in GC-GR⍺-mediated activity (P =0.04) and a progressive increase in NF-κB nuclear binding over time (P =0.0001) that was most striking in non-survivors (dysregulated, NF-κB-driven response) [23]. These findings demonstrate that insufficient GC-GR⍺-mediated activity is an important mechanism for early loss of homeostatic autoregulation (i.e., down-regulation of NF-κB activation). The divergent directions in NF-κB and GR⍺ activation (Figure 4) in patients with regulated vs. dysregulated systemic inflammation places insufficient GC-GR⍺-mediated activity as an early crucial event leading to unchecked NF-κB activation [23]. Deficient GR⍺ activity in naive cells exposed to plasma from patients with dysregulated inflammation was observed despite elevated circulating cortisol and ACTH levels, implicating inflammatory cytokine-driven excess NF-κB activation as an important mechanism for target organ insensitivity (resistance) to cortisol [23]. The concept of inflammation-associated intracellular glucocorticoid resistance in sepsis and acute lung injury is supported by in vitro and animal studies (reviewed in references [59] and [60]). In vitro studies have shown that cytokines may induce – in a dose-dependent fashion – resistance to glucocorticoids by reducing GR⍺ binding affinity to cortisol and/or DNA glucocorticoid response elements [61, 62, 63]. Because glucocorticoid resistance is most frequently observed in patients with excessive inflammation, it remains unclear whether it is a primary phenomenon and/or whether the anti-inflammatory capacity of glucocorticoids is simply overwhelmed by an excessive synthesis of pro-inflammatory cytokines [64].



Figure 4


Figure 4. 

Longitudinal relation on natural logarithmic scales between mean levels of nuclear NF-κB and nuclear GR⍺: resolving vs. unresolving Acute respiratory distress syndrome (ARDS) (right) and after randomization to methylprednisolone vs. placebo

Left: plasma samples from patients with sustained elevation in cytokine levels over time elicited only a modest longitudinal increase in GC-GRκ-mediated activity (P =0.04) and a progressive significant (P =0.0001) increase in NF-κB nuclear binding over time (dysregulated, NF-κB-driven response). In contrast, in patients with regulated inflammation an inverse relationship was observed between these two transcription factors, with the longitudinal direction of the interaction shifting to the left (decreased NF-κB) and upward (increased GC-GR⍺). The first interaction is defined as NF-κB–driven (progressive increase in NF-κB-DNA binding and transcription of TNF-⍺ and IL-1β) and the second interaction as GR⍺-driven response (progressive increase in GR⍺-DNA binding and transcription of IL-10). Right: longitudinal relation on natural logarithmic scales between mean levels of nuclear NF-⍺B and nuclear GR⍺ observed by exposing naive PBL to plasma samples collected at randomization (rand) and after 3, 5, 7 and 10 days in the methylprednisolone (open squares) and placebo (open triangles) groups. With methylprednisolone, contrary to placebo, the intracellular relationship between the NF-κB and GR⍺ signaling pathways changed from an initial NF-κB-driven and GR-resistant state to a GR⍺-driven and GR-sensitive one. It is important to compare the two figures to appreciate how methylprednisolone supplementation restored the equilibrium between activation and suppression of inflammation that is distinctive of a regulated inflammatory response.

Zoom

The above findings are in agreement with two longitudinal studies that investigated NF-κB binding activity directly in the peripheral blood mononuclear cells of patients with sepsis or trauma (reviewed in reference [65]) [57, 58]. In both studies [57, 58], non-survivors, contrary to survivors, had a progressive increase in NF-κB activity over time. In one longitudinal study, non-survivors of septic shock had, by day 2 to 6, a 200% increase in NF-κB activity from day 1 [58]. Similarly, NF-κB binding activity on day 3 of ARDS clearly separated patients by outcome, providing an argument for early initiation of prolonged glucocorticoid treatment [23]. Degree of NF-κB and GR⍺ activation also affects histological progression of ARDS. In immunohistochemical analysis of lung tissue, lobules with histologically severe vs. mild fibroproliferation had higher nuclear uptake of NF-κB (13±1.3 vs. 7±2.9; P =0.01) and lower ratio of GR⍺:NF-κB nuclear uptake (0.5±0.2 vs.1.5±0.2; P =0.007) [23]. Thus, measurements in circulating and tissue cells have established that increased NF-κB activation over time is a significant premortem pathogenetic component of lethal sepsis and ARDS and that increased GC-GR⍺-mediated activity is required for NF-κB down-regulation.

Prolonged glucocorticoid treatment in ALI-ARDS: improves glucocorticoid resistance and decreases NF-κB-driven inflammation-coagulation-tissue repair

The above findings place GC-GR⍺-mediated down-regulation of NF-κB activity as a critical factor for the reestablishment of homeostasis during the acute, life-threatening systemic inflammation-associated with sepsis and ARDS [23]. In a randomized trial [66], longitudinal measurements of biomarkers provided compelling evidence that prolonged methylprednisolone treatment modifies, at the cellular level, the core pathogenetic mechanism (systemic inflammation-acquired GC resistance) of ARDS and positively affects the biology, histology and physiology of the disease process [65]. Normal blood leukocytes exposed to plasma samples collected during glucocorticoid vs. placebo treatment exhibited rapid, progressive and significant increases in GC-GR⍺-mediated activities (GR⍺ binding to NF-κB, GR⍺ binding to glucocorticoid response element [GRE] DNA, stimulation of inhibitory protein IκB⍺ and stimulation of IL-10 transcription) and significant reductions in NF-κB κb-DNA-binding (Figure 4) [4] and transcription of TNF-⍺ and IL-1β [56]. During glucocorticoid treatment, the relationship between NF-κB and GC-GR⍺ signaling pathways changed from an initial NF-κB-driven and GC-GR⍺-resistant state to a GC-GR⍺-driven and GC-GR⍺-sensitive one (Figure 4) [4, 56]. A prolonged glucocorticoid treatment-induced increase in GR nuclear translocation was also reported in polymorphonuclear leukocytes of patients with sepsis [67]. As shown in Table II, in ARDS, methylprednisolone treatment led to a rapid and sustained reduction in mean plasma and BAL levels of TNF-⍺, IL-1β, IL-6, IL-8, soluble intercellular adhesion molecule-1, IL-1 receptor antagonist (IL-1ra), soluble TNF receptor 1 and 2 and procollagen amino terminal propeptide type I and III and increases in IL-10 and anti-inflammatory to pro-inflammatory cytokine ratios (IL-1ra:IL-1β, IL-10:TNF-⍺, IL-10:IL-1β) compared to placebo [32, 35, 56, 68].

Taken together, these findings indicate that systemic inflammation-induced glucocorticoid resistance is an acquired, generalized process mediated by excess NF-κB activation and potentially reversible by increasing GC-GR⍺ activation with quantitatively adequate and prolonged glucocorticoid supplementation. During prolonged glucocorticoid treatment, reduction in inflammation, coagulation and fibroproliferation at the tissue level (Figure 2) was associated with a parallel improvement in pulmonary [31, 66, 69, 70, 71, 72, 73, 74] and extrapulmonary organ dysfunction scores [31, 66, 70, 71, 72, 74] and indices of ACM permeability [74, 75]. Importantly, the extent of biological improvement in markers of systemic and pulmonary inflammation demonstrated during prolonged methylprednisolone administration is superior (qualitatively and quantitatively) to any other investigated intervention in ARDS [65]. Experimental evidence supporting the use of prolonged glucocorticoid treatment in acute lung injury-ARDS was recently reviewed [76].

