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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
hormone (250 g) administration or a random total cortisol of <10 g/dL. The
management of corticosteroid insufficiency in critically ill adult patients.
benefit of treatment with glucocorticoids at this time seems to be limited to patients
Participants: A multidisciplinary, multispecialty task force of experts in
with vasopressor-dependent septic shock and patients with early severe acute
critical care medicine was convened from the membership of the Society of
respiratory distress syndrome (PaO /F
of <200 and within 14 days of onset). The
Critical Care Medicine and the European Society of Intensive Care Medicine.
adrenocorticotrophic hormone stimulation test should not be used to identify those
In addition, international experts in endocrinology were invited to partici-
patients with septic shock or acute respiratory distress syndrome who should
receive glucocorticoids. Hydrocortisone in a dose of 200 mg/day in four divided
Design/Methods: The task force members reviewed published literature
doses or as a continuous infusion in a dose of 240 mg/day (10 mg/hr) for >7 days
and provided expert opinion from which the consensus was derived. The
is recommended for septic shock. Methylprednisolone in a dose of 1
consensus statements were developed using a modified Delphi methodology.
mg·kgⴚ1·dayⴚ1 for >14 days is recommended in patients with severe early acute
The strength of each recommendation was quantified using the Modified
respiratory distress syndrome. Glucocorticoids should be weaned and not stopped
GRADE system, which classifies recommendations as strong (grade 1) or weak
abruptly. Reinstitution of treatment should be considered with recurrence of signs
(grade 2) and the quality of evidence as high (grade A), moderate (grade B), or
of sepsis, hypotension, or worsening oxygenation. Dexamethasone is not recom-
low (grade C) based on factors that include the study design, the consistency
mended to treat critical illness–related corticosteroid insufficiency. The role of
of the results, and the directness of the evidence.
glucocorticoids in the management of patients with community-acquired pneumo-
Results: The task force coined the term critical illness–related corticosteroid
nia, liver failure, pancreatitis, those undergoing cardiac surgery, and other groups
insufficiency to describe the dysfunction of the hypothalamic-pituitary-adrenal axis
of critically ill patients requires further investigation.
that occurs during critical illness. Critical illness–related corticosteroid insufficiency
Conclusion: Evidence-linked consensus statements with regard to the
is caused by adrenal insufficiency together with tissue corticosteroid resistance and
diagnosis and management of corticosteroid deficiency in critically ill
is characterized by an exaggerated and protracted proinflammatory response.
patients have been developed by a multidisciplinary, multispecialty task
Critical illness–related corticosteroid insufficiency should be suspected in hypoten-
force. (Crit Care Med 2008; 36:1937–1949)
sive patients who have responded poorly to fluids and vasopressor agents, partic-
KEY WORDS: corticosteroid; glucocorticoid; insufficiency; deficiency; adult;
ularly in the setting of sepsis. At this time, the diagnosis of tissue corticosteroid
adrenal glands; diagnosis; management; consensus statement; guidelines; Del-
resistance remains problematic. Adrenal insufficiency in critically ill patients is best
phi methodology; evidence-based medicine; sepsis; cortisol; critical care; in-
made by a delta total serum cortisol of <9 g/dL after adrenocorticotrophic
tensive care units; intensive care; shock septic; surgery; stress dosing
*See also p. 1987.
Stronger Hospital of Cook County, Chicago, IL (FB); Hospital cine, the European Critical Care Research Network, the From the Division of Pulmonary and Critical Care Med- of the University of Munich, Institute of Clinical Chemistry, International Sepsis Forum, and the Gorham Foundation. Dr.
icine, Thomas Jefferson University, Philadelphia, PA (PEM); Munich, Germany (MV).
Annane has received grant support from the French Ministry Critical Care Medicine Fellowship Program, Memorial Sloan- The American College of Critical Care Medicine (ACCM), of Health for the prognostic value of a adrenocorticotrophic Kettering Cancer Center, New York, NY (SMP); Critical Care which honors individuals for their achievements and contri- hormone test in septic shock; the French multicenter, ran- Department, Universite de Versailes Saint-Quentin en Yve- butions to multidisciplinary critical care medicine, is the domized, controlled trial on hydrocortisone plus fludrocorti- lines, Hospital Raymond Poincare, Garches, France (DA); consultative body of the Society of Critical Care Medi- sone in septic shock; the ongoing French multicenter 2 ⫻ 2 Division of Pulmonary and Critical Care Medicine, University cine (SCCM) that possesses recognized expertise in factorial study that compares strict glucose control vs. con- of Tennessee HSC, Memphis, TN (GUM); Department of the practice of critical care. The College has developed ventional treatment for steroid-treated septic shock and hy- Anesthesiology, Hadassah Hebrew University Medical Cen- administrative guidelines and clinical practice parameters for drocortisone alone vs. hydrocortisone and fludrocortisone; ter, Jerusalem, Israel (CLS); Division of Medical Sciences, the critical care practitioner. New guidelines and practice and a French multicenter 2 ⫻ 2 factorial trial that compares Institute of Biomedical Research, Endocrinology & Metabo- parameters are continually developed, and current ones are lism, The Medical School, University of Birmingham, Bir- systematically reviewed and revised.
hydrocortisone plus fludrocortisone, activated protein C, the mingham, UK (WA); Department of Anesthesiology and In- Dr. Marik has received lecture fees from Eli Lilly and combination of the two drugs, and placebos for the treatment tensive Care Medicine, Campus Virchow-Clinic, Humboldt Merck. Dr. Keh has received grant support from the German of septic shock. Dr. Pastores has received grant support form University, Berlin, Germany (DK); Department of Anesthesi- Research Foundation and German Ministry of Education and Eisai Medical Research (phase 3 trial of E5564 in severe ology, University of Munich, Klinikum Grosshadern, Munich, Research (HYPRESS: Hydrocortisone for Prevention of Septic sepsis), and Artisan Pharma (phase 2 sepsis with dissemi- Germany (JB); Department of Intensive Care, VU University Shock). Dr. Sprung has been a member of a data monitoring nated intravascular coagulation trial). The remaining authors Medical Center, Amsterdam, Netherlands (AB); Department and safety committee for Artisan Pharma, Novartis Corpora- have not disclosed any conflicts of interest with respect to of Critical Care Medicine, Athens University, Medical School, tion, and Hutchinson Technology Incorporated. He has this article.
