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Critical Illness-Related Corticosteroid Insufficiency (CIRCI): A Narrative Review from a Multispecialty Task Force of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM)

Annane, Djillali MD, PhD1; Pastores, Stephen M. MD, FCCM2; Arlt, Wiebke MD, DSc, FRCP3; Balk, Robert A. MD, MCCM4; Beishuizen, Albertus MD, PhD5; Briegel, Josef MD, PhD6; Carcillo, Joseph MD, FCCM7; Christ-Crain, Mirjam MD, PhD8; Cooper, Mark S. MD9; Marik, Paul E. MD, FCCM10; Meduri, Gianfranco Umberto MD11; Olsen, Keith M. PharmD, FCCM12; Rochwerg, Bram MD13; Rodgers, Sophia C. RN, MSN, ACNP, FCCM14; Russell, James A. MD15; Van den Berghe, Greet MD, PhD16

doi: 10.1097/CCM.0000000000002724
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Objective: To provide a narrative review of the latest concepts and understanding of the pathophysiology of critical illness-related corticosteroid insufficiency (CIRCI).

Participants: A multi-specialty task force of international experts in critical care medicine and endocrinology and members of the Society of Critical Care Medicine and the European Society of Intensive Care Medicine.

Data Sources: Medline, Database of Abstracts of Reviews of Effects (DARE), Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane Database of Systematic Reviews.

Results: Three major pathophysiologic events were considered to constitute CIRCI: dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, altered cortisol metabolism, and tissue resistance to glucocorticoids. The dysregulation of the HPA axis is complex, involving multidirectional crosstalk between the CRH/ACTH pathways, autonomic nervous system, vasopressinergic system, and immune system. Recent studies have demonstrated that plasma clearance of cortisol is markedly reduced during critical illness, explained by suppressed expression and activity of the primary cortisol-metabolizing enzymes in the liver and kidney. Despite the elevated cortisol levels during critical illness, tissue resistance to glucocorticoids is believed to occur due to insufficient glucocorticoid alpha-mediated anti-inflammatory activity.

Conclusions: Novel insights into the pathophysiology of CIRCI add to the limitations of the current diagnostic tools to identify at-risk patients and may also impact how corticosteroids are used in patients with CIRCI.

1General ICU Department, Raymond Poincaré hospital (APHP), Health Science Centre Simone Veil, Université Versailles SQY-Paris Saclay; Garches, France.

2Department of Anesthesiology and Critical Care Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America.

3Institute of Metabolism and Systems Research (IMSR), University of Birmingham & Centre for Endocrinology, Diabetes and Metabolism (CEDAM), Birmingham Health Partners, Birmingham, United Kingdom.

4Division of Pulmonary and Critical Care Medicine, Rush University Medical Center, Chicago, IL, United States of America.

5Department of Intensive Care Medicine, Medisch Spectrum Twente, Enschede, Netherlands

6Anesthesiology and Critical Care Medicine, Klinik für Anästhesiologie, Klinikum der Universität, Munich, Germany.

7Department of Critical Care Medicine and Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America.

8Department of Endocrinology, Diabetology and Metabolism, Department of Clinical Research, University Hospital Basel, Basel, Switzerland.

9Department of Endocrinology, Concord Hospital, University of Sydney, Sydney, New South Wales, Australia.

10Division of Pulmonary and Critical Care Medicine, Eastern Virginia Medical School, Norfolk, VA, United States of America.

11Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Memphis Veterans Affairs Medical Center, Memphis, TN, United States of America.

12Dean, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America.

13Division of Critical Care, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.

14Clinical Adjunct Faculty, University of New Mexico and Sandoval Regional Medical Center, Albuquerque, NM, United States of America.

15Division of Critical Care Medicine, Centre for Heart Lung Innovation, St. Paul’s Hospital, University of British Columbia, Vancouver, Canada.

16Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven University and Hospitals, B-3000 Leuven, Belgium.

Dr. Djillali Annane and Dr. Stephen M. Pastores are co-chairs and co-first authors who have contributed equally to this work.

Dr. Annane has been involved with research relating to this guideline. Dr. Pastores participates in the American College of Physicians: Speaker at ACP Critical Care Update Precourse, the American College of Chest Physicians (CHEST) (faculty speaker at Annual Congress), the American Thoracic Society (ATS): Moderator at Annual Meeting, the European Society of Intensive Care Medicine (EISCM) (co-chair of Corticosteroid Guideline in collaboration with SCCM), and the Korean Society of Critical Care Medicine (co-director and speaker at Multiprofessional Critical Care Board Review Course). He has spoken on the topic of corticosteroid use in critical illness and specifically in sepsis at the International Symposium in Critical and Emergency Medicine in March 2017. Dr. Arlt participates in the Society for Endocrinology UK (Chair of the Clinical Committee, member of Council, member of the Nominations Committee) and the Endocrine Society USA (member, Publication Core Committee). Dr. Briegel participates in the European Society of Intensive Care Medicine, the Deutsche interdisziplinäre Vereinigung Intensivmedizin, and the Deutsche Gesellschaft für Anästhesie und Intensivmedizin, and he has given lectures and talks on hydrocortisone treatment of septic shock. Dr. Cooper participates in a range of specialist societies relating to endocrinology and bone disease. Dr. Meduri disclosed he is a government employee. Dr. Olsen participates in the American College of Clinical Pharmacy (grant review committee), and he represents the American Society of Health-System Pharmacists on the National Quality Forum for Surgery Measures. Dr. Rochwerg disclosed he is a methodologist for ATS, CBS, ESCIM, ASH. The remaining authors have disclosed that they do not have any potential conflicts of interest.

This article is being simultaneously published in Critical Care Medicine and Intensive Care Medicine. ICM DOI: 10.1007/s00134-017-4914-x This article is linked to another article entitled “Guidelines for the Diagnosis and Management of Critical Illness-Related Corticosteroid Insufficiency (CIRCI) in Critically Ill Patients: Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM): 2017” also published in the parallel.

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