Dysregulated systemic inflammation and increased risk for nosocomial infections

ARDS patients with dysregulated systemic inflammation have a higher rate of nosocomial infections [77], partly due to the effect of elevated inflammatory cytokine levels on intracellular and extracellular bacterial growth [5]. While a moderate degree of local inflammation is required to control infection, excessive release of inflammatory cytokines favors bacterial proliferation and virulence following a U-shaped response. When freshly isolated bacteria (fresh isolates of Staphylococcus aureus, Pseudomonas aeruginosa and Acinetobacter sp.) obtained from patients with ARDS were exposed in vitro to a lower concentration (10pg to 250pg) of TNF–⍺, IL–1β, or IL–6 – similar to the plasma values detected in ARDS survivors – extracellular and intracellular bacterial growth was not promoted and human monocytic cells were efficient in killing the ingested bacteria [78, 79]. However, when bacteria were exposed to higher concentrations of pro-inflammatory cytokines, similar to those found in ARDS non-survivors, intracellular and extracellular bacterial growth was enhanced in a dose-dependent fashion [78, 79]. In separate parallel experiments, impairment in intracellular bacterial killing in activated monocytes correlated with the increased expression of pro-inflammatory cytokines, while restoration of monocyte killing function upon exposure to methylprednisolone coincided with the down-regulation of the expression of TNF–⍺, IL–1β and IL–6 [80]. These data indicate that down-regulation of excessive inflammation is important not only to accelerate disease resolution but also to decrease the risk for development of nosocomial infections.

Prolonged glucocorticoid treatment in ALI-ARDS: factors affecting response

Duration of treatment is an important determinant of both efficacy and toxicity [59]. Optimization of glucocorticoid treatment is affected by three factors: actual biological (not clinical) duration of the disease process (systemic inflammation and critical illness related corticosteroid insufficiency [CIRCI]), recovery time of the hypothalamic-pituitary-adrenal (HPA) axis after discontinuing treatment and, cumulative risk associated with prolonged treatment (risk) and the essential role of secondary prevention (risk reduction).

Longitudinal measurements of plasma and BAL inflammatory cytokine levels in ARDS showed that inflammation extends well beyond resolution of respiratory failure [22, 23, 27]. One uncontrolled study found that, despite prolonged methylprednisolone administration, local and systemic inflammation persisted for 14 days (limit of study) [75]. Similar findings were reported in a randomized controlled trial (RCT) for inflammatory mediators on day 10 of treatment [32, 56].

Prolonged glucocorticoid treatment is associated with down-regulation of glucocorticoid receptor levels and suppression of the HPA-axis (reviewed later), affecting systemic inflammation after discontinuing treatment. Experimental and clinical literature (reviewed in reference [81]) underscores the importance of continuing glucocorticoid treatment beyond clinical resolution of acute respiratory failure (extubation). In the recent ARDS network trial, methylprednisolone was removed within 3–4 days of extubation and likely contributed, as acknowledged by the authors, to the deterioration in Pa O2 :FI O2 ratio and higher rate of re-intubation and associated mortality [74, 81]. In two other ARDS trials [31, 66], glucocorticoid treatment was continued up to 18 days to maintain reduced inflammation [31, 66]. This prolonged glucocorticoid treatment was not associated with relapse of ARDS.

Table III shows potential complications masked by or associated with prolonged glucocorticoid treatment and secondary prevention measures [31, 66]. While the risk for infection and neuromuscular weakness is not increased during low-to-moderate dose prolonged glucocorticoid treatment (reviewed below), it is still very important to implement secondary prevention for the following reasons:

infection surveillance. Failed or delayed recognition of nosocomial infections in the presence of a blunted febrile response represents a serious threat to the recovery of patients receiving prolonged glucocorticoid treatment [59]. In two randomized trials [31, 66] that incorporated infection surveillance, nosocomial infections were frequently (56%) identified in the absence of fever. The infection surveillance protocol incorporated bronchoscopy with bilateral BAL at 5- to 7-day intervals in intubated patients (without contraindication) and a systematic diagnostic protocol when patients developed clinical and laboratory signs suggestive of infection in the absence of fever [82];
increased risk for neuromuscular weakness with neuromuscular blocking agents. The combination of glucocorticoids and neuromuscular blocking agents versus glucocorticoids alone significantly increases the risk for prolonged neuromuscular weakness [83]. For this reason, using neuromuscular blocking agents is strongly discouraged in patients receiving concomitant glucocorticoid treatment, particularly when other risk factors are present (sepsis, aminoglycosides, etc.);
glucocorticoid treatment can impair glycemic control. It is well established that exogenous glucocorticoids administered as a bolus produce hyperglycemic variability, an independent predictor of ICU and hospital mortality [84]. Two studies have shown that glucocorticoid infusion is superior to intermittent boluses in preventing glycemic variability by decreasing changes in insulin infusion rate [85, 86];
avoidance of rebound inflammation. There is ample evidence [35, 87, 88, 89, 90, 91, 92, 93, 94] that early removal of glucocorticoid treatment may lead to rebound inflammation and an exaggerated cytokine response to endotoxin [95]. Experimental work has shown that short-term exposure of alveolar macrophages [96] or animals to dexamethasone is followed by enhanced inflammatory cytokine response to endotoxin [97]. Similarly, normal human subjects pretreated with hydrocortisone had significantly higher TNF-⍺ and IL-6 response after endotoxin challenge compared to controls [98]. Two potential mechanisms may explain rebound inflammation: homologous down-regulation and GC-induced adrenal insufficiency. Glucocorticoid treatment down-regulates glucocorticoid receptor levels in most cell types, thereby decreasing the efficacy of the treatment. The mechanisms of homologous down-regulation have been reviewed elsewhere [99]. Down-regulation occurs at both the transcriptional and translational level and hormone treatment decreases receptor half-life by approximately 50% [99]. In experimental animals, overexpression of glucocorticoid receptors improves resistance to endotoxin-mediated septic shock, while glucocorticoid receptor blockade increases mortality [100]. No study (to the best of our knowledge) has investigated recovery of glucocorticoid receptor levels and function following prolonged glucocorticoid treatment in patients with sepsis or ARDS.

Prolonged glucocorticoid treatment in ALI-ARDS: effect on disease resolution and duration of mechanical ventilation

Eight controlled studies (five randomized and three concurrent case-controlled) have evaluated the effectiveness of prolonged glucocorticoid treatment in patients with early ALI-ARDS (N=314) [31, 72, 73] and late ARDS (N=314) [66, 69, 70, 71, 74] and were the subject of two recent meta-analyses (limited to studies that have investigated pronged treatment) [6, 81]. Table IV [4] shows dosage and duration of treatment, while Table V [4] shows important patient-centered outcome variables. These trials consistently reported that treatment-induced reduction in markers of systemic inflammation [31, 66, 69, 70, 71, 72, 73, 74] was associated with significant improvement in Pa O2 :FI O2 [31, 66, 69, 70, 71, 72, 73, 74] and a significant reduction in MODS score [31, 66, 70, 71, 72, 74] duration of mechanical ventilation, [31, 66, 72, 73, 74] and intensive care unit (ICU) length of stay (all with P values<0.05) [31, 66, 72, 74] These consistently reproducible findings [31, 66, 69, 70, 71, 72, 73, 74] provide additional support for a causal relationship between reduction in systemic inflammation and resolution of ARDS that is further reinforced by experimental and clinical data showing rebound inflammation following early removal of glucocorticoid treatment leads to recrudescence of ARDS that improves with re-institution of glucocorticoid therapy [35, 69, 87, 88, 89, 90, 91].

