Special Article
`
`Recommendations for the diagnosis and management of corticosteroid
`insufficiency in critically ill adult patients: Consensus statements from an
`international task force by the American College of Critical Care Medicine
`
`Paul E. Marik, MD, FCCM; Stephen M. Pastores, MD, FCCM; Djillali Annane, MD; G. Umberto Meduri, MD;
`Charles L. Sprung, MD, FCCM; Wiebke Arlt, MD; Didier Keh, MD; Josef Briegel, MD;
`Albertus Beishuizen, MD; Ioanna Dimopoulou, MD; Stylianos Tsagarakis, MD, PhD; Mervyn Singer, MD;
`George P. Chrousos, MD; Gary Zaloga, MD, FCCM; Faran Bokhari, MD, FACS; Michael Vogeser, MD
`
`Objective: To develop consensus statements for the diagnosis and
`management of corticosteroid insufficiency in critically ill adult patients.
`Participants: A multidisciplinary, multispecialty task force of experts in
`critical care medicine was convened from the membership of the Society of
`Critical Care Medicine and the European Society of Intensive Care Medicine.
`In addition, international experts in endocrinology were invited to partici-
`pate.
`Design/Methods: The task force members reviewed published literature
`and provided expert opinion from which the consensus was derived. The
`consensus statements were developed using a modified Delphi methodology.
`The strength of each recommendation was quantified using the Modified
`GRADE system, which classifies recommendations as strong (grade 1) or weak
`(grade 2) and the quality of evidence as high (grade A), moderate (grade B), or
`low (grade C) based on factors that include the study design, the consistency
`of the results, and the directness of the evidence.
`Results: The task force coined the term critical illness–related corticosteroid
`insufficiency to describe the dysfunction of the hypothalamic-pituitary-adrenal axis
`that occurs during critical illness. Critical illness–related corticosteroid insufficiency
`is caused by adrenal insufficiency together with tissue corticosteroid resistance and
`is characterized by an exaggerated and protracted proinflammatory response.
`Critical illness–related corticosteroid insufficiency should be suspected in hypoten-
`sive patients who have responded poorly to fluids and vasopressor agents, partic-
`ularly in the setting of sepsis. At this time, the diagnosis of tissue corticosteroid
`resistance remains problematic. Adrenal insufficiency in critically ill patients is best
`made by a delta total serum cortisol of <9 ␮g/dL after adrenocorticotrophic
`
`hormone (250 ␮g) administration or a random total cortisol of <10 ␮g/dL. The
`benefit of treatment with glucocorticoids at this time seems to be limited to patients
`with vasopressor-dependent septic shock and patients with early severe acute
`respiratory distress syndrome (PaO2/FIO2 of <200 and within 14 days of onset). The
`adrenocorticotrophic hormone stimulation test should not be used to identify those
`patients with septic shock or acute respiratory distress syndrome who should
`receive glucocorticoids. Hydrocortisone in a dose of 200 mg/day in four divided
`doses or as a continuous infusion in a dose of 240 mg/day (10 mg/hr) for >7 days
`is recommended for septic shock. Methylprednisolone in a dose of 1
`mg·kgⴚ1·dayⴚ1 for >14 days is recommended in patients with severe early acute
`respiratory distress syndrome. Glucocorticoids should be weaned and not stopped
`abruptly. Reinstitution of treatment should be considered with recurrence of signs
`of sepsis, hypotension, or worsening oxygenation. Dexamethasone is not recom-
`mended to treat critical illness–related corticosteroid insufficiency. The role of
`glucocorticoids in the management of patients with community-acquired pneumo-
`nia, liver failure, pancreatitis, those undergoing cardiac surgery, and other groups
`of critically ill patients requires further investigation.
`Conclusion: Evidence-linked consensus statements with regard to the
`diagnosis and management of corticosteroid deficiency in critically ill
`patients have been developed by a multidisciplinary, multispecialty task
`force. (Crit Care Med 2008; 36:1937–1949)
`KEY WORDS: corticosteroid; glucocorticoid; insufficiency; deficiency; adult;
`adrenal glands; diagnosis; management; consensus statement; guidelines; Del-
`phi methodology; evidence-based medicine; sepsis; cortisol; critical care; in-
`tensive care units; intensive care; shock septic; surgery; stress dosing
`
`*See also p. 1987.