Athens, Greece (ID); Department of Endocrinology, Athens' served as a consultant for AstraZeneca, Eisai Corporation, Eli For information regarding this article, E-mail: Polyclinic, Athens, Greece (ST); Department of Medicine and Lilly, and GlaxoSmithKline. He has received grant support Wolfson Institute of Biomedical Research, University College from the European Commission, Takeda, and Eisai Corpora- Copyright 2008 by the Society of Critical Care London, Jules Thorn Building, Middlesex Hospital, London, tion. He has received lecture fees from Eli Lilly. Drs. Sprung, Medicine and Lippincott Williams & Wilkins UK (MS); First Department of Pediatrics, Athens University Annane, Keh, Singer, and Briegel were investigators in the Medical School, Athens, Greece (GPC); Baxter Healthcare, CORTICUS study, which was supported by the European Clintec Nutrition, Deerfield, IL (GZ); Department of Trauma, Commission, the European Society of Intensive Care Medi- Crit Care Med 2008 Vol. 36, No. 6
activate the hypothalamic-pitu- majority is reached. This approach has tory distress syndrome (ARDS) who re- itary-adrenal (HPA) axis and several distinct advantages. It allows the ceived either moderate-dose corticoste- stimulate the release of adreno- inclusion of a large number of individuals roid or placebo was performed. Four of corticotrophic hormone (ACTH) from the across diverse geographic locations and the task force members (P. E. Marik, D.
pituitary, which in turn increases the re- with a broad range of expertise. One of its Annane, S. M. Pastores, G. U. Meduri) lease of cortisol from the adrenal cortex key advantages is that unlike a face-to- reviewed the task force bibliography for (1–3). This activation is an essential com- face meeting of experts, it eliminates the relevant studies. Septic shock was defined ponent of the general adaptation to illness possibility that a specific expert might by the American College of Chest Physi- and stress and contributes to the mainte- dominate the consensus process. The cians/Society of Critical Care Medicine nance of cellular and organ homeostasis.
Delphi method helps to minimize the ef- Consensus Conference and ARDS by the Adrenalectomized animals succumb rap- fects of group interactions and maximizes American–European Consensus Confer- idly to hemorrhagic and septic shock, and the ability to elicit expert knowledge.
ence (16, 17). Vasopressor dependency steroid replacement is protective against The task force members individually was defined as the requirement for a va- these challenges (4, 5).
and collectively undertook a systematic sopressor agent after 7 days of treatment Once considered a rare diagnosis in search of published literature pertaining with a glucocorticoid (GC). The reviewers the intensive care unit, "adrenal failure" to the diagnosis and treatment of adrenal independently abstracted data from all el- is being reported with increasing fre- failure in critically ill adult patients using igible studies. Data were abstracted on quency in critically ill patients with septic Medline, CINAHL, EMBASE, and the Co- study design, study size, corticosteroid shock, severe community-acquired pneu- chrane library. In addition, the reference dosage, vasopressor dependency, and 28- monia, trauma, head injury, burns, liver lists of relevant articles were reviewed for day mortality. Study and data inclusion failure, HIV infection, pancreatitis, after additional published works. Key words was by consensus. We used the random cardiac surgery, after the use of etomi- used in these searches included "pitu- effects models using Review Manager 4.2 date, and in brain-dead organ donors (6 – itary–adrenal system, adrenal insuffi- (Cochrane Collaboration, Oxford, UK) for 11). Adrenal failure may be associated ciency, adrenal glands, pituitary–adrenal all analyses and considered p ⬍ .05 (two- with structural damage to the adrenal function tests, hydrocortisone, glucocor- sided) as significant. Summary effects es- gland, pituitary gland, or hypothalamus; ticoids (GC), adrenal cortex hormones, timates are presented as odds ratio with however, many critically ill patients de- glucocorticoid receptor (GR), critical 95% confidence intervals. We assessed velop reversible failure of the HPA axis.
care, intensive care units, intensive care, heterogeneity between studies using the Although it is generally agreed that ARDS, shock septic, sepsis, and sepsis Cochran Q statistic with p ⬍ .10 indicat- adrenal failure may be common in sub- syndrome." A comprehensive bibliogra- ing significant heterogeneity and the I2 groups of critically ill patients, the diag- phy was developed, with the references with suggested thresholds for low (25– nosis and management of this disorder stored and cataloged using an electronic 49%), moderate (50 –74%), and high remains controversial, with poor agree- reference manager (Reference Manager (⬎75%) values (18 –21).
ment among the experts. The objective of v11.1, Thompson ResearchSoft, Carlsbad, this task force was therefore to develop consensus statements by experts in the We used electronic mail to conduct field based on the best available scientific the Delphi process. A list of questions for Exposure to hostile conditions results evidence (12).
review was determined. Once a majority in a series of coordinated responses— agreement was reached on each question, often referred to as stress responses— the strength of each recommendation organized to enhance survival; these in- was quantified using the Modified Grades clude a series of complex central and Experts were selected from the mem- of Recommendation Assessment, Devel- peripheral adaptations. This stress re- bership lists of the Society of Critical opment, and Evaluation (GRADE) system sponse is mediated mainly by the HPA Care Medicine (SCCM) and the European developed by the American College of axis and the sympathoadrenal system, Society of Intensive Care Medicine (ES- Chest Physicians (Appendix 1) (15). In all, which includes the sympathetic nervous ICM). Specific individuals were selected there were seven rounds until a majority system and the adrenal medulla (Fig. 1) to represent geographic diversity and a agreement was achieved on all the ques- (22–24). The HPA axis and the sympa- broad range of expertise on the basis of tions. In addition, the group met in Paris, thoadrenal system are functionally re- their published research. In addition, en- France, in September 2005 and again at lated. Activation of the sympathoadrenal docrinologists with expertise in this area the Society of Critical Care Medicine 35th system results in the secretion of epi- were invited to join the task force.