Four of the five randomized trials provided Kaplan Meier curves for continuation of mechanical ventilation; each showed a 2-fold or greater rate of extubation in the first 5 to 7 days of treatment compared to placebo [31, 66, 72, 74]. In the ARDS network trial, the treated group had – before discontinuation of treatment – a noteworthy 9.5 days’ reduction in duration of mechanical ventilation (14.1±1.7 vs. 23.6±2.9; P =0.006) and more patients discharged home after initial weaning (62% vs. 49%; P =0.006) [74]. As shown in Figure 5, analysis of randomized trials showed a sizable increase in the number of mechanical ventilation-free days (weighted mean difference, 6.58 days; 95% CI, 2.93–10.23; P <0.001) and ICU-free days to day 28 (weighted mean difference, 7.02 days; 95% CI 3.20–10.85; P <0.001), that is 3-fold greater than the one reported with low tidal volume ventilation (12±11 vs. 10±11; P =0.007) [101] or conservative strategy of fluid-management (14.6±0.5 vs. 12.1±0.5, P <0.001) [102]. The reduction in duration of mechanical ventilation and ICU length of stay is associated with a substantial reduction in health care expenditure [103]. While, recent meta-analyses (limited to prolonged treatment [6, 81] or incorporating both short and prolonged treatment [104, 105]) and reviews [106] have reached different conclusions on the quality of evidence supporting a survival benefit, all concur that the quality of evidence for reduction in duration of mechanical ventilation is moderate or strong.



Figure 5


Figure 5. 

Effects of prolonged glucocorticoid treatment on mechanical ventilation (top) and intensive care unit (bottom) -free days to day 28

Zoom

Prolonged glucocorticoid treatment in ALI-ARDS: effect on preventing development or progression of ALI-ARDS

Controlled trials have also prospectively evaluated the impact of early initiation of glucocorticoid treatment on preventing progression of the temporal continuum of systemic inflammation in patients with, or at risk for, ARDS [31, 72, 107, 108]. A prospective controlled study (N=72) found that the intraoperative intravenous administration of 250mg of methylprednisolone just before pulmonary artery ligation during pneumonectomy reduced the incidence of postsurgical ARDS (0% vs. 13.5%; P <0.05) and duration of hospital stay (6.1 days vs. 11.9 days, P =0.02) [107]. Early treatment with hydrocortisone in patients with severe community-acquired pneumonia prevented progression to septic shock (0% vs. 43%; P =0.001) and ARDS (0% vs. 17%; P =0.11) [72] and in patients with early ARDS, prolonged methylprednisolone treatment prevented progression to respiratory failure requiring mechanical ventilation (42% vs. 100%; P =0.02) [108] or progression to unresolving ARDS (8% vs. 36%; P =0.002) [31]. These results contrast with the negative findings of older trials investigating a time-limited (24–48h) massive daily dose of glucocorticoids [104].

Prolonged glucocorticoid treatment in ALI-ARDS: risk/benefits ratio

Treatment decisions involve a tradeoff between benefits and risks, as well as costs [109]. Side effects attributed to steroid treatment, such as an increased risk of infection and neuromuscular dysfunction, have partly tempered enthusiasm for their broader use in sepsis and ARDS [110]. In recent years, however, substantial evidence has accumulated showing that systemic inflammation is also implicated in the pathogenesis of these complications (Figure 3) [5, 29, 39], suggesting that down-regulation of systemic inflammation with prolonged low-to-moderate dose glucocorticoid treatment could theoretically prevent, or partly offset, their development and/or progression. As shown in Table V, glucocorticoid treatment was not associated with an increased rate of nosocomial infection. Contrary to older studies investigating a time-limited (24–48h) massive daily dose of glucocorticoids (methylprednisolone, up to 120mg/kg par day) [111, 112], recent trials have not reported an increased rate of nosocomial infections. Moreover, new cumulative evidence (reviewed in references [5, 113] indicates that, in ARDS and severe sepsis, down-regulation of life-threatening systemic inflammation with prolonged low-to-moderate dose glucocorticoid treatment improves innate immunity [93, 114] and provides an environment less favorable to the intra- and extracellular growth of bacteria (see above) [80, 115].

In three randomized trials, the rates of gastrointestinal bleeding were monitored and no difference between treatment and placebo groups was detected [31, 72, 73]. Increased risk of gastrointestinal bleeding has been associated with glucocorticoid doses greater than 250mg of hydrocortisone or equivalent [116, 117]. Though this association was reported in retrospective reviews, meta-analyses failed to correlate glucocorticoid use to increased rates of gastrointestinal bleeding in patients without other risk factors [118, 119]. For this reason current guidelines recommend patients on greater than 250mg hydrocortisone with at least one other minor risk factor for stress ulcers should receive stress ulcer prophylaxis with either a H2-receptor antagonist or a proton pump inhibitor [120]. Moreover, there is evidence that glucocorticoids may protect the gastrointestinal tract in patients with adrenal insufficiency deficiency, acute stress and sepsis [121, 122].

In the reviewed studies, the incidence of neuromuscular weakness was similar in the treatment and placebo groups (17% vs. 18%) [6]. Moveover, two recent publications found no association between prolonged glucocorticoid treatment and electrophysiologically or clinically proven neuromuscular dysfunction [123, 124]. Given that neuromuscular dysfunction is an independent predictor of prolonged weaning [125] and ARDS randomized trials have consistently reported a sizable and significant reduction in duration of mechanical ventilation [31, 66, 72, 73, 74], clinically relevant neuromuscular dysfunction caused by glucocorticoid or glucocorticoid-induced hyperglycemia is unlikely. The aggregate of these consistently reproducible findings shows that desirable effects (Table V) clearly outweigh undesirable effects and provide a strong (grade 1B) level of evidence that the sustained anti-inflammatory effect achieved during prolonged glucocorticoid treatment accelerates resolution of ARDS leading to earlier removal of mechanical ventilation. Importantly, the low cost of off-patent methylprednisolone, in the United States approximately $240 for 28 days of intravenous therapy [31], makes this treatment globally and equitably available.

Prolonged glucocorticoid treatment in ALI-ARDS: effect on mortality

Table V [4] shows mortality findings for each study. All but three controlled studies [69, 70, 74] showed a reduction in ICU or hospital mortality and, in one retrospective subgroup analysis, mortality benefits were limited to those with relative adrenal insufficiency [73]. In two of these studies, treatment was associated with significant early physiological improvement; however, rapid dosage reduction [70] or premature removal after extubation (as acknowledged by the authors) [74] may have affected final outcome (see below). The ARDS network trial reported that treated patients had a lower mortality (27% vs. 36%; P =0.14) when randomized before day 14 and an increased mortality when randomized after day 14 of ARDS (8% vs. 35%; P =0.01) [74]. The latter subgroup (n =48), however, had large differences in baseline characteristics and the mortality difference lost significance (P =0.57) when the analysis was adjusted for these imbalances [126].