`From the Division of Pulmonary and Critical Care Med-
`icine, Thomas Jefferson University, Philadelphia, PA (PEM);
`Critical Care Medicine Fellowship Program, Memorial Sloan-
`Kettering Cancer Center, New York, NY (SMP); Critical Care
`Department, Universite de Versailes Saint-Quentin en Yve-
`lines, Hospital Raymond Poincare, Garches, France (DA);
`Division of Pulmonary and Critical Care Medicine, University
`of Tennessee HSC, Memphis, TN (GUM); Department of
`Anesthesiology, Hadassah Hebrew University Medical Cen-
`ter, Jerusalem, Israel (CLS); Division of Medical Sciences,
`Institute of Biomedical Research, Endocrinology & Metabo-
`lism, The Medical School, University of Birmingham, Bir-
`mingham, UK (WA); Department of Anesthesiology and In-
`tensive Care Medicine, Campus Virchow-Clinic, Humboldt
`University, Berlin, Germany (DK); Department of Anesthesi-
`ology, University of Munich, Klinikum Grosshadern, Munich,
`Germany (JB); Department of Intensive Care, VU University
`Medical Center, Amsterdam, Netherlands (AB); Department
`of Critical Care Medicine, Athens University, Medical School,
`Athens, Greece (ID); Department of Endocrinology, Athens’
`Polyclinic, Athens, Greece (ST); Department of Medicine and
`Wolfson Institute of Biomedical Research, University College
`London, Jules Thorn Building, Middlesex Hospital, London,
`UK (MS); First Department of Pediatrics, Athens University
`Medical School, Athens, Greece (GPC); Baxter Healthcare,
`Clintec Nutrition, Deerfield, IL (GZ); Department of Trauma,
`
`Stronger Hospital of Cook County, Chicago, IL (FB); Hospital
`of the University of Munich, Institute of Clinical Chemistry,
`Munich, Germany (MV).
`The American College of Critical Care Medicine (ACCM),
`which honors individuals for their achievements and contri-
`butions to multidisciplinary critical care medicine, is the
`consultative body of the Society of Critical Care Medi-
`cine (SCCM) that possesses recognized expertise in
`the practice of critical care. The College has developed
`administrative guidelines and clinical practice parameters for
`the critical care practitioner. New guidelines and practice
`parameters are continually developed, and current ones are
`systematically reviewed and revised.
`Dr. Marik has received lecture fees from Eli Lilly and
`Merck. Dr. Keh has received grant support from the German
`Research Foundation and German Ministry of Education and
`Research (HYPRESS: Hydrocortisone for Prevention of Septic
`Shock). Dr. Sprung has been a member of a data monitoring
`and safety committee for Artisan Pharma, Novartis Corpora-
`tion, and Hutchinson Technology Incorporated. He has
`served as a consultant for AstraZeneca, Eisai Corporation, Eli
`Lilly, and GlaxoSmithKline. He has received grant support
`from the European Commission, Takeda, and Eisai Corpora-
`tion. He has received lecture fees from Eli Lilly. Drs. Sprung,
`Annane, Keh, Singer, and Briegel were investigators in the
`CORTICUS study, which was supported by the European
`Commission, the European Society of Intensive Care Medi-
`
`cine, the European Critical Care Research Network, the
`International Sepsis Forum, and the Gorham Foundation. Dr.
`Annane has received grant support from the French Ministry
`of Health for the prognostic value of a adrenocorticotrophic
`hormone test in septic shock; the French multicenter, ran-
`domized, controlled trial on hydrocortisone plus fludrocorti-
`sone in septic shock; the ongoing French multicenter 2 ⫻ 2
`factorial study that compares strict glucose control vs. con-
`ventional treatment for steroid-treated septic shock and hy-
`drocortisone alone vs. hydrocortisone and fludrocortisone;
`and a French multicenter 2 ⫻ 2 factorial trial that compares
`hydrocortisone plus fludrocortisone, activated protein C, the
`combination of the two drugs, and placebos for the treatment
`of septic shock. Dr. Pastores has received grant support form
`Eisai Medical Research (phase 3 trial of E5564 in severe
`sepsis), and Artisan Pharma (phase 2 sepsis with dissemi-
`nated intravascular coagulation trial). The remaining authors
`have not disclosed any conflicts of interest with respect to
`this article.
