endocrinologia coricosteroidinsufficiencyadult

Special Article

Recommendations for the diagnosis and management of corticosteroidinsufficiency in critically ill adult patients: Consensus statements from aninternational 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

*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 CareDepartment, Universite de Versailes Saint-Quentin en Yve-lines, Hospital Raymond Poincare, Garches, France (DA);Division of Pulmonary and Critical Care Medicine, Universityof Tennessee HSC, Memphis, TN (GUM); Department ofAnesthesiology, 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, HumboldtUniversity, Berlin, Germany (DK); Department of Anesthesi-ology, University of Munich, Klinikum Grosshadern, Munich,Germany (JB); Department of Intensive Care, VU UniversityMedical Center, Amsterdam, Netherlands (AB); Departmentof Critical Care Medicine, Athens University, Medical School,Athens, Greece (ID); Department of Endocrinology, AthensPolyclinic, Athens, Greece (ST); Department of Medicine andWolfson Institute of Biomedical Research, University CollegeLondon, Jules Thorn Building, Middlesex Hospital, London,UK (MS); First Department of Pediatrics, Athens UniversityMedical School, Athens, Greece (GPC); Baxter Healthcare,Clintec Nutrition, Deerfield, IL (GZ); Department of Trauma,

Stronger Hospital of Cook County, Chicago, IL (FB); Hospitalof 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 theconsultative body of the Society of Critical Care Medi-cine (SCCM) that possesses recognized expertise inthe practice of critical care. The College has developedadministrative guidelines and clinical practice parameters forthe critical care practitioner. New guidelines and practiceparameters are continually developed, and current ones aresystematically reviewed and revised.

Dr. Marik has received lecture fees from Eli Lilly andMerck. Dr. Keh has received grant support from the GermanResearch Foundation and German Ministry of Education andResearch (HYPRESS: Hydrocortisone for Prevention of SepticShock). Dr. Sprung has been a member of a data monitoringand safety committee for Artisan Pharma, Novartis Corpora-tion, and Hutchinson Technology Incorporated. He hasserved as a consultant for AstraZeneca, Eisai Corporation, EliLilly, and GlaxoSmithKline. He has received grant supportfrom 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 theCORTICUS study, which was supported by the EuropeanCommission, the European Society of Intensive Care Medi-

cine, the European Critical Care Research Network, theInternational Sepsis Forum, and the Gorham Foundation. Dr.Annane has received grant support from the French Ministryof Health for the prognostic value of a adrenocorticotrophichormone test in septic shock; the French multicenter, ran-domized, controlled trial on hydrocortisone plus fludrocorti-sone in septic shock; the ongoing French multicenter 2 2factorial 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 compareshydrocortisone plus fludrocortisone, activated protein C, thecombination of the two drugs, and placebos for the treatmentof septic shock. Dr. Pastores has received grant support formEisai Medical Research (phase 3 trial of E5564 in severesepsis), and Artisan Pharma (phase 2 sepsis with dissemi-nated intravascular coagulation trial). The remaining authorshave not disclosed any conflicts of interest with respect tothis article.

For information regarding this article, E-mail:[email protected]

Copyright 2008 by the Society of Critical CareMedicine and Lippincott Williams & Wilkins

DOI: 10.1097/CCM.0b013e31817603ba

Objective: To develop consensus statements for the diagnosis andmanagement of corticosteroid insufficiency in critically ill adult patients.

Participants: A multidisciplinary, multispecialty task force of experts incritical care medicine was convened from the membership of the Society ofCritical 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 literatureand provided expert opinion from which the consensus was derived. Theconsensus statements were developed using a modified Delphi methodology.The strength of each recommendation was quantified using the ModifiedGRADE system, which classifies recommendations as strong (grade 1) or weak(grade 2) and the quality of evidence as high (grade A), moderate (grade B), orlow (grade C) based on factors that include the study design, the consistencyof the results, and the directness of the evidence.

Results: The task force coined the term critical illnessrelated corticosteroidinsufficiency to describe the dysfunction of the hypothalamic-pituitary-adrenal axisthat occurs during critical illness. Critical illnessrelated corticosteroid insufficiencyis caused by adrenal insufficiency togetherwith tissue corticosteroid resistance andis characterized by an exaggerated and protracted proinflammatory response.Critical illnessrelated 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 corticosteroidresistance remains problematic. Adrenal insufficiency in critically ill patients is bestmade by a delta total serum cortisol of

Severe illness and stress stronglyactivate the hypothalamic-pitu-itary-adrenal (HPA) axis andstimulate the release of adreno-corticotrophic hormone (ACTH) from thepituitary, which in turn increases the re-lease of cortisol from the adrenal cortex(13). This activation is an essential com-ponent of the general adaptation to illnessand stress and contributes to the mainte-nance of cellular and organ homeostasis.Adrenalectomized animals succumb rap-idly to hemorrhagic and septic shock, andsteroid replacement is protective againstthese challenges (4, 5).

Once considered a rare diagnosis inthe intensive care unit, adrenal failureis being reported with increasing fre-quency in critically ill patients with septicshock, severe community-acquired pneu-monia, trauma, head injury, burns, liverfailure, HIV infection, pancreatitis, aftercardiac surgery, after the use of etomi-date, and in brain-dead organ donors (611). Adrenal failure may be associatedwith structural damage to the adrenalgland, pituitary gland, or hypothalamus;however, many critically ill patients de-velop reversible failure of the HPA axis.