Critical Care Congress in San Francisco, nephrine and norepinephrine from the The consensus statement was devel- CA, in January 2006 to review the adrenal medulla and also leads to an in- oped using a modified Delphi methodol- progress of the Delphi process. The initial creased production of inflammatory cyto- ogy (12). The Delphi method, originally draft of the manuscript was written by kines, such as interleukin-6. Activation of developed by the RAND Corporation, is a the Chair (P. E. Marik). The draft manu- the HPA axis results in increased secre- structured process that uses a series of script was reviewed and iteratively edited tion from the paraventricular nucleus of questionnaires, each referred to as a by all members of the task force.
the hypothalamus of corticotropin- round, to both gather and provide infor- A meta-analysis of randomized con- releasing hormone, a 41-amino acid pep- mation (13, 14). With each round, the trolled trials that compared the 28-day tide, and arginine vasopressin. Cortico- answers are modified based on the re- mortality and vasopressor dependency of tropin-releasing hormone plays a pivotal sponses of the previous round. The patients with septic shock and the 28-day integrative role in the response to stress.
Crit Care Med 2008 Vol. 36, No. 6
receptor mediating selective cholesteroluptake (32–34). These receptors are ex-pressed at high levels in the parenchymalcells of the liver and the steroidogeniccells of the adrenal glands, ovary, andtestis (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 aC-terminal ligand binding domain, a cen-tral DNA binding domain interactingwith specific DNA sequences on targetgenes, and an N-terminal hypervariableregion. The binding of cortisol to GR inthe cytoplasm results in the activation ofthe steroid receptor complex via a processinvolving the dissociation of heat shockproteins (heat shock proteins 90 and 70)and FK-506 binding proteins (36 –38). In-tracellularly, the cortisol-GR complexmoves to the nucleus, where it binds as ahomodimer to DNA sequences called glu-cocorticoid-responsive elements locatedin the promoter regions of target genes, Figure 1. Activation of the hypothalamic-pituitary-adrenal axis by a stressor and the interaction with
which then activate or repress transcrip- the inflammatory response. ACTH, adrenocorticotrophic hormone; CRH, corticotropin-releasing hor- tion of the associated genes. In addition, mone; IL-6, interleukin-6; IL-11, interleukin-11; LIF, leukemia inhibitory factor; POMC, pro- the cortisol-GR complex may affect cellu- opiomelanocortin; TGF-beta, transforming growth factor-␤; TNF, tumor necrosis factor.
lar function indirectly by binding to andmodulating the transcriptional activity ofother nuclear transcription factors, such Corticotropin-releasing hormone stimu- ing in a significant increase in the as nuclear factor B (NF-B) and activa- lates the production of ACTH by the an- percentage of free cortisol (27, 28). The tor protein-1. Overall, GCs affect the terior pituitary, causing the zona fascicu- circulating half-life of cortisol varies from transcription of thousands of genes in lata of the adrenal cortex to produce 70 to 120 mins. The adrenal gland does every cell of the body. It has been esti- more GCs (cortisol in humans, cortico- not store cortisol; increased secretion mated that GCs affect 20% of the genome sterone in rats). Arginine vasopressin is a arises due to increased synthesis under of mononuclear blood cells (39).
weak ACTH secretagogue and vasoactive the control of ACTH (29). Cholesterol is GCs play a major role in regulating peptide that acts synergistically with cor- the principal precursor for steroid bio- the activity of NF-B, which plays a cru- ticotropin-releasing hormone to increase synthesis in steroidogenic tissue. In a se- cial and generalized role in inducing cy- secretion of ACTH. The increase in corti- ries of sequential enzymatic steps, cho- tokine gene transcription (40 – 42).
sol production results in multiple effects lesterol is converted to pregnenolone and NF-B is normally maintained in an in- (metabolic, cardiovascular, and immune) then to the end products of adrenal bio- active form by sequestration in the cyto- aimed at maintaining or restoring ho- synthesis, namely, aldosterone, dehydro- plasm through interaction with inhibi- meostasis during stress.
epiandrostenedione, and cortisol (29).
tory proteins (IBs). On stimulation by The first and rate-limiting step in adrenal Cortisol Physiology, Synthesis,
steroidogenesis is the formation of preg- DNA, physical and chemical stresses, and and Glucocorticoid Receptors
nenolone from cholesterol. At rest and inflammatory cytokines, the latent NF- during stress, about 80% of circulating B/IB complex is activated by phosphor- Cortisol is the major endogenous GC cortisol is derived from plasma choles- ylation and proteolytic degradation of secreted by the adrenal cortex. More than terol, the remaining 20% being synthe- IB, with exposure of the NF-B nuclear 90% of circulating cortisol is bound to sized in situ from acetate and other pre- localization sequence. The liberated corticosteroid-binding globulin, with cursors (30). Experimental studies NF-B then translocates to the nucleus ⬍10% in the free, biologically active suggest that high-density lipoprotein is and binds to promoter regions of targetform (25, 26). Corticosteroid-binding the preferred cholesterol source of steroi- genes to initiate the transcription of mul- globulin is the predominant binding pro- dogenic substrate in the adrenal gland tiple cytokines (including tumor necrosis tein, with albumin binding a lesser (31). Recently, mouse SR-B1 (scavenger factor-␣, interleukin-1, and interleukin- amount. During acute illness, particu- receptor, class B, type 1) and its human 6), cell adhesion molecules (e.g., intercel- larly sepsis, corticosteroid-binding glob- homolog (Cla-1) have been identified as lular adhesion molecule-1, E-selectin), ulin levels fall by as much as 50%, result- the high-affinity high-density lipoprotein and other mediators of inflammation.