`For information regarding this article, E-mail:
`paul.marik@jefferson.edu
`Copyright © 2008 by the Society of Critical Care
`Medicine and Lippincott Williams & Wilkins
`
`DOI: 10.1097/CCM.0b013e31817603ba
`
`Crit Care Med 2008 Vol. 36, No. 6
`
`1937
`
`Amerigen Exhibit 1165
`Amerigen v. Janssen IPR2016-00286
`
`

`
`S evere illness and stress strongly
`
`activate the hypothalamic-pitu-
`itary-adrenal (HPA) axis and
`stimulate the release of adreno-
`corticotrophic hormone (ACTH) from the
`pituitary, which in turn increases the re-
`lease of cortisol from the adrenal cortex
`(1–3). This activation is an essential com-
`ponent of the general adaptation to illness
`and stress and contributes to the mainte-
`nance of cellular and organ homeostasis.
`Adrenalectomized animals succumb rap-
`idly to hemorrhagic and septic shock, and
`steroid replacement is protective against
`these challenges (4, 5).
`Once considered a rare diagnosis in
`the intensive care unit, “adrenal failure”
`is being reported with increasing fre-
`quency in critically ill patients with septic
`shock, severe community-acquired pneu-
`monia, trauma, head injury, burns, liver
`failure, HIV infection, pancreatitis, after
`cardiac surgery, after the use of etomi-
`date, and in brain-dead organ donors (6 –
`11). Adrenal
`failure may be associated
`with structural damage to the adrenal
`gland, pituitary gland, or hypothalamus;
`however, many critically ill patients de-
`velop reversible failure of the HPA axis.
`Although it is generally agreed that
`adrenal failure may be common in sub-
`groups of critically ill patients, the diag-
`nosis and management of this disorder
`remains controversial, with poor agree-
`ment among the experts. The objective of
`this task force was therefore to develop
`consensus statements by experts in the
`field based on the best available scientific
`evidence (12).
`
`METHODS
`
`Experts were selected from the mem-
`bership lists of the Society of Critical
`Care Medicine (SCCM) and the European
`Society of Intensive Care Medicine (ES-
`ICM). Specific individuals were selected
`to represent geographic diversity and a
`broad range of expertise on the basis of
`their published research. In addition, en-
`docrinologists with expertise in this area
`were invited to join the task force.
`The consensus statement was devel-
`oped using a modified Delphi methodol-
`ogy (12). The Delphi method, originally
`developed by the RAND Corporation, is a
`structured process that uses a series of
`questionnaires, each referred to as a
`round, to both gather and provide infor-
`mation (13, 14). With each round, the
`answers are modified based on the re-
`sponses of the previous round. The
`
`rounds continue until group consensus/
`majority is reached. This approach has
`several distinct advantages. It allows the
`inclusion of a large number of individuals
`across diverse geographic locations and
`with a broad range of expertise. One of its
`key advantages is that unlike a face-to-
`face meeting of experts, it eliminates the
`possibility that a specific expert might
`dominate the consensus process. The
`Delphi method helps to minimize the ef-
`fects of group interactions and maximizes
`the ability to elicit expert knowledge.
`The task force members individually
`and collectively undertook a systematic
`search of published literature pertaining
`to the diagnosis and treatment of adrenal
`failure in critically ill adult patients using
`Medline, CINAHL, EMBASE, and the Co-
`chrane library. In addition, the reference
`lists of relevant articles were reviewed for
`additional published works. Key words
`used in these searches included “pitu-
`itary–adrenal system, adrenal
`insuffi-
`ciency, adrenal glands, pituitary–adrenal
`function tests, hydrocortisone, glucocor-
`ticoids (GC), adrenal cortex hormones,
`glucocorticoid receptor (GR), critical
`care, intensive care units, intensive care,
`ARDS, shock septic, sepsis, and sepsis
`syndrome.” A comprehensive bibliogra-
`phy was developed, with the references
`stored and cataloged using an electronic
`reference manager (Reference Manager
`v11.1, Thompson ResearchSoft, Carlsbad,
`CA).