As a result of the marked differences in study design and patient characteristics, the limited size of the studies (fewer than 200 patients), the cumulative mortality summary of these studies should be interpreted with some caution. Nevertheless, in the aggregate (N=628), absolute and relative reduction in mortality was substantial for all patients (16% and 31%) and for those treated before day 14 (19% and 35%). As shown in Figure 6, glucocorticoid treatment was associated with a marked reduction in the risk of death for all patients (RR=0.75, 95% CI: 0.63 to 0.89; P <0.001; I2 43%) and for those treated before day 14 (RR=0.71, 95% CI: 0.59 to 0.85; P <0.001; I2 40%). However, there was a moderate degree of heterogeneity across the studies, namely differences in timing for initiation, dosage, duration of treatment and tapering and study design. For this reason, a recent consensus statement recommended early initiation of prolonged glucocorticoid treatment for patients with severe ARDS (Pa O2 :FI O2 <200 on PEEP 10cmH2 O) and before day 14 for patients with unresolving ARDS (Table VI), grading as weak (grade 2b) the evidence for a survival benefit [52]. This recommendation is supported by recent reviews [8, 105]. While all meta-analyses [6, 81, 104, 105] and reviews [106] call for large clinical trial, there is a general lack of interest in funding this trial via public or private sources.



Figure 6


Figure 6. 

Effects of prolonged glucocorticoid treatment on acute respiratory distress syndrome (ARDS) survival

Zoom

Recommendations for treatment

We have reviewed data showing that the drug dosage, timing and duration of administration, weaning protocol and implementation of secondary preventive measures largely determine the benefit-risk of glucocorticoid treatment in ARDS. Table VI shows treatment regimens for early and unresolving ARDS. In agreement with a recent consensus statement from the American College of Critical Care Medicine [8], the results of one randomized trial in patients with early severe ARDS [31] indicates that 1mg/kg per day of methylprednisolone given as an infusion and tapered over 4 weeks is associated with a favorable risk-benefit profile when secondary preventive measures are implemented. For patients with unresolving ARDS, beneficial effects were shown for treatment (methylprednisolone 2mg/kg per day) initiated before day 14 of ARDS and continued for at least 2 weeks following extubation 8 [66, 74]. If treatment is initiated after day 14, there is no evidence of either benefit or harm [81, 126]. Treatment response should be monitored with daily measurement of LIS and multiple-organ dysfunction syndrome (MODS) scores and C-reactive protein level [31, 72].

Secondary prevention is important to minimize complications. Glucocorticoid treatment should be administered as a continuous infusion (while the patient is in ICU) to minimize glycemic variations [85, 86]. When given concurrently with glucocorticoids, two medications are strongly discourage and, when possible, should be avoided: neuromuscular blocking agents to minimize the risk of neuromuscular weakness [83] and etomidate that causes suppression of cortisol synthesis [127]. Glucocorticoid treatment blunts the febrile response; therefore, infection surveillance is essential to promptly identify and treat nosocomial infections. Finally, in agreement with a recent consensus statement from the American College of Critical Care Medicine [8], a slow glucocorticoid dosage reduction (9–12 days) after a complete course allows recovery of glucocorticoid receptors number and the HPA-axis, thereby reducing the risk of rebound inflammation. Laboratory evidence of physiological deterioration (i.e., worsening PaO2 :FiO2 ) associated with rebound inflammation (increased serum C-reactive protein) after the completion of glucocorticoid treatment may require its re-institution.

Disclosure of interest

the authors declare that they have no conflicts of interest concerning this article.