Crit Care Med 2008 Vol. 36, No. 6
GCs inhibit the activity of NF-B by in- widely (0 –77%), depending on the popu- severe asthma, systematic lupus ery- creasing the transcription of IBs and by lation of patients studied and the diag- thematosus, ulcerative colitis, and rheu- directly binding to and inhibiting NF-B nostic criteria. However, the overall prev- matoid arthritis (62– 65). It is therefore alence of adrenal insufficiency in likely that acute inflammation, similar to Cortisol has several important physio- critically ill medical patients approxi- chronic inflammation, may be associated logic actions on metabolism, cardiovas- mates 10 –20%, with a rate as high as with tissue corticosteroid resistance (61).
cular function, and the immune system 60% in patients with septic shock. In a In experimental models, endotoxin and (6, 43). The metabolic effects of cortisol study recently published by Annane et al.
proinflammatory cytokines have been include an increase in blood glucose con- (53), the prevalence of adrenal insuffi- shown to cause decreased GR nuclear centrations through the activation of key ciency (as determined by metyrapone translocation (66 – 68). In an ex vivo enzymes involved in hepatic gluconeo- testing) in patients with severe sepsis and model, Meduri et al. (69) demonstrated genesis and inhibition of glucose uptake septic shock was reported to be 60%. The reduced nuclear translocation of the GR in peripheral tissues such as the skeletal major effect of adrenal insufficiency in complex in patients with fatal ARDS, de- muscles. In addition, in adipose tissue, the critically ill patient is manifested spite adequate cytoplasmic (and serum) lipolysis is activated, resulting in the re- through alterations in the systemic in- levels of cortisol. It is likely that multiple lease of free fatty acids into the circula- flammatory response and cardiovascular mechanisms cause systemic inflamma- tion. Cortisol also has a permissive effect tion-associated GC resistance, including on other hormones, increasing glucose The mechanisms leading to dysfunc- decreased GR number, increased expres- levels, including catecholamines and glu- tion of the HPA axis during critical illness sion of the beta isoform of the GR (unable cagon. Sustained cortisol hypersecretion are complex and poorly understood and to bind ligand), altered ratio of chaperone stimulates glucose production at the ex- likely include decreased production of proteins (FK binding proteins and heat pense of protein and lipid catabolism and corticotropin-releasing hormone, ACTH, shock protein 90), reduced affinity of the insulin resistance.
and cortisol and the dysfunction of their GR for ligand, altered nuclear receptor Cortisol increases blood pressure receptors. A subset of patients may have coactivators, reduced DNA binding, de- through several mechanisms involving structural damage to the adrenal gland creased histone acetylation, increased ac- the kidney and vasculature. In vascular from either hemorrhage or infarction, tivity of the P-glycoprotein membrane smooth muscle, cortisol increases sensi- and this may result in long-term adrenal transport pump, and increased conver- tivity to vasopressor agents such as cat- dysfunction. Adrenal hemorrhage has sion of cortisol to cortisone (61, 68, 70 – echolamines and angiotensin II (44, 45).
been described with blunt abdominal 72). Furthermore, polymorphisms of the These effects are mediated partly by the trauma, after major surgery, in dissemi- GR and other pivotal genes may influence increased transcription and expression of nated intravascular coagulation associ- the downstream effects of the GC–GR in- the receptors for these hormones (44, ated with sepsis, and in patients with teraction (73, 74). Additional research in 45). Although the effect of GCs on nitric burns, heparin-induced thrombocytope- this area, particularly as it applies to crit- oxide is complex, it seems to increase nia, the antiphospholipid syndrome, HIV ically ill patients, is urgently required.
endothelial nitric oxide synthetase, infection, disseminated fungal infections, Current evidence suggests that medi- thereby maintaining microvascular per- and tuberculosis (3, 54 –59). In addition, ators released in patients with critical ill- fusion (46 – 49). Cortisol has potent anti- patients who have been treated long term ness, and sepsis in particular, may either inflammatory actions, including the re- with adrenally suppressive doses of exog- stimulate or impair the synthesis and ac- duction in the number and function of enous GCs are likely to develop secondary tion of cortisol via actions on the HPA various immune cells, such as T and B adrenal insufficiency (3, 6). However, it axis and the GR signaling system. The net lymphocytes, monocytes, neutrophils, seems that most critically ill patients who effect of these opposing actions on the and eosinophils, at sites of inflammation.
develop adrenal insufficiency develop re- HPA axis and GR may be time dependent Cortisol decreases the production of cy- versible dysfunction of the HPA axis (6, and, in addition, depend on the severity of tokines, chemokines, and eicosanoids and 60). Decreased production of cortisol or illness and the extent and pattern of me- enhances the production of macrophage ACTH is particularly common in patients diator production. Although the focus on migration inhibitory factor (22, 50).
with severe sepsis and septic shock (60).
most research has been in the area of Annane et al. (53) demonstrated an in- sepsis and ARDS, it is likely that similar Dysfunction of the HPA Axis
creased risk of adrenal insufficiency in mechanisms operate in other disorders During Acute Illness
patients with positive blood cultures and characterized by significant systemic in- those with Gram-negative infections.
flammation, including pancreatitis, The acute stress response during crit- Clinical and experimental data indi- burns, post-cardiopulmonary bypass, and ical illness is characterized by activation cate that the failure to improve in sepsis liver failure (75–79).
of the HPA and sympathoadrenal system and ARDS is frequently associated with axis, with increased secretion of cortisol, failure of activated GRs to down-regulate RECOMMENDATIONS OF THE
an increase in the percentage of free cor- the transcription of inflammatory cyto- TASK FORCE
tisol, and increased translocation of the kines, despite elevated levels of circulat- GR complex into the nucleus. Impor- ing cortisol, a condition defined as sys- Critical Illness–Related Corticosteroid tantly, there is increasing evidence that temic inflammation-associated GC in many critically ill patients, this path- resistance (61). Tissue corticosteroid re- way may be impaired (27, 51, 52). The sistance is a well-known manifestation of Recommendation 1: Dysfunction of the reported prevalence of adrenal insuffi- chronic inflammatory diseases, such as HPA axis in critical illness is best de- ciency in critically ill patients varies chronic obstructive pulmonary disease, scribed by the term critical illness– Crit Care Med 2008 Vol. 36, No. 6
related corticosteroid insufficiency Strength of Recommendation: 2B adrenal gland to increase production of cortisol in response to ACTH; it does not Recommendation 2: The terms abso- The diagnosis of adrenal insufficiency assess the integrity of the HPA axis, the lute or relative adrenal insufficiency in critically ill patients has been based on response of the HPA axis to other stresses are best avoided in the context of crit- the measurement of a random total se- (i.e., hypotension, hypoglycemia), or the ical illness.