`We used electronic mail to conduct
`the Delphi process. A list of questions for
`review was determined. Once a majority
`agreement was reached on each question,
`the strength of each recommendation
`was quantified using the Modified Grades
`of Recommendation Assessment, Devel-
`opment, and Evaluation (GRADE) system
`developed by the American College of
`Chest Physicians (Appendix 1) (15). In all,
`there were seven rounds until a majority
`agreement was achieved on all the ques-
`tions. In addition, the group met in Paris,
`France, in September 2005 and again at
`the Society of Critical Care Medicine 35th
`Critical Care Congress in San Francisco,
`CA,
`in January 2006 to review the
`progress of the Delphi process. The initial
`draft of the manuscript was written by
`the Chair (P. E. Marik). The draft manu-
`script was reviewed and iteratively edited
`by all members of the task force.
`A meta-analysis of randomized con-
`trolled trials that compared the 28-day
`mortality and vasopressor dependency of
`patients with septic shock and the 28-day
`
`mortality of patients with acute respira-
`tory distress syndrome (ARDS) who re-
`ceived either moderate-dose corticoste-
`roid or placebo was performed. Four of
`the task force members (P. E. Marik, D.
`Annane, S. M. Pastores, G. U. Meduri)
`reviewed the task force bibliography for
`relevant studies. Septic shock was defined
`by the American College of Chest Physi-
`cians/Society of Critical Care Medicine
`Consensus Conference and ARDS by the
`American–European Consensus Confer-
`ence (16, 17). Vasopressor dependency
`was defined as the requirement for a va-
`sopressor agent after 7 days of treatment
`with a glucocorticoid (GC). The reviewers
`independently abstracted data from all el-
`igible studies. Data were abstracted on
`study design, study size, corticosteroid
`dosage, vasopressor dependency, and 28-
`day mortality. Study and data inclusion
`was by consensus. We used the random
`effects models using Review Manager 4.2
`(Cochrane Collaboration, Oxford, UK) for
`all analyses and considered p ⬍ .05 (two-
`sided) as significant. Summary effects es-
`timates are presented as odds ratio with
`95% confidence intervals. We assessed
`heterogeneity between studies using the
`Cochran Q statistic with p ⬍ .10 indicat-
`ing significant heterogeneity and the I2
`with suggested thresholds for low (25–
`49%), moderate (50 –74%), and high
`(⬎75%) values (18 –21).
`
`BACKGROUND
`
`Exposure to hostile conditions results
`in a series of coordinated responses—
`often referred to as stress responses—
`organized to enhance survival; these in-
`clude a series of complex central and
`peripheral adaptations. This stress re-
`sponse is mediated mainly by the HPA
`axis and the sympathoadrenal system,
`which includes the sympathetic nervous
`system and the adrenal medulla (Fig. 1)
`(22–24). The HPA axis and the sympa-
`thoadrenal system are functionally re-
`lated. Activation of the sympathoadrenal
`system results in the secretion of epi-
`nephrine and norepinephrine from the
`adrenal medulla and also leads to an in-
`creased production of inflammatory cyto-
`kines, such as interleukin-6. Activation of
`the HPA axis results in increased secre-
`tion from the paraventricular nucleus of
`the hypothalamus of corticotropin-
`releasing hormone, a 41-amino acid pep-
`tide, and arginine vasopressin. Cortico-
`tropin-releasing hormone plays a pivotal
`integrative role in the response to stress.
`
`1938
`
`Crit Care Med 2008 Vol. 36, No. 6
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`

`
`receptor mediating selective cholesterol
`uptake (32–34). These receptors are ex-
`pressed at high levels in the parenchymal
`cells of the liver and the steroidogenic
`cells of the adrenal glands, ovary, and
`testis (35).