Although it is generally agreed thatadrenal failure may be common in sub-groups of critically ill patients, the diag-nosis and management of this disorderremains controversial, with poor agree-ment among the experts. The objective ofthis task force was therefore to developconsensus statements by experts in thefield based on the best available scientificevidence (12).

METHODS

Experts were selected from the mem-bership lists of the Society of CriticalCare Medicine (SCCM) and the EuropeanSociety of Intensive Care Medicine (ES-ICM). Specific individuals were selectedto represent geographic diversity and abroad range of expertise on the basis oftheir published research. In addition, en-docrinologists with expertise in this areawere invited to join the task force.

The consensus statement was devel-oped using a modified Delphi methodol-ogy (12). The Delphi method, originallydeveloped by the RAND Corporation, is astructured process that uses a series ofquestionnaires, each referred to as around, to both gather and provide infor-mation (13, 14). With each round, theanswers are modified based on the re-sponses of the previous round. The

rounds continue until group consensus/majority is reached. This approach hasseveral distinct advantages. It allows theinclusion of a large number of individualsacross diverse geographic locations andwith a broad range of expertise. One of itskey advantages is that unlike a face-to-face meeting of experts, it eliminates thepossibility that a specific expert mightdominate the consensus process. TheDelphi method helps to minimize the ef-fects of group interactions and maximizesthe ability to elicit expert knowledge.

The task force members individuallyand collectively undertook a systematicsearch of published literature pertainingto the diagnosis and treatment of adrenalfailure in critically ill adult patients usingMedline, CINAHL, EMBASE, and the Co-chrane library. In addition, the referencelists of relevant articles were reviewed foradditional published works. Key wordsused in these searches included pitu-itaryadrenal system, adrenal insuffi-ciency, adrenal glands, pituitaryadrenalfunction tests, hydrocortisone, glucocor-ticoids (GC), adrenal cortex hormones,glucocorticoid receptor (GR), criticalcare, intensive care units, intensive care,ARDS, shock septic, sepsis, and sepsissyndrome. A comprehensive bibliogra-phy was developed, with the referencesstored and cataloged using an electronicreference manager (Reference Managerv11.1, Thompson ResearchSoft, Carlsbad,CA).

We used electronic mail to conductthe Delphi process. A list of questions forreview was determined. Once a majorityagreement was reached on each question,the strength of each recommendationwas quantified using the Modified Gradesof Recommendation Assessment, Devel-opment, and Evaluation (GRADE) systemdeveloped by the American College ofChest Physicians (Appendix 1) (15). In all,there were seven rounds until a majorityagreement was achieved on all the ques-tions. In addition, the group met in Paris,France, in September 2005 and again atthe Society of Critical Care Medicine 35thCritical Care Congress in San Francisco,CA, in January 2006 to review theprogress of the Delphi process. The initialdraft of the manuscript was written bythe Chair (P. E. Marik). The draft manu-script was reviewed and iteratively editedby all members of the task force.

A meta-analysis of randomized con-trolled trials that compared the 28-daymortality and vasopressor dependency ofpatients 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 ofthe task force members (P. E. Marik, D.Annane, S. M. Pastores, G. U. Meduri)reviewed the task force bibliography forrelevant studies. Septic shock was definedby the American College of Chest Physi-cians/Society of Critical Care MedicineConsensus Conference and ARDS by theAmericanEuropean Consensus Confer-ence (16, 17). Vasopressor dependencywas defined as the requirement for a va-sopressor agent after 7 days of treatmentwith a glucocorticoid (GC). The reviewersindependently abstracted data from all el-igible studies. Data were abstracted onstudy design, study size, corticosteroiddosage, vasopressor dependency, and 28-day mortality. Study and data inclusionwas by consensus. We used the randomeffects models using Review Manager 4.2(Cochrane Collaboration, Oxford, UK) forall analyses and considered p .05 (two-sided) as significant. Summary effects es-timates are presented as odds ratio with95% confidence intervals. We assessedheterogeneity between studies using theCochran Q statistic with p .10 indicat-ing significant heterogeneity and the I2

with suggested thresholds for low (2549%), moderate (50 74%), and high(75%) values (1821).

BACKGROUND

Exposure to hostile conditions resultsin a series of coordinated responsesoften referred to as stress responsesorganized to enhance survival; these in-clude a series of complex central andperipheral adaptations. This stress re-sponse is mediated mainly by the HPAaxis and the sympathoadrenal system,which includes the sympathetic nervoussystem and the adrenal medulla (Fig. 1)(2224). The HPA axis and the sympa-thoadrenal system are functionally re-lated. Activation of the sympathoadrenalsystem results in the secretion of epi-nephrine and norepinephrine from theadrenal medulla and also leads to an in-creased production of inflammatory cyto-kines, such as interleukin-6. Activation ofthe HPA axis results in increased secre-tion from the paraventricular nucleus ofthe hypothalamus of corticotropin-releasing hormone, a 41-amino acid pep-tide, and arginine vasopressin. Cortico-tropin-releasing hormone plays a pivotalintegrative role in the response to stress.