References

Katzenstein A.L., Bloor C.M., Leibow A.A. Diffuse alveolar damage: the role of oxygen, shock and related factors. A review Am J Pathol 1976 ;  85 (1) : 209-228
Jantz M.A., Sahn S.A. Corticosteroids in acute respiratory failure Am J Respir Crit Care Med 1999 ;  160 (4) : 1079-1100
Murray J.F., Matthay M.A., Luce J.M., Flick M.R. An expanded definition of the adult respiratory distress syndrome Am Rev Respir Dis 1988 ;  138 (3) : 720-723
Meduri G.U., Annane D., Chrousos G.P., Marik P.E., Sinclair S.E. Activation and regulation of systemic inflammation in ARDS: rationale for prolonged glucocorticoid therapy Chest 2009 ;  136 : 1631-1643 [cross-ref]
Meduri G.U. Clinical review: a paradigm shift: the bidirectional effect of inflammation on bacterial growth. Clinical implications for patients with acute respiratory distress syndrome Crit Care 2002 ;  6 (1) : 24-29
Tang B., Craig J., Eslick G., Seppelt I., McLean A. Use of corticosteroids in acute lung injury and acute respiratory distress syndrome: a systematic review and meta-analysis Crit Care Med 2009 ;  37 : 1594-1603 [cross-ref]
Burton T. Why cheap drugs that appear to halt fatal sepsis go unused  : Wall Street Journal (2002). 
Raoof S., Goulet K., Esan A., Hess D.R., Sessler C.N. Severe hypoxemic respiratory failure: part 2--nonventilatory strategies Chest 2010 ;  137 (6) : 1437-1448 [inter-ref]
Meduri G.U. The role of the host defence response in the progression and outcome of ARDS: pathophysiological correlations and response to glucocorticoid treatment Eur Respir J 1996 ;  9 (12) : 2650-2670 [cross-ref]
Dantzer R., Kelley K.W. Twenty years of research on cytokine-induced sickness behavior Brain Behav Immun 2007 ;  21 (2) : 153-160 [cross-ref]
Elenkov I.J., Iezzoni D.G., Daly A., Harris A.G., Chrousos G.P. Cytokine dysregulation, inflammation and well-being Neuroimmunomodulation 2005 ;  12 (5) : 255-269 [cross-ref]
Imai Y., Parodo J., Kajikawa O., de Perrot M., Fischer S., Edwards V., and al. Injurious mechanical ventilation and end-organ epithelial cell apoptosis and organ dysfunction in an experimental model of acute respiratory distress syndrome JAMA 2003 ;  289 (16) : 2104-2112 [cross-ref]
Ranieri V.M., Giunta F., Suter P.M., Slutsky A.S. Mechanical ventilation as a mediator of multisystem organ failure in acute respiratory distress syndrome JAMA 2000 ;  284 (1) : 43-44 [cross-ref]
Suffredini A.F., Fantuzzi G., Badolato R., Oppenheim J.J., O’Grady N.P. New insights into the biology of the acute-phase response J Clin Immunol 1999 ;  19 (4) : 203-214 [cross-ref]
Englert J.A., Fink M.P. The multiple-organ dysfunction syndrome and late-phase mortality in sepsis Curr Infect Dis Rep 2005 ;  7 (5) : 335-341 [cross-ref]
Mizgerd J.P. Acute lower respiratory tract infection N Engl J Med 2008 ;  358 (7) : 716-727 [cross-ref]
Rhen T., Cidlowski J.A. Anti-inflammatory action of glucocorticoids. new mechanisms for old drugs N Engl J Med 2005 ;  353 (16) : 1711-1723 [cross-ref]
Hudson L.D., Milberg J.A., Anardi D., Maunder R.J. Clinical risks for development of the acute respiratory distress syndrome Am J Respir Crit Care Med 1995 ;  151 (2 Pt 1) : 293-301
Steinberg K.P., Hudson L.D. Acute lung injury and acute respiratory distress syndrome. The clinical syndrome Clin Chest Med 2000 ;  21 (3) : 401-417vii.  [inter-ref]
Ashbaugh D.G., Bigelow D.B., Petty T.L., Levine B.E. Acute respiratory distress in adults Lancet 1967 ;  2 (7511) : 319-323 [cross-ref]
Cotran R.S., Kumar V., Robbins S.L. Cellular injury and cellular death Pathologic basis of disease Philadelphia: W. B. Saunders (1994).  p. 1–34.
Meduri G.U., Headley S., Kohler G., Stentz F., Tolley E., Umberger R., and al. Persistent elevation of inflammatory cytokines predicts a poor outcome in ARDS. Plasma IL-1 beta and IL-6 levels are consistent and efficient predictors of outcome over time Chest 1995 ;  107 (4) : 1062-1673 [cross-ref]
Meduri G.U., Muthiah M.P., Carratu P., Eltorky M., Chrousos G.P. Nuclear factor-kappaB- and glucocorticoid receptor alpha- mediated mechanisms in the regulation of systemic and pulmonary inflammation during sepsis and acute respiratory distress syndrome. Evidence for inflammation-induced target tissue resistance to glucocorticoids Neuroimmunomodulation 2005 ;  12 (6) : 321-338 [cross-ref]
Roumen R.M., Hendriks T., van der Ven-Jongekrijg J., Nieuwenhuijzen G.A., Sauerwein R.W., van der Meer J.W., and al. Cytokine patterns in patients after major vascular surgery, hemorrhagic shock and severe blunt trauma. Relation with subsequent adult respiratory distress syndrome and multiple-organ failure Ann Surg 1993 ;  218 (6) : 769-776 [cross-ref]
Romaschin A.D., DeMajo W.C., Winton T., D’Costa M., Chang G., Rubin B., and al. Systemic phospholipase A2 and cachectin levels in adult respiratory distress syndrome and multiple-organ failure Clin Biochem 1992 ;  25 (1) : 55-60 [cross-ref]
Groeneveld A.B., Raijmakers P.G., Hack C.E., Thijs L.G. Interleukin 8-related neutrophil elastase and the severity of the adult respiratory distress syndrome Cytokine 1995 ;  7 (7) : 746-752
Meduri G.U., Kohler G., Headley S., Tolley E., Stentz F., Postlethwaite A. Inflammatory cytokines in the BAL of patients with ARDS. Persistent elevation over time predicts poor outcome Chest 1995 ;  108 (5) : 1303-1314 [cross-ref]
Baughman R.P., Gunther K.L., Rashkin M.C., Keeton D.A., Pattishall E.N. Changes in the inflammatory response of the lung during acute respiratory distress syndrome: prognostic indicators Am J Respir Crit Care Med 1996 ;  154 (1) : 76-81
Headley A.S., Tolley E., Meduri G.U. Infections and the inflammatory response in acute respiratory distress syndrome Chest 1997 ;  111 (5) : 1306-1321 [cross-ref]
Parsons P.E., Eisner M.D., Thompson B.T., Matthay M.A., Ancukiewicz M., Bernard G.R., and al. Lower tidal volume ventilation and plasma cytokine markers of inflammation in patients with acute lung injury Crit Care Med 2005 ;  33 (1) : 1-6[discussion 230–232].  [cross-ref]
Meduri G.U., Golden E., Freire A.X., Taylor E., Zaman M., Carson S.J., and al. Methylprednisolone infusion in early severe ARDS: results of a randomized controlled trial Chest 2007 ;  131 : 954-963 [cross-ref]
Sinclair S.E., Bijoy J., Golden E., Carratu P., Umberger R., Meduri G.U. Interleukin-8 and soluble intercellular adhesion molecule-1 during acute respiratory distress syndrome and in response to prolonged methylprednisolone treatment Minerva Pneumologica 2006 ;  45 (2) : 93-104
Steinberg K.P., Milberg J.A., Martin T.R., Maunder R.J., Cockrill B.A., Hudson L.D. Evolution of bronchoalveolar cell populations in the adult respiratory distress syndrome Am J Respir Crit Care Med 1994 ;  150 (1) : 113-122