`Cortisol exerts its effects after uptake
`from the circulation by binding to intra-
`cellular glucocorticoid receptors (GRs)
`(3). These receptors belong to a steroid-
`hormone-receptor superfamily of tran-
`scription factors, which are made up of a
`C-terminal ligand binding domain, a cen-
`tral DNA binding domain interacting
`with specific DNA sequences on target
`genes, and an N-terminal hypervariable
`region. The binding of cortisol to GR in
`the cytoplasm results in the activation of
`the steroid receptor complex via a process
`involving the dissociation of heat shock
`proteins (heat shock proteins 90 and 70)
`and FK-506 binding proteins (36 –38). In-
`tracellularly, the cortisol-GR complex
`moves to the nucleus, where it binds as a
`homodimer to DNA sequences called glu-
`cocorticoid-responsive elements located
`in the promoter regions of target genes,
`which then activate or repress transcrip-
`tion of the associated genes. In addition,
`the cortisol-GR complex may affect cellu-
`lar function indirectly by binding to and
`modulating the transcriptional activity of
`other nuclear transcription factors, such
`as nuclear factor ␬B (NF-␬B) and activa-
`tor protein-1. Overall, GCs affect the
`transcription of thousands of genes in
`every cell of the body. It has been esti-
`mated that GCs affect 20% of the genome
`of mononuclear blood cells (39).
`GCs play a major role in regulating
`the activity of NF-␬B, which plays a cru-
`cial and generalized role in inducing cy-
`tokine gene transcription (40 – 42).
`NF-␬B is normally maintained in an in-
`active form by sequestration in the cyto-
`plasm through interaction with inhibi-
`tory proteins (I␬Bs). On stimulation by
`lipopolysaccharide, double-stranded
`DNA, physical and chemical stresses, and
`inflammatory cytokines, the latent NF-
`␬B/I␬B complex is activated by phosphor-
`ylation and proteolytic degradation of
`I␬B, with exposure of the NF-␬B nuclear
`localization sequence. The liberated
`NF-␬B then translocates to the nucleus
`and binds to promoter regions of target
`genes to initiate the transcription of mul-
`tiple cytokines (including tumor necrosis
`factor-␣, interleukin-1, and interleukin-
`6), cell adhesion molecules (e.g., intercel-
`lular adhesion molecule-1, E-selectin),
`and other mediators of
`inflammation.
`
`Figure 1. Activation of the hypothalamic-pituitary-adrenal axis by a stressor and the interaction with
`the inflammatory response. ACTH, adrenocorticotrophic hormone; CRH, corticotropin-releasing hor-
`mone; IL-6,
`interleukin-6; IL-11,
`interleukin-11; LIF,
`leukemia inhibitory factor; POMC, pro-
`opiomelanocortin; TGF-beta, transforming growth factor-␤; TNF, tumor necrosis factor.
`
`Corticotropin-releasing hormone stimu-
`lates the production of ACTH by the an-
`terior pituitary, causing the zona fascicu-
`lata of the adrenal cortex to produce
`more GCs (cortisol in humans, cortico-
`sterone in rats). Arginine vasopressin is a
`weak ACTH secretagogue and vasoactive
`peptide that acts synergistically with cor-
`ticotropin-releasing hormone to increase
`secretion of ACTH. The increase in corti-
`sol production results in multiple effects
`(metabolic, cardiovascular, and immune)
`aimed at maintaining or restoring ho-
`meostasis during stress.
`
`Cortisol Physiology, Synthesis,
`and Glucocorticoid Receptors
`
`Cortisol is the major endogenous GC
`secreted by the adrenal cortex. More than
`90% of circulating cortisol is bound to
`corticosteroid-binding globulin, with
`⬍10% in the free, biologically active
`form (25, 26). Corticosteroid-binding
`globulin is the predominant binding pro-
`tein, with albumin binding a lesser
`amount. During acute illness, particu-
`larly sepsis, corticosteroid-binding glob-
`ulin levels fall by as much as 50%, result-
`
`ing in a significant increase in the
`percentage of free cortisol (27, 28). The
`circulating half-life of cortisol varies from
`70 to 120 mins. The adrenal gland does
`not store cortisol;
`increased secretion
`arises due to increased synthesis under
`the control of ACTH (29). Cholesterol is
`the principal precursor for steroid bio-
`synthesis in steroidogenic tissue. In a se-
`ries of sequential enzymatic steps, cho-
`lesterol is converted to pregnenolone and
`then to the end products of adrenal bio-
`synthesis, namely, aldosterone, dehydro-
`epiandrostenedione, and cortisol (29).