rum cortisol ("stress" cortisol level) or adequacy of stress cortisol levels. In ad- the change in the serum cortisol in re- dition, the ACTH stimulation test may be Dysfunction of the HPA axis in critical sponse to 250 g of synthetic ACTH poorly reproducible, especially in patients illness is best described by the term crit- (ACTH stimulation test), the so-called with septic shock (97, 98). Despite these ical illness–related corticosteroid insuffi- delta cortisol (6, 84). Both of these tests limitations, Annane et al. (53) have re- ciency (CIRCI). CIRCI is defined as inad- have significant limitations in the criti- ported that a delta cortisol of ⬍9 g/dL equate cellular corticosteroid activity for cally ill (85). Assays for serum cortisol and a random total cortisol of ⬍10 g/dL the severity of the patient's illness. CIRCI measure the total hormone concentra- were the best predictors of adrenal insuf- manifests with insufficient GC-GR– tion (serum-free cortisol plus the pro- ficiency (as determined by metyrapone mediated down-regulation of proinflam- tein-bound fraction). The consensus is testing) in patients with severe sepsis/ matory transcription factors, leading to that the free cortisol, rather than the septic shock. Furthermore, although the persistent elevation of proinflammatory protein-bound fraction, is responsible for 1-g ACTH stimulation test may be more mediators over time. CIRCI occurs as a the physiologic function of the hormone physiologic and have a greater sensitivity result of a decrease in adrenal steroid at the cellular level (6, 50, 86). In most than the 250-g test, due to limited data, production (adrenal insufficiency) or tis- critically ill patients, corticosteroid- the 1-g test dose is currently not rec- sue resistance to GCs (with or without binding globulin levels are decreased and ommended (99). It should also be appre- adrenal insufficiency). Adrenal insuffi- the percentage of free cortisol is in- ciated that at present, we are unable to ciency may arise due to dysfunction at creased (27, 51, 52, 86, 87). Furthermore, measure tissue GC resistance or deter- any point in the HPA axis. The terms with acute stimulation of the adrenal mine the circulating cortisol level that is absolute or relative adrenal insufficiency gland, the relative increase of free bioac- required to overcome tissue resistance.
are best avoided in the context of critical tive cortisol concentrations is substan- In those patients (severe sepsis, septic illness (80). CIRCI is a dynamic process tially more pronounced than the increase shock, and ARDS) most likely to benefit (i.e., patients may not have CIRCI at ad- of total cortisol concentrations (27, 51, from treatment with moderate-dose GCs, mission to the hospital/intensive care 52, 86 – 88). Consequently, in critically ill it is not clear that treatment should be unit but may develop CIRCI during the patients, the total serum cortisol level based on the results of adrenal function course of their illness) (81– 83). CIRCI is may not accurately reflect the free corti- testing. To date, six randomized, placebo- usually a reversible condition caused by sol level. This dissociation between the controlled studies have evaluated hydro- proinflammatory mediators; however, it total and free cortisol level is most cortisone treatment (200 –300 mg/day) in may also arise due to structural damage marked in patients with a serum albumin patients with septic shock (95, 100 –103) of the adrenal gland. CIRCI may affect the of ⬍2.5 mg/dL (85, 87, 89).
(Figs. 2 and 3). In these studies, more balance between proinflammatory and Although measurement of the free rapid shock reversal was noted in patients anti-inflammatory pathways and thereby cortisol level may arguably be prefera- treated with hydrocortisone, and this influence immune, metabolic, vascular, ble, this test is currently not widely benefit was noted in both ACTH respond- and organ dysfunction.
available. It is likely, however, that with ers (delta cortisol of ⬎9 mg/dL) and non- Diagnosis of Adrenal Insufficiency improvement in laboratory techniques responders (delta cortisol of ⬍9 mg/dL) and clinical demand, this test will be- (Fig. 2). Furthermore, recent randomized Recommendation 3: At this time, adre- come commercially available (90). The controlled studies in patients with early nal insufficiency in critical illness is interpretation of the total serum cortisol ARDS (treatment within 14 days) and se- best diagnosed by a delta cortisol (after concentration is further complicated by vere community-acquired pneumonia 250 g cosyntropin) of ⬍9 g/dL or a the fact that the specificity, sensitivity, demonstrated improved outcome with random total cortisol of ⬍10 g/dL.
and performance of the commercially GCs (when compared with placebo), in- Strength of Recommendation: 2B available assays are not uniform (91). It is dependent of adrenal function testing likely that the variation in assay charac- (see section below) (7, 104, 105). These Recommendation 4: The use of free teristics might be even more significant data suggest that in patients with septic cortisol measurements cannot be rec- in critically ill patients, especially those shock and early ARDS, the decision to ommended for routine use at this time.
with septic shock (91, 92). Cross-reactiv- treat with moderate-dose corticosteroids Although the free cortisol assay has ity of the cortisol immunoassay with pre- should be based on clinical criteria and advantages over the total serum corti- cursors or metabolites of cortisol that not on the results of adrenal function sol, this test is not readily available.
accumulate in sepsis may account for this testing. The inability to diagnose cortico- Furthermore, the normal range of the steroid tissue resistance may partly ex- free cortisol in critically ill patients is Although a delta cortisol of ⬍9 g/dL plain these observations.
has proven to be an important prognostic Strength of Recommendation: 2B Who to Treat with Glucocorticoids? marker (9, 53, 93, 94), and a marker of Recommendation 5: The ACTH stimu- response to treatment with corticoste- Recommendation 6: Hydrocortisone lation test should not be used to iden- roids (95, 96), the ACTH stimulation test should be considered in the manage- tify those patients with septic shock or has a number of limitations. The delta ment strategy of patients with septic ARDS who should receive GCs.
cortisol is a measure of the ability of the shock, particularly those patients who Crit Care Med 2008 Vol. 36, No. 6 Figure 2. Meta-analysis of treatment with moderate-dose hydrocortisone on shock reversal at day 7 in patients with septic shock grouped by response to
adrenocorticotrophic hormone. RR, relative risk; 95% CI, 95% confidence interval.