1938 Crit Care Med 2008 Vol. 36, No. 6

Corticotropin-releasing hormone stimu-lates the production of ACTH by the an-terior pituitary, causing the zona fascicu-lata of the adrenal cortex to producemore GCs (cortisol in humans, cortico-sterone in rats). Arginine vasopressin is aweak ACTH secretagogue and vasoactivepeptide that acts synergistically with cor-ticotropin-releasing hormone to increasesecretion 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 GCsecreted by the adrenal cortex. More than90% of circulating cortisol is bound tocorticosteroid-binding globulin, with10% in the free, biologically activeform (25, 26). Corticosteroid-bindingglobulin is the predominant binding pro-tein, with albumin binding a lesseramount. During acute illness, particu-larly sepsis, corticosteroid-binding glob-ulin levels fall by as much as 50%, result-

ing in a significant increase in thepercentage of free cortisol (27, 28). Thecirculating half-life of cortisol varies from70 to 120 mins. The adrenal gland doesnot store cortisol; increased secretionarises due to increased synthesis underthe control of ACTH (29). Cholesterol isthe principal precursor for steroid bio-synthesis in steroidogenic tissue. In a se-ries of sequential enzymatic steps, cho-lesterol is converted to pregnenolone andthen to the end products of adrenal bio-synthesis, namely, aldosterone, dehydro-epiandrostenedione, and cortisol (29).The first and rate-limiting step in adrenalsteroidogenesis is the formation of preg-nenolone from cholesterol. At rest andduring stress, about 80% of circulatingcortisol is derived from plasma choles-terol, the remaining 20% being synthe-sized in situ from acetate and other pre-cursors (30). Experimental studiessuggest that high-density lipoprotein isthe preferred cholesterol source of steroi-dogenic substrate in the adrenal gland(31). Recently, mouse SR-B1 (scavengerreceptor, class B, type 1) and its humanhomolog (Cla-1) have been identified asthe high-affinity high-density lipoprotein

receptor mediating selective cholesteroluptake (3234). 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 uptakefrom 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 (3638). 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,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 andmodulating the transcriptional activity ofother nuclear transcription factors, suchas nuclear factor B (NF-B) and activa-tor protein-1. Overall, GCs affect thetranscription of thousands of genes inevery cell of the body. It has been esti-mated that GCs affect 20% of the genomeof mononuclear blood cells (39).

GCs play a major role in regulatingthe 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 (IBs). On stimulation bylipopolysaccharide, double-strandedDNA, physical and chemical stresses, andinflammatory cytokines, the latent NF-B/IB complex is activated by phosphor-ylation and proteolytic degradation ofIB, with exposure of the NF-B nuclearlocalization sequence. The liberatedNF-B then translocates to the nucleusand binds to promoter regions of targetgenes to initiate the transcription of mul-tiple cytokines (including tumor necrosisfactor-, 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 withthe 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.

1939Crit Care Med 2008 Vol. 36, No. 6

GCs inhibit the activity of NF-B by in-creasing the transcription of IBs and bydirectly 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 cortisolinclude an increase in blood glucose con-centrations through the activation of keyenzymes involved in hepatic gluconeo-genesis and inhibition of glucose uptakein peripheral tissues such as the skeletalmuscles. 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 effecton other hormones, increasing glucoselevels, including catecholamines and glu-cagon. Sustained cortisol hypersecretionstimulates glucose production at the ex-pense of protein and lipid catabolism andinsulin resistance.

Cortisol increases blood pressurethrough several mechanisms involvingthe kidney and vasculature. In vascularsmooth muscle, cortisol increases sensi-tivity to vasopressor agents such as cat-echolamines and angiotensin II (44, 45).These effects are mediated partly by theincreased transcription and expression ofthe receptors for these hormones (44,45). Although the effect of GCs on nitricoxide is complex, it seems to increaseendothelial nitric oxide synthetase,thereby maintaining microvascular per-fusion (4649). Cortisol has potent anti-inflammatory actions, including the re-duction in the number and function ofvarious immune cells, such as T and Blymphocytes, monocytes, neutrophils,and eosinophils, at sites of inflammation.Cortisol decreases the production of cy-tokines, chemokines, and eicosanoids andenhances the production of macrophagemigration inhibitory factor (22, 50).

Dysfunction of the HPA AxisDuring Acute Illness

The acute stress response during crit-ical illness is characterized by activationof the HPA and sympathoadrenal systemaxis, with increased secretion of cortisol,an increase in the percentage of free cor-tisol, and increased translocation of theGR complex into the nucleus. Impor-tantly, there is increasing evidence thatin many critically ill patients, this path-way may be impaired (27, 51, 52). Thereported prevalence of adrenal insuffi-ciency in critically ill patients varies

widely (077%), depending on the popu-lation of patients studied and the diag-nostic criteria. However, the overall prev-alence of adrenal insufficiency incritically ill medical patients approxi-mates 1020%, with a rate as high as60% in patients with septic shock. In astudy recently published by Annane et al.(53), the prevalence of adrenal insuffi-ciency (as determined by metyraponetesting) in patients with severe sepsis andseptic shock was reported to be 60%. Themajor effect of adrenal insufficiency inthe critically ill patient is manifestedthrough alterations in the systemic in-flammatory response and cardiovascularfunction.

The mechanisms leading to dysfunc-tion of the HPA axis during critical illnessare complex and poorly understood andlikely include decreased production ofcorticotropin-releasing hormone, ACTH,and cortisol and the dysfunction of theirreceptors. A subset of patients may havestructural damage to the adrenal glandfrom either hemorrhage or infarction,and this may result in long-term adrenaldysfunction. Adrenal hemorrhage hasbeen described with blunt abdominaltrauma, after major surgery, in dissemi-nated intravascular coagulation associ-ated with sepsis, and in patients withburns, heparin-induced thrombocytope-nia, the antiphospholipid syndrome, HIVinfection, disseminated fungal infections,and tuberculosis (3, 5459). In addition,patients who have been treated long termwith adrenally suppressive doses of exog-enous GCs are likely to develop secondaryadrenal insufficiency (3, 6). However, itseems that most critically ill patients whodevelop adrenal insufficiency develop re-versible dysfunction of the HPA axis (6,60). Decreased production of cortisol orACTH is particularly common in patientswith severe sepsis and septic shock (60).Annane et al. (53) demonstrated an in-creased risk of adrenal insufficiency inpatients with positive blood cultures andthose with Gram-negative infections.