`The first and rate-limiting step in adrenal
`steroidogenesis is the formation of preg-
`nenolone from cholesterol. At rest and
`during stress, about 80% of circulating
`cortisol is derived from plasma choles-
`terol, the remaining 20% being synthe-
`sized in situ from acetate and other pre-
`cursors (30). Experimental studies
`suggest that high-density lipoprotein is
`the preferred cholesterol source of steroi-
`dogenic substrate in the adrenal gland
`(31). Recently, mouse SR-B1 (scavenger
`receptor, class B, type 1) and its human
`homolog (Cla-1) have been identified as
`the high-affinity high-density lipoprotein
`
`Crit Care Med 2008 Vol. 36, No. 6
`
`1939
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`

`
`GCs inhibit the activity of NF-␬B by in-
`creasing the transcription of I␬Bs and by
`directly binding to and inhibiting NF-␬B
`(41, 42).
`Cortisol has several important physio-
`logic actions on metabolism, cardiovas-
`cular function, and the immune system
`(6, 43). The metabolic effects of cortisol
`include an increase in blood glucose con-
`centrations through the activation of key
`enzymes involved in hepatic gluconeo-
`genesis and inhibition of glucose uptake
`in peripheral tissues such as the skeletal
`muscles. In addition, in adipose tissue,
`lipolysis is activated, resulting in the re-
`lease of free fatty acids into the circula-
`tion. Cortisol also has a permissive effect
`on other hormones, increasing glucose
`levels, including catecholamines and glu-
`cagon. Sustained cortisol hypersecretion
`stimulates glucose production at the ex-
`pense of protein and lipid catabolism and
`insulin resistance.
`Cortisol
`increases blood pressure
`through several mechanisms involving
`the kidney and vasculature. In vascular
`smooth muscle, cortisol increases sensi-
`tivity to vasopressor agents such as cat-
`echolamines and angiotensin II (44, 45).
`These effects are mediated partly by the
`increased transcription and expression of
`the receptors for these hormones (44,
`45). Although the effect of GCs on nitric
`oxide is complex, it seems to increase
`endothelial nitric oxide synthetase,
`thereby maintaining microvascular per-
`fusion (46 – 49). Cortisol has potent anti-
`inflammatory actions, including the re-
`duction in the number and function of
`various immune cells, such as T and B
`lymphocytes, monocytes, neutrophils,
`and eosinophils, at sites of inflammation.
`Cortisol decreases the production of cy-
`tokines, chemokines, and eicosanoids and
`enhances the production of macrophage
`migration inhibitory factor (22, 50).
`
`Dysfunction of the HPA Axis
`During Acute Illness
`
`The acute stress response during crit-
`ical illness is characterized by activation
`of the HPA and sympathoadrenal system
`axis, with increased secretion of cortisol,
`an increase in the percentage of free cor-
`tisol, and increased translocation of the
`GR complex into the nucleus. Impor-
`tantly, there is increasing evidence that
`in many critically ill patients, this path-
`way may be impaired (27, 51, 52). The
`reported prevalence of adrenal
`insuffi-
`ciency in critically ill patients varies
`
`widely (0 –77%), depending on the popu-
`lation of patients studied and the diag-
`nostic criteria. However, the overall prev-
`alence of adrenal
`insufficiency in
`critically ill medical patients approxi-
`mates 10 –20%, with a rate as high as
`60% in patients with septic shock. In a
`study recently published by Annane et al.
`(53), the prevalence of adrenal insuffi-
`ciency (as determined by metyrapone
`testing) in patients with severe sepsis and
`septic shock was reported to be 60%. The
`major effect of adrenal insufficiency in
`the critically ill patient is manifested
`through alterations in the systemic in-
`flammatory response and cardiovascular
`function.
`The mechanisms leading to dysfunc-
`tion of the HPA axis during critical illness
`are complex and poorly understood and
`likely include decreased production of
`corticotropin-releasing hormone, ACTH,
`and cortisol and the dysfunction of their
`receptors. A subset of patients may have
`structural damage to the adrenal gland
`from either hemorrhage or infarction,
`and this may result in long-term adrenal
`dysfunction. Adrenal hemorrhage has
`been described with blunt abdominal
`trauma, after major surgery, in dissemi-
`nated intravascular coagulation associ-
`ated with sepsis, and in patients with
`burns, heparin-induced thrombocytope-
`nia, the antiphospholipid syndrome, HIV
`infection, disseminated fungal infections,
`and tuberculosis (3, 54 –59). In addition,
`patients who have been treated long term
`with adrenally suppressive doses of exog-
`enous GCs are likely to develop secondary
`adrenal insufficiency (3, 6). However, it
`seems that most critically ill patients who
`develop adrenal insufficiency develop re-
`versible dysfunction of the HPA axis (6,
`60). Decreased production of cortisol or
`ACTH is particularly common in patients
`with severe sepsis and septic shock (60).