Figure 3. Meta-analysis of treatment with moderate-dose hydrocortisone on 28-day survival in patients with septic shock. RR, relative risk; 95% CI, 95%
have responded poorly to fluid resusci- in study size, inclusion criteria, and cor- fludrocortisone (50 g daily) or matching tation and vasopressor agents.
ticosteroid dosing limits the interpreta- placebo for 7 days. All patients underwent Strength of Recommendations: 2B tion of this meta-analysis. Nevertheless, an ACTH stimulation test. There was a the French multicenter study and the re- 30% decrease in 28-day mortality in the The benefit of moderate-dose hydro- cently completed European multicenter cortisone (200 –300 mg/day) in patients study (CORTICUS) were better powered (hazard ratio, 0.67; 95% confidence inter- with septic shock has been evaluated in to detect a survival difference and deserve val, 0.47– 0.95; p ⫽ .02) (95). This benefit six randomized controlled trials (95, further analysis. Annane et al. (95) ran- was confined to the group of nonre- 100 –103, 106). A meta-analysis of these domized 300 patients with refractory sep- sponders (delta cortisol of ⬍9 g/dL).
six studies (including the recently com- tic shock (systolic blood pressure of ⬍90 The CORTICUS study was a double- pleted CORTICUS study) demonstrates mm Hg for ⬎1 hr, despite fluid resusci- blind, randomized, placebo-controlled greater shock reversal (at day 7) with tation and the use of vasopressor agents) study performed in 52 centers through- hydrocortisone but no benefit in terms of to treatment with hydrocortisone (50 mg out Europe (106). A total of 500 patients mortality (Figs. 2 and 3). The variability intravenously every 6 hrs) and oral (499 available to analyze) were enrolled Crit Care Med 2008 Vol. 36, No. 6
between March 2002 and November lay in instituting treatment. It is also resolution of shock was noted in both 2005. Inclusion criteria included septic possible that improvements in the sup- responders and nonresponders. Thus, at shock (systolic blood pressure of ⬍90 portive care of critically ill patients with this time, it seems that the decision to mm Hg, despite adequate fluid resuscita- septic shock over the last decade have treat patients with septic shock should tion or need for vasopressors) and evi- increased the survival of patients with not be based on the results of a random dence of organ dysfunction attributable CIRCI who would otherwise have died.
total cortisol level or the response to to sepsis. Patients were randomized to The demographics and clinical character- ACTH. In addition, it should be noted hydrocortisone (50 mg intravenously ev- istics of the patients enrolled in the two that the administration of hydrocortisone ery 6 hrs for 5 days, then 50 mg intrave- studies were quite different, with 40.1% during septic shock has been demon- nously every 12 hrs for 3 days, followed of patients in the French study being strated to reduce the prevalence of post- by 50 mg intravenously daily for 3 days) surgical patients as compared with 64.5% traumatic stress disorder and improve or matching placebo. Patients did not re- in the CORTICUS study. Source control the emotional well-being of survivors of ceive fludrocortisone. Although the base- may be more important in determining septic shock (110).
line characteristics of the patients were the outcome of sepsis in surgical patients similar, only 35% of the cohort were than that of adjunctive interventions.
Recommendation 7: Moderate-dose GC medical patients, with the abdomen be- Furthermore, it is possible that selection should be considered in the manage- ing the commonest source of infection bias affected the demographics and out- ment strategy of patients with early (48%). There was no difference in the come of the CORTICUS study. Although severe ARDS (PaO /F 28-day all-cause mortality between those it has been suggested that clinical equi- before day 14 in patients with unre- patients who received hydrocortisone as poise existed during enrollment into the solving ARDS. The role of GC treat- compared with placebo. Furthermore, CORTICUS study (107), many intensivists ment in acute lung injury and less se- there was no difference in mortality be- continue to use corticosteroids in the vere ARDS (PaO /F of ⬎200) is less tween the groups when stratified as re- management of patients with septic sponders (delta cortisol of ⬎9 g/dL) or shock (108, 109).
Strength of Recommendations: 2B nonresponders (delta cortisol of ⬍9 g/ Given the different outcomes of the dL) to the ACTH stimulation test. How- French and CORTICUS studies, what Five randomized studies (n ⫽ 518) ever, the patients who received hydrocor- should the clinician do? Considering the have evaluated the role of GC treatment tisone had more rapid resolution of shock central role of cortisol in modulating the in patients with acute lung injury due to (p ⫽ .001 for responders and p ⫽ .06 for stress response and recognizing the po- community-acquired pneumonia (7) and nonresponders). There were, however, tential suppressive effects of sepsis on the in patients with ARDS of varied origins more episodes of new infection (not sta- HPA axis and on GR activity, the use of (104, 105, 111, 112). Varying doses (200 – tistically significant) and septic shock (re- moderate-dose hydrocortisone seems ra- 750 mg of hydrocortisone equivalents per bound inflammation) in the hydrocorti- tional in patients with septic shock poorly day), dosing strategies (infusion/bolus), sone group. The prevalence of other responsive to fluid and vasopressor resus- and duration of therapy (7–32 days) were adverse events, including critical illness citation. This is supported by recent data used in these studies. Due to the marked polyneuropathy, was similar between that demonstrate that up to 60% of pa- differences in study design and patient tients with severe sepsis and septic shock characteristics, the cumulative summary A number of factors may account for have adrenal insufficiency (53). The best of these studies should be interpreted the different results of the French multi- available clinical evidence suggests that with some caution. Nevertheless, these center study and the CORTICUS study.
moderate-dose hydrocortisone results in trials consistently reported that treat- The patients enrolled in the French study significantly more rapid resolution of ment was associated with significant im- were sicker than those enrolled in the shock (Fig. 2). The effects of moderate- provement in PaO /F (7, 104, 105, 111, CORTICUS study (28-day mortality in the dose hydrocortisone on mortality seem 112), a significant reduction in markers placebo arm of 61% vs. 31.5%). Further- less clear (Fig. 3). Nevertheless, based on of systemic inflammation (7, 104, 105, more, the time window of enrollment was current data, hydrocortisone should be 111, 112), duration of mechanical venti- 8 hrs in the French study as compared considered in the management strategy lation (7, 104, 105, 111, 112), and inten- with 72 hrs in the CORTICUS study. It is of patients with septic shock, particularly sive care unit length of stay (all with p likely that only patients at a high risk of those patients who have responded poorly values of ⬍.05) (7, 104, 105, 111). Sub- death will benefit from corticosteroids, to fluid resuscitation and vasopressor group analysis (Fig. 4) based on studies and this benefit may diminish with a de- agents. As noted in Figure 2, more rapid that investigated only treatment (methyl- Figure 4. Effects of prolonged methylprednisolone treatment on mechanical ventilation–free days at day 28. Reproduced with permission from Meduri et
al (114). WMD, weighted mean difference; 95% CI, 95% confidence interval.