Clinical and experimental data indi-cate that the failure to improve in sepsisand ARDS is frequently associated withfailure of activated GRs to down-regulatethe transcription of inflammatory cyto-kines, despite elevated levels of circulat-ing cortisol, a condition defined as sys-temic inflammation-associated GCresistance (61). Tissue corticosteroid re-sistance is a well-known manifestation ofchronic inflammatory diseases, such aschronic obstructive pulmonary disease,

severe asthma, systematic lupus ery-thematosus, ulcerative colitis, and rheu-matoid arthritis (6265). It is thereforelikely that acute inflammation, similar tochronic inflammation, may be associatedwith tissue corticosteroid resistance (61).In experimental models, endotoxin andproinflammatory cytokines have beenshown to cause decreased GR nucleartranslocation (66 68). In an ex vivomodel, Meduri et al. (69) demonstratedreduced nuclear translocation of the GRcomplex in patients with fatal ARDS, de-spite adequate cytoplasmic (and serum)levels of cortisol. It is likely that multiplemechanisms cause systemic inflamma-tion-associated GC resistance, includingdecreased GR number, increased expres-sion of the beta isoform of the GR (unableto bind ligand), altered ratio of chaperoneproteins (FK binding proteins and heatshock protein 90), reduced affinity of theGR for ligand, altered nuclear receptorcoactivators, reduced DNA binding, de-creased histone acetylation, increased ac-tivity of the P-glycoprotein membranetransport pump, and increased conver-sion of cortisol to cortisone (61, 68, 7072). Furthermore, polymorphisms of theGR and other pivotal genes may influencethe downstream effects of the GCGR in-teraction (73, 74). Additional research inthis 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 eitherstimulate or impair the synthesis and ac-tion of cortisol via actions on the HPAaxis and the GR signaling system. The neteffect of these opposing actions on theHPA axis and GR may be time dependentand, in addition, depend on the severity ofillness and the extent and pattern of me-diator production. Although the focus onmost research has been in the area ofsepsis and ARDS, it is likely that similarmechanisms operate in other disorderscharacterized by significant systemic in-flammation, including pancreatitis,burns, post-cardiopulmonary bypass, andliver failure (7579).

RECOMMENDATIONS OF THETASK FORCE

Critical IllnessRelated CorticosteroidInsufficiency

Recommendation 1: Dysfunction of theHPA axis in critical illness is best de-scribed by the term critical illness


related corticosteroid insufficiency(CIRCI).

Recommendation 2: The terms abso-lute or relative adrenal insufficiencyare best avoided in the context of crit-ical illness.

Dysfunction of the HPA axis in criticalillness is best described by the term crit-ical illnessrelated corticosteroid insuffi-ciency (CIRCI). CIRCI is defined as inad-equate cellular corticosteroid activity forthe severity of the patients illness. CIRCImanifests with insufficient GC-GRmediated down-regulation of proinflam-matory transcription factors, leading topersistent elevation of proinflammatorymediators over time. CIRCI occurs as aresult of a decrease in adrenal steroidproduction (adrenal insufficiency) or tis-sue resistance to GCs (with or withoutadrenal insufficiency). Adrenal insuffi-ciency may arise due to dysfunction atany point in the HPA axis. The termsabsolute or relative adrenal insufficiencyare best avoided in the context of criticalillness (80). CIRCI is a dynamic process(i.e., patients may not have CIRCI at ad-mission to the hospital/intensive careunit but may develop CIRCI during thecourse of their illness) (8183). CIRCI isusually a reversible condition caused byproinflammatory mediators; however, itmay also arise due to structural damageof the adrenal gland. CIRCI may affect thebalance between proinflammatory andanti-inflammatory pathways and therebyinfluence immune, metabolic, vascular,and organ dysfunction.

Diagnosis of Adrenal Insufficiency

Recommendation 3: At this time, adre-nal insufficiency in critical illness isbest diagnosed by a delta cortisol (after250 g cosyntropin) of 9 g/dL or arandom total cortisol of 10 g/dL.

Strength of Recommendation: 2B

Recommendation 4: The use of freecortisol measurements cannot be rec-ommended for routine use at this time.Although the free cortisol assay hasadvantages over the total serum corti-sol, this test is not readily available.Furthermore, the normal range of thefree cortisol in critically ill patients iscurrently unclear.


Recommendation 5: The ACTH stimu-lation test should not be used to iden-tify those patients with septic shock orARDS who should receive GCs.


The diagnosis of adrenal insufficiencyin critically ill patients has been based onthe measurement of a random total se-rum cortisol (stress cortisol level) orthe change in the serum cortisol in re-sponse to 250 g of synthetic ACTH(ACTH stimulation test), the so-calleddelta cortisol (6, 84). Both of these testshave significant limitations in the criti-cally ill (85). Assays for serum cortisolmeasure the total hormone concentra-tion (serum-free cortisol plus the pro-tein-bound fraction). The consensus isthat the free cortisol, rather than theprotein-bound fraction, is responsible forthe physiologic function of the hormoneat the cellular level (6, 50, 86). In mostcritically ill patients, corticosteroid-binding globulin levels are decreased andthe percentage of free cortisol is in-creased (27, 51, 52, 86, 87). Furthermore,with acute stimulation of the adrenalgland, the relative increase of free bioac-tive cortisol concentrations is substan-tially more pronounced than the increaseof total cortisol concentrations (27, 51,52, 8688). Consequently, in critically illpatients, the total serum cortisol levelmay not accurately reflect the free corti-sol level. This dissociation between thetotal and free cortisol level is mostmarked in patients with a serum albuminof 2.5 mg/dL (85, 87, 89).