Gunther K., Baughman R.P., Rashkin M., Pattishall E. Bronchoalveolar lavage results in patients with sepsis-induced adult respiratory distress syndrome: evaluation of mortality and inflammatory response Amer Rev Respir Dis 1993 ;  147 : A346
Meduri G.U., Tolley E.A., Chinn A., Stentz F., Postlethwaite A. Procollagen types I and III aminoterminal propeptide levels during acute respiratory distress syndrome and in response to methylprednisolone treatment Am J Respir Crit Care Med 1998 ;  158 (5 Pt 1) : 1432-1441
Andrews C.P., Coalson J.J., Smith J.D., Johanson W.G. Diagnosis of nosocomial bacterial pneumonia in acute, diffuse lung injury Chest 1981 ;  80 (3) : 254-258 [cross-ref]
Meduri G.U., Belenchia J.M., Estes R.J., Wunderink R.G., el Torky M., Leeper K.V. Fibroproliferative phase of ARDS. Clinical findings and effects of corticosteroids Chest 1991 ;  100 (4) : 943-952 [cross-ref]
Raghavan M., Marik P.E. Stress hyperglycemia and adrenal insufficiency in the critically ill Semin Respir Crit Care Med 2006 ;  27 (3) : 274-285 [cross-ref]
Pustavoitau A., Stevens R.D. Mechanisms of neurologic failure in critical illness Crit Care Clin 2008 ;  24 (1) : 1-24vii.  [inter-ref]
von Kanel R., Hepp U., Kraemer B., Traber R., Keel M., Mica L., and al. Evidence for low-grade systemic pro-inflammatory activity in patients with posttraumatic stress disorder J Psychiatr Res 2007 ;  41 (9) : 744-752 [cross-ref]
El Gamal A., Aleech Y., Umberger R., Meduri G. Sudden cardiac arrest is a leading cause of death in patients with ASCVD admitted to the ICU with acute systemic inflammation Chest 2008 ;  134 : e587
Bachofen A., Weibel E.R. Alterations of the gas exchange apparatus in adult respiratory insufficiency associated with septicemia Am Rev Respir Dis 1977 ;  116 (4) : 589-615
Meduri G.U., Eltorky M., Winer-Muram H.T. The fibroproliferative phase of late adult respiratory distress syndrome Semin Respir Infect 1995 ;  10 (3) : 154-175
Cordier J.F., Peyrol S., Loire R. Bronchiolitis obliterans organizing pneumonia as a model of inflammatory lung disease Diseases of the Bronchioles New York: Raven Press Ltd (1994).  p 313–45.
Galon J., Franchimont D., Hiroi N., Frey G., Boettner A., Ehrhart-Bornstein M., and al. Gene profiling reveals unknown enhancing and suppressive actions of glucocorticoids on immune cells Faseb J 2002 ;  16 (1) : 61-71 [cross-ref]
Ehrchen J., Steinmuller L., Barczyk K., Tenbrock K., Nacken W., Eisenacher M., and al. Glucocorticoids induce differentiation of a specifically activated, anti-inflammatory subtype of human monocytes Blood 2007 ;  109 (3) : 1265-1274
Mastorakos G., Bamberger C., Chrousos G.P. Neuroendocrine regulation of the immune process Cytokines: stress and immunity Boca Raton: FL: CRC Press (1999).  p. 17–37.
Barnes P.J., Adcock I.M. Glucocorticoids receptors The lung scientific foundations Philadelphis: Lippincott-Raven (1997).  p. 37–55.
Baeuerle P.A., Baltimore D. Activation of DNA-binding activity in an apparently cytoplasmic precursor of the NF-kappa B transcription factor Cell 1988 ;  53 (2) : 211-217 [cross-ref]
Fan J., Ye R.D., Malik A.B. Transcriptional mechanisms of acute lung injury Am J Physiol Lung Cell Mol Physiol 2001 ;  281 (5) : L1037-L1050
Liu S.F., Malik A.B. NF-kappa B activation as a pathological mechanism of septic shock and inflammation Am J Physiol Lung Cell Mol Physiol 2006 ;  290 (4) : L622-L645
Marik P.E., Pastores S., Annane D., Meduri G., Sprung C., Arlt W., and al. Clinical practice guidelines for the diagnosis and management of corticosteroid insufficiency in critical illness: Recommendations of an international task force Crit Care Med 2008 ;  36 : 1937-1949 [inter-ref]
Hermus A.R., Sweep C.G. Cytokines and the hypothalamic-pituitary-adrenal axis J Steroid Biochem Mol Biol 1990 ;  37 (6) : 867-871 [cross-ref]
Perlstein R.S., Whitnall M.H., Abrams J.S., Mougey E.H., Neta R. Synergistic roles of interleukin-6, interleukin-1 and tumor necrosis factor in the adrenocorticotropin response to bacterial lipopolysaccharide in vivo Endocrinology 1993 ;  132 (3) : 946-952 [cross-ref]
Munck A., Guyre P.M., Holbrook N.J. Physiological functions of glucocorticoids in stress and their relation to pharmacological actions Endocr Rev 1984 ;  5 (1) : 25-44 [cross-ref]
Meduri G.U., Tolley E.A., Chrousos G.P., Stentz F. Prolonged methylprednisolone treatment suppresses systemic inflammation in patients with unresolving acute respiratory distress syndrome. Evidence for inadequate endogenous glucocorticoid secretion and inflammation-induced immune cell resistance to glucocorticoids Am J Respir Crit Care Med 2002 ;  165 (7) : 983-991
Bohrer H., Qiu F., Zimmermann T., Zhang Y., Jllmer T., Mannel D., and al. Role of NF-kappa B in the mortality of sepsis J Clin Invest 1997 ;  100 (5) : 972-985 [cross-ref]
Paterson R.L., Galley H.F., Dhillon J.K., Webster N.R. Increased nuclear factor-kB activation in critically ill patients who die Crit Care Med 2000 ;  28 (4) : 1047-1051 [cross-ref]
Meduri G.U. An historical review of glucocorticoid treatment in Sepsis. Disease pathophysiology and the design of treatment investigation Sepsis 1999 ;  3 : 21-38 [cross-ref]
Annane D., Bellissant E., Bollaert P.E., Briegel J., Keh D., Kupfer Y. Corticosteroids for treating severe sepsis and septic shock Cochrane Database Syst Rev 2004 ; CD002243
Almawi W.Y., Lipman M.L., Stevens A.C., Zanker B., Hadro E.T., Strom T.B. Abrogation of glucocorticoid-mediated inhibition of T cell proliferation by the synergistic action of IL-1, IL-6 and IFN-gamma J Immunol 1991 ;  146 (10) : 3523-3527
Kam J.C., Szefler S.J., Surs W., Sher E.R., Leung D.Y. Combination IL-2 and IL-4 reduces glucocorticoid receptor-binding affinity and T cell response to glucocorticoids J Immunol 1993 ;  151 (7) : 3460-3466
Spahn J.D., Szefler S.J., Surs W., Doherty D.E., Nimmagadda S.R., Leung D.Y. A novel action of IL-13: induction of diminished monocyte glucocorticoid receptor-binding affinity J Immunol 1996 ;  157 (6) : 2654-2659
Farrell R.J., Kelleher D. Glucocorticoid resistance in inflammatory bowel disease J Endocrinol 2003 ;  178 (3) : 339-346 [cross-ref]
Meduri G.U., Yates C.R. Systemic inflammation-associated glucocorticoid resistance and outcome of ARDS Ann N Y Acad Sci 2004 ;  1024 : 24-53 [cross-ref]
Meduri G.U., Headley S., Golden E., Carson S., Umberger R., Kelso T., and al. Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome. A randomized controlled trial JAMA 1998 ;  280 : 159-165 [cross-ref]
Nakamori Y., Ogura H., Koh T., Fujita K., Tanaka H., Sumi Y., and al. The balance between expression of intranuclear NF-kappaB and glucocorticoid receptor in polymorphonuclear leukocytes in SIRS patients J Trauma 2005 ;  59 (2) : 308-314[discussion 14–15].