`Annane et al. (53) demonstrated an in-
`creased risk of adrenal insufficiency in
`patients with positive blood cultures and
`those with Gram-negative infections.
`Clinical and experimental data indi-
`cate that the failure to improve in sepsis
`and ARDS is frequently associated with
`failure of activated GRs to down-regulate
`the transcription of inflammatory cyto-
`kines, despite elevated levels of circulat-
`ing cortisol, a condition defined as sys-
`temic inflammation-associated GC
`resistance (61). Tissue corticosteroid re-
`sistance is a well-known manifestation of
`chronic inflammatory diseases, such as
`chronic obstructive pulmonary disease,
`
`severe asthma, systematic lupus ery-
`thematosus, ulcerative colitis, and rheu-
`matoid arthritis (62– 65). It is therefore
`likely that acute inflammation, similar to
`chronic inflammation, may be associated
`with tissue corticosteroid resistance (61).
`In experimental models, endotoxin and
`proinflammatory cytokines have been
`shown to cause decreased GR nuclear
`translocation (66 – 68). In an ex vivo
`model, Meduri et al. (69) demonstrated
`reduced nuclear translocation of the GR
`complex in patients with fatal ARDS, de-
`spite adequate cytoplasmic (and serum)
`levels of cortisol. It is likely that multiple
`mechanisms cause systemic inflamma-
`tion-associated GC resistance, including
`decreased GR number, increased expres-
`sion of the beta isoform of the GR (unable
`to bind ligand), altered ratio of chaperone
`proteins (FK binding proteins and heat
`shock protein 90), reduced affinity of the
`GR for ligand, altered nuclear receptor
`coactivators, reduced DNA binding, de-
`creased histone acetylation, increased ac-
`tivity of the P-glycoprotein membrane
`transport pump, and increased conver-
`sion of cortisol to cortisone (61, 68, 70 –
`72). Furthermore, polymorphisms of the
`GR and other pivotal genes may influence
`the downstream effects of the GC–GR in-
`teraction (73, 74). Additional research in
`this area, particularly as it applies to crit-
`ically ill patients, is urgently required.
`Current evidence suggests that medi-
`ators released in patients with critical ill-
`ness, and sepsis in particular, may either
`stimulate or impair the synthesis and ac-
`tion of cortisol via actions on the HPA
`axis and the GR signaling system. The net
`effect of these opposing actions on the
`HPA axis and GR may be time dependent
`and, in addition, depend on the severity of
`illness and the extent and pattern of me-
`diator production. Although the focus on
`most research has been in the area of
`sepsis and ARDS, it is likely that similar
`mechanisms operate in other disorders
`characterized by significant systemic in-
`flammation,
`including pancreatitis,
`burns, post-cardiopulmonary bypass, and
`liver failure (75–79).
`
`RECOMMENDATIONS OF THE
`TASK FORCE
`
`Critical Illness–Related Corticosteroid
`Insufficiency
`
`Recommendation 1: Dysfunction of the
`HPA axis in critical illness is best de-
`scribed by the term critical illness–
`
`1940
`
`Crit Care Med 2008 Vol. 36, No. 6
`
`

`
`related corticosteroid insufficiency
`(CIRCI).
`
`Recommendation 2: The terms abso-
`lute or relative adrenal insufficiency
`are best avoided in the context of crit-
`ical illness.