Although measurement of the freecortisol level may arguably be prefera-ble, this test is currently not widelyavailable. It is likely, however, that withimprovement in laboratory techniquesand clinical demand, this test will be-come commercially available (90). Theinterpretation of the total serum cortisolconcentration is further complicated bythe fact that the specificity, sensitivity,and performance of the commerciallyavailable assays are not uniform (91). It islikely that the variation in assay charac-teristics might be even more significantin critically ill patients, especially thosewith septic shock (91, 92). Cross-reactiv-ity of the cortisol immunoassay with pre-cursors or metabolites of cortisol thataccumulate in sepsis may account for thisobservation.

Although a delta cortisol of 9 g/dLhas proven to be an important prognosticmarker (9, 53, 93, 94), and a marker ofresponse to treatment with corticoste-roids (95, 96), the ACTH stimulation testhas a number of limitations. The deltacortisol is a measure of the ability of the

adrenal gland to increase production ofcortisol in response to ACTH; it does notassess the integrity of the HPA axis, theresponse of the HPA axis to other stresses(i.e., hypotension, hypoglycemia), or theadequacy of stress cortisol levels. In ad-dition, the ACTH stimulation test may bepoorly reproducible, especially in patientswith septic shock (97, 98). Despite theselimitations, Annane et al. (53) have re-ported that a delta cortisol of 9 g/dLand a random total cortisol of 10 g/dLwere the best predictors of adrenal insuf-ficiency (as determined by metyraponetesting) in patients with severe sepsis/septic shock. Furthermore, although the1-g ACTH stimulation test may be morephysiologic and have a greater sensitivitythan the 250-g test, due to limited data,the 1-g test dose is currently not rec-ommended (99). It should also be appre-ciated that at present, we are unable tomeasure tissue GC resistance or deter-mine the circulating cortisol level that isrequired to overcome tissue resistance.

In those patients (severe sepsis, septicshock, and ARDS) most likely to benefitfrom treatment with moderate-dose GCs,it is not clear that treatment should bebased on the results of adrenal functiontesting. To date, six randomized, placebo-controlled studies have evaluated hydro-cortisone treatment (200300 mg/day) inpatients with septic shock (95, 100103)(Figs. 2 and 3). In these studies, morerapid shock reversal was noted in patientstreated with hydrocortisone, and thisbenefit was noted in both ACTH respond-ers (delta cortisol of 9 mg/dL) and non-responders (delta cortisol of 9 mg/dL)(Fig. 2). Furthermore, recent randomizedcontrolled studies in patients with earlyARDS (treatment within 14 days) and se-vere community-acquired pneumoniademonstrated improved outcome withGCs (when compared with placebo), in-dependent of adrenal function testing(see section below) (7, 104, 105). Thesedata suggest that in patients with septicshock and early ARDS, the decision totreat with moderate-dose corticosteroidsshould be based on clinical criteria andnot on the results of adrenal functiontesting. The inability to diagnose cortico-steroid tissue resistance may partly ex-plain these observations.

Who to Treat with Glucocorticoids?

Recommendation 6: Hydrocortisoneshould be considered in the manage-ment strategy of patients with septicshock, particularly those patients who


have responded poorly to fluid resusci-tation and vasopressor agents.

Strength of Recommendations: 2B

The benefit of moderate-dose hydro-cortisone (200300 mg/day) in patientswith septic shock has been evaluated insix randomized controlled trials (95,100103, 106). A meta-analysis of thesesix studies (including the recently com-pleted CORTICUS study) demonstratesgreater shock reversal (at day 7) withhydrocortisone but no benefit in terms ofmortality (Figs. 2 and 3). The variability

in study size, inclusion criteria, and cor-ticosteroid dosing limits the interpreta-tion of this meta-analysis. Nevertheless,the French multicenter study and the re-cently completed European multicenterstudy (CORTICUS) were better poweredto detect a survival difference and deservefurther analysis. Annane et al. (95) ran-domized 300 patients with refractory sep-tic shock (systolic blood pressure of 90mm Hg for 1 hr, despite fluid resusci-tation and the use of vasopressor agents)to treatment with hydrocortisone (50 mgintravenously every 6 hrs) and oral

fludrocortisone (50 g daily) or matchingplacebo for 7 days. All patients underwentan ACTH stimulation test. There was a30% decrease in 28-day mortality in thehydrocortisonefludrocortisone group(hazard ratio, 0.67; 95% confidence inter-val, 0.470.95; p .02) (95). This benefitwas confined to the group of nonre-sponders (delta cortisol of 9 g/dL).