Crit Care Med 2008 Vol. 36, No. 6 prednisolone) durations of ⬎1 wk (n ⫽ a distinct reduction in the relative risk of day). The optimal initial dosing regi- 295) (104, 105, 111) showed a distinct death (82/214 [38%] vs. 98/186 [52.5%]; men in patients with early severe ARDS increase in the number of mechanical relative risk, 0.78; 95% confidence inter- is 1 mg·kg⫺1·day⫺1 methylpred- ventilation–free days (weighted mean dif- val, 0.64 – 0.96; p ⫽ .02) (114). When an- nisolone as a continuous infusion.
ference, 5.59 days; 95% confidence inter- alyzing the three trials investigating cor- Strength of Recommendation: 1B val, 3.49 –7.68; p ⬍ .001).
ticosteroids for durations of ⬎1 wk GC treatment in acute lung injury– initiated before day 14 of ARDS (n ⫽ Recommendation 9: The optimal dura- ARDS was not associated with increased 245), mortality was equally decreased tion of GC treatment in patients with rates of gastrointestinal bleeding or nos- (35/144 [24%] vs. 40/101 [40%]; relative septic shock and early ARDS is unclear.
ocomial infections, and two of the studies risk, 0.62; 95% confidence interval, 0.43– However, based on published studies reported a reduction in the rate of noso- 0.90; p ⫽ .01) (Fig. 5) (114).
and pathophysiological data, patients comial infections, likely attributable to The results of one randomized trial with septic shock should be treated for the shorter duration of mechanical ven- (111) indicate that 1 mg·kg⫺1·day⫺1 ⱖ7 days before tapering, assuming tilation (104, 105). In the two random- methylprednisolone, given as an infusion that there is no recurrence of signs of ized trials (104, 111) that incorporated and tapered over the course of 4 wks, is sepsis or shock. Patients with early infection surveillance, nosocomial infec- associated with a favorable risk– benefit ARDS should be treated for ⱖ14 days tions were frequently (56%) identified in profile when secondary preventive mea- before tapering.
the absence of fever. The combination of sures are implemented. These measures Strength of Recommendation: 2B GCs and neuromuscular blocking agents include 1) intensive infection surveil- significantly increases the risk for pro- lance, 2) avoidance of paralytic agents, Recommendation 10: GC treatment longed neuromuscular weakness (113).
and 3) avoidance of rebound inflamma- should be tapered slowly and not In the ARDS Network trial, although both tion with premature discontinuation of stopped abruptly.
groups had similar exposure to paralytic treatment that may lead to physiologic Strength of Recommendation: 2B agents (49% vs. 42%; p ⫽ .3), those ran- deterioration and reintubation. It should domized to methylprednisolone had a be noted that the premature and rapid Recommendation 11: Treatment with higher rate of serious events associated taper of corticosteroids in the ARDS Net- fludrocortisone (50 g orally once with myopathy or neuropathy (105). The work trial resulted in a deterioration of daily) is considered optional.
other four trials did not report an in- and a higher reintubation Strength of Recommendation: 2B creased rate of neuromuscular complica- rate in the treatment group (105, 114).
tions (7, 104, 111, 112).
Preliminary data suggest that GCs Recommendation 12: Dexamethasone A reduction in mortality was noted in may be of benefit in patients with severe is not recommended for the treatment four studies (7, 104, 111, 112). The ARDS community-acquired pneumonia, liver of septic shock or ARDS.
Network trial reported increased 60-day failure, pancreatitis, patients undergoing Strength of Recommendation: 1B mortality in the subgroup randomized to cardiopulmonary bypass, and during methylprednisolone after 14 days of weaning from mechanical ventilation (7, Ideally, the dose of GC should be suf- ARDS (105). This small subgroup (n ⫽ 10, 11, 75, 96, 115). The potential bene- ficient to down-regulate the proinflam- 48), however, had large imbalances in fits of treatment with hydrocortisone in matory response without causing im- baseline characteristics, and the mortal- these patient subgroups and other criti- mune-paresis and interfering with wound ity difference lost significance (p ⫽ .57) cally ill patients deserve further investi- healing. Similarly, the duration of GC when adjusting for these imbalances therapy should be guided by the duration (114). The two small clinical trials (n ⫽ of CIRCI and the associated duration of How to Treat 68) (7, 111) showed marked reduction in systemic inflammation. The optimal dose the relative risk of death with GC therapy Recommendation 8: In patients with and duration of treatment with hydrocor- (2/39 [5%] vs. 11/31 [35%]; relative risk, septic shock, intravenous hydrocorti- tisone/methylprednisolone remains to be 0.15; 95% confidence interval, 0.04 – sone should be given in a dose of 200 determined in well-controlled and well- 0.59; p ⫽ .007). The three subsequently mg/day in four divided doses or as a powered studies. However, the results of published larger clinical trials (104, 105, bolus of 100 mg followed by a contin- published studies do allow us to make a 112), when combined (n ⫽ 400), achieved uous infusion at 10 mg/hr (240 mg/ number of recommendations. A number Figure 5. Effects of prolonged glucocorticoid treatment initiated before day 14 of acute lung injury-acute respiratory distress syndrome on survival.
Reproduced with permission from Meduri et al (114). RR, relative risk; 95% CI, 95% confidence interval.
Crit Care Med 2008 Vol. 36, No. 6 of randomized controlled studies have in- nisolone for ⱖ14 days, followed by a slow with septic shock and ARDS. At this time, vestigated the utility of a high-dose, taper while monitoring indices of oxygen- treatment with moderate-dose corticoste- short-course treatment with corticoste- roids is recommended in patients with roids in patients with ARDS and sepsis.