`
`Dysfunction of the HPA axis in critical
`illness is best described by the term crit-
`ical illness–related corticosteroid insuffi-
`ciency (CIRCI). CIRCI is defined as inad-
`equate cellular corticosteroid activity for
`the severity of the patient’s illness. CIRCI
`manifests with insufficient GC-GR–
`mediated down-regulation of proinflam-
`matory transcription factors, leading to
`persistent elevation of proinflammatory
`mediators over time. CIRCI occurs as a
`result of a decrease in adrenal steroid
`production (adrenal insufficiency) or tis-
`sue resistance to GCs (with or without
`adrenal
`insufficiency). Adrenal
`insuffi-
`ciency may arise due to dysfunction at
`any point in the HPA axis. The terms
`absolute or relative adrenal insufficiency
`are best avoided in the context of critical
`illness (80). CIRCI is a dynamic process
`(i.e., patients may not have CIRCI at ad-
`mission to the hospital/intensive care
`unit but may develop CIRCI during the
`course of their illness) (81– 83). CIRCI is
`usually a reversible condition caused by
`proinflammatory mediators; however, it
`may also arise due to structural damage
`of the adrenal gland. CIRCI may affect the
`balance between proinflammatory and
`anti-inflammatory pathways and thereby
`influence immune, metabolic, vascular,
`and organ dysfunction.
`
`Diagnosis of Adrenal Insufficiency
`
`Recommendation 3: At this time, adre-
`nal insufficiency in critical illness is
`best diagnosed by a delta cortisol (after
`250 ␮g cosyntropin) of ⬍9 ␮g/dL or a
`random total cortisol of ⬍10 ␮g/dL.
`
`Strength of Recommendation: 2B
`
`Recommendation 4: The use of free
`cortisol measurements cannot be rec-
`ommended for routine use at this time.
`Although the free cortisol assay has
`advantages over the total serum corti-
`sol, this test is not readily available.
`Furthermore, the normal range of the
`free cortisol in critically ill patients is
`currently unclear.
`
`Strength of Recommendation: 2B
`
`Recommendation 5: The ACTH stimu-
`lation test should not be used to iden-
`tify those patients with septic shock or
`ARDS who should receive GCs.
`
`Strength of Recommendation: 2B
`
`The diagnosis of adrenal insufficiency
`in critically ill patients has been based on
`the measurement of a random total se-
`rum cortisol (“stress” cortisol level) or
`the change in the serum cortisol in re-
`sponse to 250 ␮g of synthetic ACTH
`(ACTH stimulation test), the so-called
`delta cortisol (6, 84). Both of these tests
`have significant limitations in the criti-
`cally ill (85). Assays for serum cortisol
`measure the total hormone concentra-
`tion (serum-free cortisol plus the pro-
`tein-bound fraction). The consensus is
`that the free cortisol, rather than the
`protein-bound fraction, is responsible for
`the physiologic function of the hormone
`at the cellular level (6, 50, 86). In most
`critically ill patients, corticosteroid-
`binding globulin levels are decreased and
`the percentage of
`free cortisol
`is in-
`creased (27, 51, 52, 86, 87). Furthermore,
`with acute stimulation of the adrenal
`gland, the relative increase of free bioac-
`tive cortisol concentrations is substan-
`tially more pronounced than the increase
`of total cortisol concentrations (27, 51,
`52, 86 – 88). Consequently, in critically ill
`patients, the total serum cortisol level
`may not accurately reflect the free corti-
`sol level. This dissociation between the
`total and free cortisol
`level
`is most
`marked in patients with a serum albumin
`of ⬍2.5 mg/dL (85, 87, 89).
`Although measurement of the free
`cortisol level may arguably be prefera-
`ble, this test is currently not widely
`available. It is likely, however, that with
`improvement in laboratory techniques
`and clinical demand, this test will be-
`come commercially available (90). The
`interpretation of the total serum cortisol
`concentration is further complicated by
`the fact that the specificity, sensitivity,
`and performance of the commercially
`available assays are not uniform (91). It is
`likely that the variation in assay charac-
`teristics might be even more significant
`in critically ill patients, especially those
`with septic shock (91, 92). Cross-reactiv-
`ity of the cortisol immunoassay with pre-
`cursors or metabolites of cortisol that
`accumulate in sepsis may account for this
`observation.
`Although a delta cortisol of ⬍9 ␮g/dL
`has proven to be an important prognostic
`marker (9, 53, 93, 94), and a marker of
`response to treatment with corticoste-
`roids (95, 96), the ACTH stimulation te