Guidelines for the Diagnosis and Management of Critical Illness-Related Corticosteroid Insufficiency (CIRCI) in Critically Ill Patients (Part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017

Annane, Djillali; Pastores, Stephen M.; Rochwerg, Bram; Arlt, Wiebke; Balk, R.A.; Beishuizen, Albertus; Briegel, Josef; Carcillo, Joseph A.; Christ‐Crain, Mirjam; Cooper, Mark S.; Marik, Paul E.; Meduri, G. Umberto; Olsen, Keith M.; Rodgers, Sophia C.; Russell, James A.; Berghe, Greet Van den

doi:10.1097/ccm.0000000000002737

Cited by 247 publications

(217 citation statements)

References 56 publications

(34 reference statements)

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“…Pharmacokinetics and pharmacodynamics of systemically administered glucocorticoids are reviewed in reference (314). Hydrocortisone and methylprednisolone are the two glucocorticoids most often investigated in critical care RCTs (315). In the past, different exogenous glucocorticoids were thought to be qualitatively indistinguishable from each other because they act via the same glucocorticoid receptor, however, qualitative differences have been recently discovered, and one glucocorticoid cannot be simply replaced by another (314).…”

Section: Conclusion and Implications For Glucocorticoid Treatmentmentioning

confidence: 99%

General Adaptation in Critical Illness: Glucocorticoid Receptor-alpha Master Regulator of Homeostatic Corrections

Meduri

Chrousos

2020

Front. Endocrinol.

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In critical illness, homeostatic corrections representing the culmination of hundreds of millions of years of evolution, are modulated by the activated glucocorticoid receptor alpha (GRα) and are associated with an enormous bioenergetic and metabolic cost. Appreciation of how homeostatic corrections work and how they evolved provides a conceptual framework to understand the complex pathobiology of critical illness. Emerging literature place the activated GRα at the center of all phases of disease development and resolution, including activation and re-enforcement of innate immunity, downregulation of pro-inflammatory transcription factors, and restoration of anatomy and function. By the time critically ill patients necessitate vital organ support for survival, they have reached near exhaustion or exhaustion of neuroendocrine homeostatic compensation, cell bio-energetic and adaptation functions, and reserves of vital micronutrients. We review how critical illness-related corticosteroid insufficiency, mitochondrial dysfunction/damage, and hypovitaminosis collectively interact to accelerate an anti-homeostatic active process of natural selection. Importantly, the allostatic overload imposed by these homeostatic corrections impacts negatively on both acute and long-term morbidity and mortality. Since the bioenergetic and metabolic reserves to support homeostatic corrections are time-limited, early interventions should be directed at increasing GRα and mitochondria number and function. Present understanding of the activated GC-GRα's role in immunomodulation and disease resolution should be taken into account when re-evaluating how to administer glucocorticoid treatment and co-interventions to improve cellular responsiveness. The activated GRα interdependence with functional mitochondria and three vitamin reserves (B1, C, and D) provides a rationale for co-interventions that include prolonged glucocorticoid treatment in association with rapid correction of hypovitaminosis.

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Section: Conclusion and Implications For Glucocorticoid Treatmentmentioning

confidence: 99%

General Adaptation in Critical Illness: Glucocorticoid Receptor-alpha Master Regulator of Homeostatic Corrections

Meduri

Chrousos

2020

Front. Endocrinol.

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“…Adjunctive glucocorticoids have been used to treat patients for more than half a century because of an increased demand for patients suffered from adrenal insu ciency [7,[28][29][30][31]. Adrenal insu ciency especially occurred in patients whose endogenous adrenal response was inadequate for the degree of severe stress response during acute conditions including sepsis, septic shock and acute respiratory distress syndrome [32,33]. However, the complicated interactions among components of neuroendocrine network lead to the poor understanding of the pathogenesis underlining adrenal insu ciency ( g. 7).…”

Section: Discussionmentioning

confidence: 99%

Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) Inhibits Steroidogenesis in Adrenocortical Cell by Macrophage-derived Exosomes in Lipopolysaccharide-induced Septic Shock