Headley A.S., Meduri G.U., Tolley E., Stentz F. Infections, SIRS and CARS during ARDS and in response to prolonged glucocorticoid treatment (Abstract) Am J Respir Crit Care Med 2000 ;  161 : A378
Keel J.B., Hauser M., Stocker R., Baumann P.C., Speich R. Established acute respiratory distress syndrome: benefit of corticosteroid rescue therapy Respiration 1998 ;  65 (4) : 258-264 [cross-ref]
Varpula T., Pettila V., Rintala E., Takkunen O., Valtonen V. Late steroid therapy in primary acute lung injury Intensive Care Med 2000 ;  26 (5) : 526-531 [cross-ref]
Huh J., Lim C., Jegal Y., Le S., Kim W., Kim D., and al. The effect of steroid therapy in patients with late ARDS Tuberc Res Dis 2002 ;  52 : 376-384
Confalonieri M., Urbino R., Potena A., Piattella M., Parigi P., Puccio G., and al. Hydrocortisone infusion for severe community-acquired pneumonia: a preliminary randomized study Am J Respir Crit Care Med 2005 ;  171 (3) : 242-248
Annane D., Sebille V., Bellissant E. Effect of low doses of corticosteroids in septic shock patients with or without early acute respiratory distress syndrome Crit Care Med 2006 ;  34 (1) : 22-30 [inter-ref]
Steinberg K.P., Hudson L.D., Goodman R.B., Hough C.L., Lanken P.N., Hyzy R., and al. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome N Engl J Med 2006 ;  354 (16) : 1671-1684
Meduri G.U., Headley S., Tolley E., Shelby M., Stentz F., Postlethwaite A. Plasma and BAL cytokine response to corticosteroid rescue treatment in late ARDS Chest 1995 ;  108 (5) : 1315-1325 [cross-ref]
Fernandes A.B., Zin W.A., Rocco P.R. Corticosteroids in acute respiratory distress syndrome Braz J Med Biol Res 2005 ;  38 (2) : 147-159
Headley A.S., Meduri G.U., Tolley E., Belenchia J., Umberger R., Crouse D. Infections and the compensatory anti-inflammatory response during ARDS: Plasma and BAL levels of TGF-b, IL-1ra and sTNFR’s Chest 1997 ;  112 : 56S
Meduri G.U., Kanangat S., Stefan J., Tolley E., Schaberg S. Cytokines IL-1beta, IL-6 and TNF-alpha enhance in vitro growth of bacteria Am J Respir Crit Care Med 1999 ;  160 : 961-967
Kanangat S., Meduri G.U., Tolley E.A., Patterson D.R., Meduri C.U., Pak C., and al. Effects of cytokines and endotoxin on the intracellular growth of bacteria Infect Immun 1999 ;  67 (6) : 2834-2840
Meduri G.U., Kanangat S., Bronze M.S., Patterson D., Meduri C.U., Pak C., and al. Effects of methylprednisolone on intracellular bacterial growth Clin Diagn Lab Immunol 2001 ;  8 (6) : 1156-1163 [cross-ref]
Meduri G.U., Marik P.E., Chrousos G.P., Pastores S.M., Arlt W., Beishuizen A., and al. Steroid treatment in ARDS: a critical appraisal of the ARDS network trial and the recent literature Intensive Care Med 2008 ;  34 (1) : 61-69 [cross-ref]
Meduri G.U., Mauldin G.L., Wunderink R.G., Leeper K.V., Jones C.B., Tolley E., and al. Causes of fever and pulmonary densities in patients with clinical manifestations of ventilator-associated pneumonia Chest 1994 ;  106 (1) : 221-235 [cross-ref]
Leatherman J.W., Fluegel W.L., David W.S., Davies S.F., Iber C. Muscle weakness in mechanically ventilated patients with severe asthma Am J Respir Crit Care Med 1996 ;  153 (5) : 1686-1690
Egi M., Bellomo R., Stachowski E., French C.J., Hart G. Variability of blood glucose concentration and short-term mortality in critically ill patients Anesthesiology 2006 ;  105 (2) : 244-252 [inter-ref]
Weber-Carstens S., Keh D. Bolus or continuous hydrocortisone: that is the question Crit Care 2007 ;  11 (1) : 113 [cross-ref]
Loisa P., Parviainen I., Tenhunen J., Hovilehto S., Ruokonen E. Effect of mode of hydrocortisone administration on glycemic control in patients with septic shock: a prospective randomized trial Crit Care 2007 ;  11 (1) : R21
Hesterberg T.W., Last J.A. Ozone-induced acute pulmonary fibrosis in rats. Prevention of increased rates of collagen synthesis by methylprednisolone Am Rev Respir Dis 1981 ;  123 (1) : 47-52
Hakkinen P.J., Schmoyer R.L., Witschi H.P. Potentiation of butylated-hydroxytoluene-induced acute lung damage by oxygen. Effects of prednisolone and indomethacin Am Rev Respir Dis 1983 ;  128 (4) : 648-651
Kehrer J.P., Klein-Szanto A.J., Sorensen E.M., Pearlman R., Rosner M.H. Enhanced acute lung damage following corticosteroid treatment Am Rev Respir Dis 1984 ;  130 (2) : 256-261
Ashbaugh D.G., Maier R.V. Idiopathic pulmonary fibrosis in adult respiratory distress syndrome. Diagnosis and treatment Arch Surg 1985 ;  120 (5) : 530-535
Hooper R.G., Kearl R.A. Established ARDS treated with a sustained course of adrenocortical steroids Chest 1990 ;  97 (1) : 138-143 [cross-ref]
Briegel J., Jochum M., Gippner-Steppert C., Thiel M. Immunomodulation in septic shock: hydrocortisone differentially regulates cytokine responses J Am Soc Nephrol 2001 ;  12 (Suppl. 17) : S70-S74
Keh D.B.T., Weber-Cartens S., Schulz C., Ahlers O., Bercker S., Volk H.D., Doecke W.D., Falke K.J., Gerlach H. Immunologic and hemodynamic effects of “low-dose” hydrocortisone in septic shock: a double-blind, randomized, placebo-controlled, crossover study Am J Respir Crit Care Med 2003 ;  167 (4) : 512-520 [cross-ref]
Nawab Q., Golden E., Confalonieri M., Umberger R., Meduri G. Glucocorticoid treatment in severe community-acquired pneumonia Am J Respir Crit Care Med 2007 ;  175 : A594
Barber A.E., Coyle S.M., Fischer E., Smith C., van der Poll T., Shires G.T., and al. Influence of hypercortisolemia on soluble tumor necrosis factor receptor II and interleukin-1 receptor antagonist responses to endotoxin in human beings Surgery 1995 ;  118 (2) : 406-410[discussion 10-11].
Broug-Holub E.KG. Dose- and time-dependent activation of rat alveolar macrophages by glucocorticoids Clin Exp Immunol 1996 ;  104 (2) : 332-336
Fantuzzi G., Demitri M.T., Ghezzi P. Differential effect of glucocorticoids on tumour necrosis factor production in mice: up-regulation by early pretreatment with dexamethasone Clin Exp Immunol 1994 ;  96 (1) : 166-169
Barber A.E., Coyle S.M., Marano M.A., Fischer E., Calvano S.E., Fong Y., and al. Glucocorticoid therapy alters hormonal and cytokine responses to endotoxin in man J Immunol 1993 ;  150 (5) : 1999-2006
Schaaf M.J., Cidlowski J.A. Molecular mechanisms of glucocorticoid action and resistance J Steroid Biochem Mol Biol 2002 ;  83 (1–5) : 37-48 [cross-ref]
Cooper M.S., Stewart P.M. Adrenal insufficiency in critical illness J Intensive Care Med 2007 ;  22 (6) : 348-362 [cross-ref]
Brower G., Matthay M. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The acute respiratory distress syndrome network N Engl J Med 2000 ;  342 (18) : 1301-1308
Wiedemann H.P., Wheeler A.P., Bernard G.R., Thompson B.T., Hayden D., deBoisblanc B., and al. Comparison of two fluid-management strategies in acute lung injury N Engl J Med 2006 ;  354 (24) : 2564-2575