The CORTICUS study was a double-blind, randomized, placebo-controlledstudy performed in 52 centers through-out Europe (106). A total of 500 patients(499 available to analyze) were enrolled

Figure 2. Meta-analysis of treatment with moderate-dose hydrocortisone on shock reversal at day 7 in patients with septic shock grouped by response toadrenocorticotrophic 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%confidence interval.


between March 2002 and November2005. Inclusion criteria included septicshock (systolic blood pressure of 90mm Hg, despite adequate fluid resuscita-tion or need for vasopressors) and evi-dence of organ dysfunction attributableto sepsis. Patients were randomized tohydrocortisone (50 mg intravenously ev-ery 6 hrs for 5 days, then 50 mg intrave-nously every 12 hrs for 3 days, followedby 50 mg intravenously daily for 3 days)or matching placebo. Patients did not re-ceive fludrocortisone. Although the base-line characteristics of the patients weresimilar, only 35% of the cohort weremedical patients, with the abdomen be-ing the commonest source of infection(48%). There was no difference in the28-day all-cause mortality between thosepatients who received hydrocortisone ascompared with placebo. Furthermore,there was no difference in mortality be-tween the groups when stratified as re-sponders (delta cortisol of 9 g/dL) ornonresponders (delta cortisol of 9 g/dL) to the ACTH stimulation test. How-ever, the patients who received hydrocor-tisone had more rapid resolution of shock(p .001 for responders and p .06 fornonresponders). There were, however,more episodes of new infection (not sta-tistically significant) and septic shock (re-bound inflammation) in the hydrocorti-sone group. The prevalence of otheradverse events, including critical illnesspolyneuropathy, was similar betweengroups.

A number of factors may account forthe different results of the French multi-center study and the CORTICUS study.The patients enrolled in the French studywere sicker than those enrolled in theCORTICUS study (28-day mortality in theplacebo arm of 61% vs. 31.5%). Further-more, the time window of enrollment was8 hrs in the French study as comparedwith 72 hrs in the CORTICUS study. It islikely that only patients at a high risk ofdeath will benefit from corticosteroids,and this benefit may diminish with a de-

lay in instituting treatment. It is alsopossible that improvements in the sup-portive care of critically ill patients withseptic shock over the last decade haveincreased the survival of patients withCIRCI who would otherwise have died.The demographics and clinical character-istics of the patients enrolled in the twostudies were quite different, with 40.1%of patients in the French study beingsurgical patients as compared with 64.5%in the CORTICUS study. Source controlmay be more important in determiningthe outcome of sepsis in surgical patientsthan that of adjunctive interventions.Furthermore, it is possible that selectionbias affected the demographics and out-come of the CORTICUS study. Althoughit has been suggested that clinical equi-poise existed during enrollment into theCORTICUS study (107), many intensivistscontinue to use corticosteroids in themanagement of patients with septicshock (108, 109).

Given the different outcomes of theFrench and CORTICUS studies, whatshould the clinician do? Considering thecentral role of cortisol in modulating thestress response and recognizing the po-tential suppressive effects of sepsis on theHPA axis and on GR activity, the use ofmoderate-dose hydrocortisone seems ra-tional in patients with septic shock poorlyresponsive to fluid and vasopressor resus-citation. This is supported by recent datathat demonstrate that up to 60% of pa-tients with severe sepsis and septic shockhave adrenal insufficiency (53). The bestavailable clinical evidence suggests thatmoderate-dose hydrocortisone results insignificantly more rapid resolution ofshock (Fig. 2). The effects of moderate-dose hydrocortisone on mortality seemless clear (Fig. 3). Nevertheless, based oncurrent data, hydrocortisone should beconsidered in the management strategyof patients with septic shock, particularlythose patients who have responded poorlyto fluid resuscitation and vasopressoragents. As noted in Figure 2, more rapid

resolution of shock was noted in bothresponders and nonresponders. Thus, atthis time, it seems that the decision totreat patients with septic shock shouldnot be based on the results of a randomtotal cortisol level or the response toACTH. In addition, it should be notedthat the administration of hydrocortisoneduring septic shock has been demon-strated to reduce the prevalence of post-traumatic stress disorder and improvethe emotional well-being of survivors ofseptic shock (110).

Recommendation 7: Moderate-dose GCshould be considered in the manage-ment strategy of patients with earlysevere ARDS (PaO2/FIO2 of 200) andbefore day 14 in patients with unre-solving ARDS. The role of GC treat-ment in acute lung injury and less se-vere ARDS (PaO2/FIO2 of 200) is lessclear.

Strength of Recommendations: 2B

Five randomized studies (n 518)have evaluated the role of GC treatmentin patients with acute lung injury due tocommunity-acquired pneumonia (7) andin patients with ARDS of varied origins(104, 105, 111, 112). Varying doses (200750 mg of hydrocortisone equivalents perday), dosing strategies (infusion/bolus),and duration of therapy (732 days) wereused in these studies. Due to the markeddifferences in study design and patientcharacteristics, the cumulative summaryof these studies should be interpretedwith some caution. Nevertheless, thesetrials consistently reported that treat-ment was associated with significant im-provement in PaO2/FIO2 (7, 104, 105, 111,112), a significant reduction in markersof systemic inflammation (7, 104, 105,111, 112), duration of mechanical venti-lation (7, 104, 105, 111, 112), and inten-sive care unit length of stay (all with pvalues of .05) (7, 104, 105, 111). Sub-group analysis (Fig. 4) based on studiesthat investigated only treatment (methyl-

Figure 4. Effects of prolonged methylprednisolone treatment on mechanical ventilationfree days at day 28. Reproduced with permission from Meduri etal (114). WMD, weighted mean difference; 95% CI, 95% confidence interval.


prednisolone) durations of 1 wk (n 295) (104, 105, 111) showed a distinctincrease in the number of mechanicalventilationfree days (weighted mean dif-ference, 5.59 days; 95% confidence inter-val, 3.497.68; p .001).