Zhai

et al. 2020

Preprint

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Background: Endogenously produced glucocorticoids exhibit immunomodulating properties and are of pivotal importance for sepsis outcome. Uncontrolled activation of the immune-adrenal crosstalk increases the risk of sepsis-related death. Triggering receptor expressed on myeloid cells-2 (TREM2) is richly expressed on macrophages and has been demonstrated to improve outcome of sepsis by enhancing elimination of pathogens. However, the role and mode of action of macrophage TREM2 on adrenocortical steroidogenesis remains unclear in septic shock.Methods: The acute septic shock model was established by intraperitoneally challenging wild-type (WT) and TREM2 knock-out (Trem2-/-) mice with lipopolysaccharide (30 mg/kg). The mice were assessed for TREM2 expression and local inflammation in adrenal gland and synthesis of corticotropin releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) in vivo. Bone marrow-derived macrophages or macrophage-derived exosomes were isolated from WT and Trem2-/- mice and co-cultured with adrenocortical cells. The expression of steroidogenic enzymes and corticosterone production were assessed.Results: Genetic deficiency of TREM2 caused significantly higher corticosterone levels (326.6 ± 73.0 ng/ml in Trem2-/- mice vs. 151.1 ± 58.9 ng/ml in WT mice; p < 0.001) at the early stage of LPS-induced septic shock. While TREM2 deficiency neither increased CRH and ACTH, nor exacerbated the inflammation in adrenocortical tissue during septic shock. Ex vivo study revealed that Trem2-/- macrophages significantly promoted the expression of steroidogenic enzymes and increased production of corticosterone (27.73 ± 1.78 ng/ml in Trem2-/- mice vs. 22.96 ± 1.94 ng/ml in W T mice; p < 0.01). Furthermore, Trem2-/- macrophage-derived exosomes were able to mimic Trem2-/- macrophages in enhancing adrenocortical steroidogenesis. Conclusions: At the early stage of lipopolysaccharide-induced septic shock, macrophage TREM2 inhibited the steroid synthesis and corticosterone production in adrenocortical cells, which may be partially associated with macrophage-derived exosomes.

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“…On the contrary, short-term use of high-dose glucocorticoids had no significant beneficial effect to reduce mortality and was associated with a high incidence of side effects (4,5,11). Relevant Guidelines of the Society of Critical Care Medicine and European Society of Intensive Care Medicine 2017 conditionally recommend the use of methylprednisolone in early ARDS (up to day 7 of onset) at a dose of 1 mg/kg/d; for late persistent ARDS (after day 6 of onset), the guidelines recommend a dose of 2 mg/kg/d followed by gradual tapering (21).…”

Section: Discussionmentioning

confidence: 99%

Effect of glucocorticoids on mortality in patients with acute respiratory distress syndrome: A meta‑analysis

Zhao

Shi

et al. 2019

Exp Ther Med

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To date, the efficacy of glucocorticoid therapy to reduce mortality in patients with acute respiratory distress syndrome (ARDS) has remained controversial among the studies available. The present meta-analysis study aimed to further clarify the impact of glucocorticoid therapy on mortality in patients with ARDS by performing a pooled analysis of the previous data. The PubMed, Chinese Knowledge Infrastructure, Wanfang and Cochrane trials databases were searched for relevant studies published between 1966 and 2016. Randomized controlled trials (RCTs) that included the use of glucocorticoids in patients with ARDS and had reported on mortality were included. Odds ratios (OR) and 95% confidence intervals (CI) for mortality were calculated. A total of 10 RCTs were included in the meta-analysis. Of these, 4 studies used high-dose glucocorticoid therapy, while 6 used low-dose glucocorticoid therapy. In the pooled analysis, glucocorticoids were indicated to significantly reduce ARDS-associated mortality (OR= 0.64, 95% CI: 0.48-0.85, P= 0.002). Further subgroup analysis indicated the following: i) Long-term low-dose glucocorticoid therapy reduced ARDS-associated mortality compared with that in the control group (OR=0.60, 95% CI: 0.44-0.82, P= 0.001), whereas high-dose short-term glucocorticoid therapy did not reduce mortality (OR= 0.82, 95% CI: 0.43-1.57, P= 0.55). ii) Early initiation of glucocorticoid therapy was associated with reduced mortality compared with that in the control group (OR= 0.60, 95% CI: 0.44-0.83, P= 0.002); however, late initiation did not reduce mortality (OR=0.36, 95% CI: 0.03-3.76, P=0.39). iii) Therapeutic rather than preventive use of glucocorticoids reduced mortality (OR= 0.65, 95% CI: 0.49-0.86, P= 0.003). Overall, the present meta-analysis suggests that early initiation of long-term low-dose glucocorticoid therapy reduces mortality of patients with ARDS.

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Guidelines for the Diagnosis and Management of Critical Illness-Related Corticosteroid Insufficiency (CIRCI) in Critically Ill Patients (Part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017

Abstract: Evidence-based recommendations for the use of corticosteroids in critically ill patients with sepsis and septic shock, acute respiratory distress syndrome, and major trauma have been developed by a multispecialty task force.

Cited by 247 publications

References 56 publications

General Adaptation in Critical Illness: Glucocorticoid Receptor-alpha Master Regulator of Homeostatic Corrections

General Adaptation in Critical Illness: Glucocorticoid Receptor-alpha Master Regulator of Homeostatic Corrections

Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) Inhibits Steroidogenesis in Adrenocortical Cell by Macrophage-derived Exosomes in Lipopolysaccharide-induced Septic Shock

Effect of glucocorticoids on mortality in patients with acute respiratory distress syndrome: A meta‑analysis

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