Meduri et al. (124) demonstrated that septic shock who have responded poorly Doses of methylprednisolone as high as persistent elevation of inflammatory cy- to volume resuscitation and vasopressor 20 –30 mg/kg body weight (10,000 to tokines predicted a poor outcome in pa- agents. The consistent positive results re- 40,000 mg of hydrocortisone) during the tients with ARDS. Recently, two longitu- ported in patients with early severe ARDS course of 24 hrs were investigated (116 – dinal studies in patients with severe of ⬍200) and unresolving 118). These studies were unable to dem- community-acquired pneumonia found ARDS treated with GCs before day 14 onstrate an improved outcome, and there high levels of circulating inflammatory suggest that treatment with moderate- was a higher risk of complications in the cytokines 3 wks after clinical resolution dose GCs should be considered in these patients who received high-dose cortico- of sepsis (125, 126). The larger study, patients. Tests of adrenal function are not steroids (116 –118). The literature there- involving 1,886 patients, showed hospital routinely required in these patients. The fore does not support the use of high- mortality to be associated with higher role of GCs in the management of pa- dose corticosteroids in critically ill circulating inflammatory cytokine levels tients with community-acquired pneu- patients (except to prevent/treat rejection and persistent elevation over time (125).
monia, liver failure, pancreatitis, those in transplant patients).
Furthermore, higher circulating inter- undergoing cardiac surgery, and other Myopathy and an increased risk of su- leukin-6 levels at intensive care unit dis- groups of critically ill patients requires perinfections are more common in pa- charge were associated with increased tients receiving ⬎300 mg of hydrocorti- risk of death over 3 months (127). These sone equivalents per day (117, 118).
data support the concept of immune dys- Furthermore, while suppressing an exag- regulation in severe sepsis and ARDS (in- gerated proinflammatory response, a sufficient corticosteroid activity–CIRCI) 1. Jurney TH, Cockrell JL Jr, Lindberg JS, et dose of 200 –300 mg of hydrocortisone and suggest that the duration of treat- al: Spectrum of serum cortisol response to per day does not seem to have immuno- ment with GCs should be guided by the ACTH in ICU patients: Correlation with de- suppressive effects (119, 120). Based on duration of elevation of inflammatory cy- gree of illness and mortality. Chest 1987; these data and the treatment protocol tokines (124). Further studies should ex- 2. Reincke M, Allolio B, Wurth G, et al: The used in the French and CORTICUS stud- plore this concept.
hypothalamic-pituitary-adrenal axis in crit- ies, we recommend that patients with In the French study, patients in the ical illness: Response to dexamethasone and septic shock be treated with 50 mg of treatment group received hydrocortisone corticotropin-releasing hormone. J Clin hydrocortisone intravenously every 6 hrs together with fludrocortisone (50 g Endocrinol Metab 1993; 77:151–156 or a bolus of 100 mg, followed by a con- orally once daily), whereas in the CORTI- 3. Arlt W, Allolio B: Adrenal insufficiency.
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6. Marik PE, Zaloga GP: Adrenal Insufficiency ing that there is no recurrence of signs of gov NCT 00368381 and NCT00320099).
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7. Confalonieri M, Urbino R, Potena A, et al: abruptly. The hydrocortisone dose should Although treatment with dexametha- Hydrocortisone infusion for severe commu- be reduced every 2–3 days in small steps, sone has been suggested in patients with nity-acquired pneumonia: A preliminaryrandomized study. Am J Respir Crit Care unless there is clinical deterioration, septic shock until an ACTH stimulation Med 2005; 171:242–248 which would then require an increase in test is performed, this approach can no 8. Dimopoulou I, Tsagarakis S: Hypothalamic- hydrocortisone dose. Abruptly stopping longer be endorsed. This recommenda- pituitary dysfunction in critically ill pa- hydrocortisone will likely result in a re- tion is based on the fact that dexametha- tients with traumatic and nontraumatic bound of proinflammatory mediators, sone leads to immediate and prolonged brain injury. Intensive Care Med 2005; 31: with recurrence of the features of shock suppression of the HPA axis (limiting the (and tissue injury) (105, 119). In addi- value of ACTH testing).
9. Tsai MH, Peng YS, Chen YC, et al: Adrenal tion, it should be appreciated that GC insufficiency in patients with cirrhosis, se- treatment itself results in down-regula- vere sepsis and septic shock. Hepatology tion of GR levels in most cells, potentiat- 2006; 43:673– 681 10. Eklund A, Leppaniemi A, Kemppainen E, et ing the rebound phenomenon with the CIRCI is a complex and frequent dis- al: Vasodilatory shock in severe acute pan- abrupt cessation of GC treatment (70).
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Grade of recommendation/ Benefits vs. Risk and burdens Methodological quality of supporting evidence 1A: Strong recommendation, Benefits clearly outweigh risk RCTs without important limitations Strong recommendation can high quality evidence and burdens or vise versa or overwhelming evidence from apply to most patients in most observational studies 1B: Strong recommendation, Benefits clearly outweigh risk RCTs with important limitations or Strong recommendation can moderate quality evidence and burdens or vise versa exceptionally strong evidence apply to most patients in most from observational studies 1C: Strong recommendation, Benefits clearly outweigh risk Observational studies or case series Strong recommendation but may low quality or very low- and burdens or vise versa change when higher quality evidence becomes available 2A: Weak recommendation, Benefits closely balanced with RCTs without important limitations Weak recommendation, best high quality evidence or overwhelming evidence from action may differ depending on observational studies circumstances or patients orsocietal values 2B: Weak recommendation, Benefits closely balanced with RCTs with important limitations or Weak recommendation, best moderate quality evidence exceptionally strong evidence action may differ depending on from observational studies circumstances or patients orsocietal values 2C: Weak recommendation, Uncertainty in the estimates of Observational studies or case series Very weak recommendations; low quality or very low benefits, risks, and burdens; other alternatives may be benefits risk and burden equally reasonable may be closely balanced Reproduced with permission from Chest. RCT, randomized controlled trial.
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