GC treatment in acute lung injuryARDS was not associated with increasedrates of gastrointestinal bleeding or nos-ocomial infections, and two of the studiesreported a reduction in the rate of noso-comial infections, likely attributable tothe shorter duration of mechanical ven-tilation (104, 105). In the two random-ized trials (104, 111) that incorporatedinfection surveillance, nosocomial infec-tions were frequently (56%) identified inthe absence of fever. The combination ofGCs and neuromuscular blocking agentssignificantly increases the risk for pro-longed neuromuscular weakness (113).In the ARDS Network trial, although bothgroups had similar exposure to paralyticagents (49% vs. 42%; p .3), those ran-domized to methylprednisolone had ahigher rate of serious events associatedwith myopathy or neuropathy (105). Theother four trials did not report an in-creased rate of neuromuscular complica-tions (7, 104, 111, 112).

A reduction in mortality was noted infour studies (7, 104, 111, 112). The ARDSNetwork trial reported increased 60-daymortality in the subgroup randomized tomethylprednisolone after 14 days ofARDS (105). This small subgroup (n 48), however, had large imbalances inbaseline characteristics, and the mortal-ity difference lost significance (p .57)when adjusting for these imbalances(114). The two small clinical trials (n 68) (7, 111) showed marked reduction inthe relative risk of death with GC therapy(2/39 [5%] vs. 11/31 [35%]; relative risk,0.15; 95% confidence interval, 0.04 0.59; p .007). The three subsequentlypublished larger clinical trials (104, 105,112), when combined (n 400), achieved

a distinct reduction in the relative risk ofdeath (82/214 [38%] vs. 98/186 [52.5%];relative risk, 0.78; 95% confidence inter-val, 0.640.96; p .02) (114). When an-alyzing the three trials investigating cor-ticosteroids for durations of 1 wkinitiated before day 14 of ARDS (n 245), mortality was equally decreased(35/144 [24%] vs. 40/101 [40%]; relativerisk, 0.62; 95% confidence interval, 0.430.90; p .01) (Fig. 5) (114).

The results of one randomized trial(111) indicate that 1 mgkg1day1

methylprednisolone, given as an infusionand tapered over the course of 4 wks, isassociated with a favorable riskbenefitprofile when secondary preventive mea-sures are implemented. These measuresinclude 1) intensive infection surveil-lance, 2) avoidance of paralytic agents,and 3) avoidance of rebound inflamma-tion with premature discontinuation oftreatment that may lead to physiologicdeterioration and reintubation. It shouldbe noted that the premature and rapidtaper of corticosteroids in the ARDS Net-work trial resulted in a deterioration ofthe PaO2/FIO2 and a higher reintubationrate in the treatment group (105, 114).

Preliminary data suggest that GCsmay be of benefit in patients with severecommunity-acquired pneumonia, liverfailure, pancreatitis, patients undergoingcardiopulmonary bypass, and duringweaning from mechanical ventilation (7,10, 11, 75, 96, 115). The potential bene-fits of treatment with hydrocortisone inthese patient subgroups and other criti-cally ill patients deserve further investi-gation.

How to Treat

Recommendation 8: In patients withseptic shock, intravenous hydrocorti-sone should be given in a dose of 200mg/day in four divided doses or as abolus of 100 mg followed by a contin-uous infusion at 10 mg/hr (240 mg/

day). The optimal initial dosing regi-men in patients with early severe ARDSis 1 mgkg1day1 methylpred-nisolone as a continuous infusion.


Recommendation 9: The optimal dura-tion of GC treatment in patients withseptic shock and early ARDS is unclear.However, based on published studiesand pathophysiological data, patientswith septic shock should be treated for7 days before tapering, assumingthat there is no recurrence of signs ofsepsis or shock. Patients with earlyARDS should be treated for 14 daysbefore tapering.


Recommendation 10: GC treatmentshould be tapered slowly and notstopped abruptly.


Recommendation 11: Treatment withfludrocortisone (50 g orally oncedaily) is considered optional.


Recommendation 12: Dexamethasoneis not recommended for the treatmentof septic shock or ARDS.


Ideally, the dose of GC should be suf-ficient to down-regulate the proinflam-matory response without causing im-mune-paresis and interfering with woundhealing. Similarly, the duration of GCtherapy should be guided by the durationof CIRCI and the associated duration ofsystemic inflammation. The optimal doseand duration of treatment with hydrocor-tisone/methylprednisolone remains to bedetermined in well-controlled and well-powered studies. However, the results ofpublished studies do allow us to make anumber 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.


of randomized controlled studies have in-vestigated the utility of a high-dose,short-course treatment with corticoste-roids in patients with ARDS and sepsis.Doses of methylprednisolone as high as20 30 mg/kg body weight (10,000 to40,000 mg of hydrocortisone) during thecourse of 24 hrs were investigated (116118). These studies were unable to dem-onstrate an improved outcome, and therewas a higher risk of complications in thepatients who received high-dose cortico-steroids (116118). The literature there-fore does not support the use of high-dose corticosteroids in critically illpatients (except to prevent/treat rejectionin transplant patients).