Umberger R., Headley A.S., Waters T., Tolley E., Stentz F., Golden E., and al. Cost-effectiveness of methylprednisolone treatment in unreolving ARDS (Abstract) Am J Respir Crit Care Med 2002 ;  165 : A22
Peter J.V., John P., Graham P.L., Moran J.L., George I.A., Bersten A. Corticosteroids in the prevention and treatment of acute respiratory distress syndrome (ARDS) in adults: meta-analysis BMJ 2008 ;  336 (7651) : 1006-1009 [cross-ref]
Lamontagne F., Briel M., Guyatt G.H., Cook D.J., Bhatnagar N., Meade M. Corticosteroid therapy for acute lung injury, acute respiratory distress syndrome and severe pneumonia: a meta-analysis of randomized controlled trials J Crit Care 2010 ;  25 (3) : 420-435 [cross-ref]
Sessler C.N., Gay P.C. Are corticosteroids useful in late-stage acute respiratory distress syndrome? Respir Care 2010 ;  55 (1) : 43-55
Cerfolio R.J., Bryant A.S., Thurber J.S., Bass C.S., Lell W.A., Bartolucci A.A. Intraoperative solumedrol helps prevent postpneumonectomy pulmonary edema Ann Thorac Surg 2003 ;  76 (4) : 1029-1033[discussion 33–35].  [cross-ref]
Lee H.S., Lee J.M., Kim M.S., Kim H.Y., Hwangbo B., Zo J.I. Low-dose steroid therapy at an early phase of postoperative acute respiratory distress syndrome Ann Thorac Surg 2005 ;  79 (2) : 405-410 [cross-ref]
Guyatt G., Gutterman D., Baumann M.H., Addrizzo-Harris D., Hylek E.M., Phillips B., and al. Grading strength of recommendations and quality of evidence in clinical guidelines: report from an american college of chest physicians task force Chest 2006 ;  129 (1) : 174-181 [cross-ref]
Dellinger R.P., Levy M.M., Carlet J.M., Bion J., Parker M.M., Jaeschke R., and al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008 Intensive Care Med 2008 ;  34 (1) : 17-60 [cross-ref]
Weigelt J.A., Norcross J.F., Borman K.R., Snyder W.H.D. Early steroid therapy for respiratory failure Arch Surg 1985 ;  120 (5) : 536-540
Bernard G.R., Luce J.M., Sprung C.L., Rinaldo J.E., Tate R.M., Sibbald W.J., and al. High-dose corticosteroids in patients with the adult respiratory distress syndrome N Engl J Med 1987 ;  317 (25) : 1565-1570 [cross-ref]
Meduri G., Marik P., Annane D. Prolonged glucocorticoid treatment in ARDS: evidence supporting effectiveness and safety Critical Care Medicine 2009 ;  37 : 1800-1803 [cross-ref]
Kaufmann I., Briegel J., Schliephake F., Hoelzl A., Chouker A., Hummel T., and al. Stress doses of hydrocortisone in septic shock: beneficial effects on opsonization-dependent neutrophil functions Intensive Care Med 2008 ;  34 (2) : 344-349 [cross-ref]
Sibila O., Luna C., Agustí C., Baquero S., Garcia-Morato J., Rano A., and al. Effects of corticosteroids an animal model of ventilator-associated pneumonia Proc Am Thorac Soc 2006 ;  3 : A21
Estruch R., Pedrol E., Castells A., Masanes F., Marrades R.M., Urbano-Marquez A. Prophylaxis of gastrointestinal tract bleeding with magaldrate in patients admitted to a general hospital ward Scand J Gastroenterol 1991 ;  26 (8) : 819-826 [cross-ref]
Ben-Menachem T., Fogel R., Patel R.V., Touchette M., Zarowitz B.J., Hadzijahic N., and al. Prophylaxis for stress-related gastric hemorrhage in the medical intensive care unit. A randomized, controlled, single-blind study Ann Intern Med 1994 ;  121 (8) : 568-575
Cook D.J., Witt L.G., Cook R.J., Guyatt G.H. Stress ulcer prophylaxis in the critically ill: a meta-analysis Am J Med 1991 ;  91 (5) : 519-527 [cross-ref]
Cook D.J., Fuller H.D., Guyatt G.H., Marshall J.C., Leasa D., Hall R., and al. Risk factors for gastrointestinal bleeding in critically ill patients. Canadian Critical Care Trials Group N Engl J Med 1994 ;  330 (6) : 377-381 [cross-ref]
ASHP Therapeutic Guidelines on Stress Ulcer Prophylaxis. ASHP Commission on Therapeutics and approved by the ASHP Board of Directors on November 14 1998. Am J Health Syst Pharm 1999; 56(4):347–79.
Matsumoto T., Kaibara N., Sugimachi K., Kawarada Y. Pathophysiology and management of acute gastric mucosal hemorrhage Jpn J Surg 1978 ;  8 (4) : 261-269 [cross-ref]
Filaretova L., Podvigina T., Bagaeva T., Bobryshev P., Takeuchi K. Gastroprotective role of glucocorticoid hormones J Pharmacol Sci 2007 ;  104 (3) : 195-201 [cross-ref]
Stevens R.D., Dowdy D.W., Michaels R.K., Mendez-Tellez P.A., Pronovost P.J., Needham D.M. Neuromuscular dysfunction acquired in critical illness: a systematic review Intensive Care Med 2007 ;  33 (11) : 1876-1891 [cross-ref]
Hough C.L., Steinberg K.P., Taylor Thompson B., Rubenfeld G.D., Hudson L.D. Intensive care unit-acquired neuromyopathy and corticosteroids in survivors of persistent ARDS Intensive Care Med 2009 ;  35 (1) : 63-68 [cross-ref]
De Jonghe B., Bastuji-Garin S., Sharshar T., Outin H., Brochard L. Does ICU-acquired paresis lengthen weaning from mechanical ventilation? Intensive Care Med 2004 ;  30 (6) : 1117-1121 [cross-ref]
Thompson B.T., Ancukiewicz M., Hudson L.D., Steinberg K.P., Bernard G.R. Steroid treatment for persistent ARDS: a word of caution Crit Care 2007 ;  11 (6) : 425 [cross-ref]
Cuthbertson B.H., Sprung C.L., Annane D., Chevret S., Garfield M., Goodman S., and al. The effects of etomidate on adrenal responsiveness and mortality in patients with septic shock Intensive Care Med 2009 ;  35 (11) : 1868-1876 [cross-ref]
Whitted A.D., Stanifer J.W., Dube P., Borkowski B.J., Yusuf J., Komolafe B.O., and al. A dyshomeostasis of electrolytes and trace elements in acute stressor states: impact on the heart Am J Med Sci 2010 ;  340 (1) : 48-53 [cross-ref]
Meduri G.U., Muthiah P., Carratu P., El Torky M. Activation and regulation of systemic inflammation during acute respiratory distress syndrome. Interaction between nuclear factor-kB and glucocorticoid receptors and its effect on the transcription of inflammatory cytokines Neurol Immunol Modulation 2005 ;  12 (6) : 321-338 [cross-ref]
Meduri G.U., Rocco P.R., Annane D., Sinclair S.E. Prolonged glucocorticoid treatment and secondary prevention in acute respiratory distress syndrome Expert Rev Respir Med 2010 ;  4 (2) : 201-210 [cross-ref]



© 2011  Published by Elsevier Masson SAS.
EM-CONSULTE.COM is registrered at the CNIL, déclaration n° 1286925.
As per the Law relating to information storage and personal integrity, you have the right to oppose (art 26 of that law), access (art 34 of that law) and rectify (art 36 of that law) your personal data. You may thus request that your data, should it be inaccurate, incomplete, unclear, outdated, not be used or stored, be corrected, clarified, updated or deleted.
Personal information regarding our website's visitors, including their identity, is confidential.
The owners of this website hereby guarantee to respect the legal confidentiality conditions, applicable in France, and not to disclose this data to third parties.
Close
Article Outline