Myopathy and an increased risk of su-perinfections are more common in pa-tients receiving 300 mg of hydrocorti-sone equivalents per day (117, 118).Furthermore, while suppressing an exag-gerated proinflammatory response, adose of 200300 mg of hydrocortisoneper day does not seem to have immuno-suppressive effects (119, 120). Based onthese data and the treatment protocolused in the French and CORTICUS stud-ies, we recommend that patients withseptic shock be treated with 50 mg ofhydrocortisone intravenously every 6 hrsor a bolus of 100 mg, followed by a con-tinuous intravenous infusion at 10 mg/hr(340 mg the first day; 240 mg/day onsubsequent days). The use of a continu-ous infusion of hydrocortisone has beenreported to result in better glycemic con-trol, with less variability of blood glucoseconcentration and a reduction in the staffworkload of managing hyperglycemia(85, 121123). Treatment should con-tinue for7 days before tapering, assum-ing that there is no recurrence of signs ofsepsis or shock. Hydrocortisone shouldbe tapered slowly and not stoppedabruptly. The hydrocortisone dose shouldbe reduced every 23 days in small steps,unless there is clinical deterioration,which would then require an increase inhydrocortisone dose. Abruptly stoppinghydrocortisone will likely result in a re-bound of proinflammatory mediators,with recurrence of the features of shock(and tissue injury) (105, 119). In addi-tion, it should be appreciated that GCtreatment itself results in down-regula-tion of GR levels in most cells, potentiat-ing the rebound phenomenon with theabrupt cessation of GC treatment (70).Currently, the optimal dose and durationof therapy in patients with early severeARDS is 1 mgkg1day1 methylpred-

nisolone for 14 days, followed by a slowtaper while monitoring indices of oxygen-ation.

Meduri et al. (124) demonstrated thatpersistent elevation of inflammatory cy-tokines predicted a poor outcome in pa-tients with ARDS. Recently, two longitu-dinal studies in patients with severecommunity-acquired pneumonia foundhigh levels of circulating inflammatorycytokines 3 wks after clinical resolutionof sepsis (125, 126). The larger study,involving 1,886 patients, showed hospitalmortality to be associated with highercirculating inflammatory cytokine levelsand persistent elevation over time (125).Furthermore, higher circulating inter-leukin-6 levels at intensive care unit dis-charge were associated with increasedrisk of death over 3 months (127). Thesedata support the concept of immune dys-regulation in severe sepsis and ARDS (in-sufficient corticosteroid activityCIRCI)and suggest that the duration of treat-ment with GCs should be guided by theduration of elevation of inflammatory cy-tokines (124). Further studies should ex-plore this concept.

In the French study, patients in thetreatment group received hydrocortisonetogether with fludrocortisone (50 gorally once daily), whereas in the CORTI-CUS study patients received hydrocorti-sone alone. It is unclear if the addition offludrocortisone played a role in the favor-able outcome of the French study. Thebenefit of the addition of fludrocortisonein patients with septic shock is currentlybeing investigated in two randomizedcontrolled trials comparing hydrocorti-sone alone vs. hydrocortisone togetherwith fludrocortisone (www.ClinicalTrial.gov NCT 00368381 and NCT00320099).Treatment with fludrocortisone is consid-ered optional at this time.

Although treatment with dexametha-sone has been suggested in patients withseptic shock until an ACTH stimulationtest is performed, this approach can nolonger be endorsed. This recommenda-tion is based on the fact that dexametha-sone leads to immediate and prolongedsuppression of the HPA axis (limiting thevalue of ACTH testing).

CONCLUSION

CIRCI is a complex and frequent dis-order of which our understanding contin-ues to evolve. Although CIRCI may affecta spectrum of critically ill patients, mostof the research has focused on patients

with septic shock and ARDS. At this time,treatment with moderate-dose corticoste-roids is recommended in patients withseptic shock who have responded poorlyto volume resuscitation and vasopressoragents. The consistent positive results re-ported in patients with early severe ARDS(PaO2/FIO2 of 200) and unresolvingARDS treated with GCs before day 14suggest that treatment with moderate-dose GCs should be considered in thesepatients. Tests of adrenal function are notroutinely required in these patients. Therole of GCs in the management of pa-tients with community-acquired pneu-monia, liver failure, pancreatitis, thoseundergoing cardiac surgery, and othergroups of critically ill patients requiresfurther investigation.

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Appendix 1. Modified Grades of Recommendation Assessment, Development, and Evaluation (GRADE) system for Grading the strength of the evidence (15)

Grade of recommendation/description

Benefits vs. Risk and burdens Methodological quality ofsupporting evidence

Implications

1A: Strong recommendation,high quality evidence

Benefits clearly outweigh riskand burdens or vise versa

RCTs without important limitationsor overwhelming evidence fromobservational studies

Strong recommendation canapply to most patients in mostcircumstances withoutreservation

1B: Strong recommendation,moderate quality evidence


RCTs with important limitations orexceptionally strong evidencefrom observational studies

Strong recommendation canapply to most patients in mostcircumstances withoutreservation

1C: Strong recommendation,low quality or very low-quality evidence


Observational studies or case series Strong recommendation but maychange when higher qualityevidence becomes available

2A: Weak recommendation,high quality evidence

Benefits closely balanced withrisk and burden

RCTs without important limitationsor overwhelming evidence fromobservational studies

Weak recommendation, bestaction may differ depending oncircumstances or patients orsocietal values

2B: Weak recommendation,moderate quality evidence

Benefits closely balanced withrisk and burden

RCTs with important limitations orexceptionally strong evidencefrom observational studies

Weak recommendation, bestaction may differ depending oncircumstances or patients orsocietal values

2C: Weak recommendation,low quality or very lowquality evidence

Uncertainty in the estimates ofbenefits, risks, and burdens;benefits risk and burdenmay be closely balanced

Observational studies or case series Very weak recommendations;other alternatives may beequally reasonable

Reproduced with permission from Chest. RCT, randomized controlled trial.


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