This is the current release of the guideline.

Critical illness-related corticosteroid insufficiency (adrenal insufficiency), including:

• Septic shock
• Acute respiratory distress syndrome (ARDS)

Diagnosis
Management

Critical Care
Emergency Medicine
Endocrinology
Family Practice
Internal Medicine
Pulmonary Medicine

Advanced Practice Nurses
Health Care Providers
Hospitals
Nurses
Physician Assistants
Physicians

To develop consensus statements for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients

Critically ill adult patients

Diagnosis

Adrenal function testing:

• Delta total serum cortisol
• Random total serum cortisol

Note: The use of free cortisol assay cannot be recommended for use at this time. The adrenocorticotrophic hormone (ACTH) stimulation test should not be used to identify those patients with septic shock or acute respiratory disease (ARDS) who should receive glucocorticoids.

Treatment/Management

1. Hydrocortisone
2. Methylprednisolone
3. Fludrocortisone (optional)
4. Tapering of glucocorticoids
5. Reinstitution of treatment with recurrence of symptoms

Note: Dexamethasone is not recommended for the treatment of septic shock or ARDS.

• 28-day mortality
• Vasopressor dependency
• Adverse events of glucocorticoid (GC) therapy
• Duration of mechanical ventilation
• Intensive care unit length of stay
• Incidence of myopathy or neuropathy
• Immediate or prolonged suppression of hypothalamic-pituitary-adrenal (HPA) axis

Hand-searches of Published Literature (Primary Sources)
Hand-searches of Published Literature (Secondary Sources)
Searches of Electronic Databases

The task force members individually and collectively undertook a systematic search of published literature pertaining to the diagnosis and treatment of adrenal failure in critically ill adult patients using Medline, CINAHL, EMBASE, and the Cochrane library. In addition, the reference lists of relevant articles were reviewed for additional published works. Key words used in these searches included "pituitary–adrenal system, adrenal insufficiency, adrenal glands, pituitary–adrenal function tests, hydrocortisone, glucocorticoids (GC), adrenal cortex hormones, glucocorticoid receptor (GR), critical care, intensive care units, intensive care, ARDS, shock septic, sepsis, and sepsis syndrome."

Not stated

Expert Consensus (Delphi Method)
Weighting According to a Rating Scheme (Scheme Given)

Modified Grades of Recommendation Assessment, Development, and Evaluation (GRADE) system for grading the strength of evidence

Meta-Analysis of Randomized Controlled Trials

A meta-analysis of randomized controlled trials that compared the 28-day mortality and vasopressor dependency of patients with septic shock and the 28-day mortality of patients with acute respiratory distress syndrome (ARDS) who received either moderate-dose corticosteroid or placebo was performed. Four of the task force members reviewed the task force bibliography for relevant studies. Septic shock was defined by the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference and ARDS by the American–European Consensus Conference. Vasopressor dependency was defined as the requirement for a vasopressor agent after 7 days of treatment with a glucocorticoid (GC). The reviewers independently abstracted data from all eligible studies. Data were abstracted on study design, study size, corticosteroid dosage, vasopressor dependency, and 28-day mortality. Study and data inclusion was by consensus. We used the random effects models using Review Manager 4.2 (Cochrane Collaboration, Oxford, UK) for all analyses and considered p<.05 (two-sided) as significant. Summary effects estimates are presented as odds ratio with 95% confidence intervals. The authors assessed heterogeneity between studies using the Cochran Q statistic with p<.10 indicating significant heterogeneity and the I² with suggested thresholds for low (25 to 49%), moderate (50 to 74%), and high (>75%) values (18 to 21).

Expert Consensus (Delphi)

Experts were selected from the membership lists of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM). Specific individuals were selected to represent geographic diversity and a broad range of expertise on the basis of their published research. In addition, endocrinologists with expertise in this area were invited to join the task force.

The authors used electronic mail to conduct the Delphi process. A list of questions for review was determined. Once a majority agreement was reached on each question, the strength of each recommendation was quantified using the Modified Grades of Recommendation Assessment, Development, and Evaluation (GRADE) system developed by the American College of Chest Physicians (see the "Rating Scheme for the Strength of the Evidence" field). In all, there were seven rounds until a majority agreement was achieved on all the questions. In addition, the group met in Paris, France, in September 2005 and again at the Society of Critical Care Medicine 35^th Critical Care Congress in San Francisco, CA, in January 2006 to review the progress of the Delphi process. The initial draft of the manuscript was written by the Chair.

Refer to the "Rating Scheme for the Strength of the Evidence" field.

A formal cost analysis was not performed and published cost analyses were not reviewed.

Internal Peer Review

The draft manuscript was reviewed and iteratively edited by all members of the task force.

The strength of the recommendations (1A,1B, 1C, 2A, 2B, 2C) are defined at the end of the "Major Recommendations" field.

Critical Illness-Related Corticosteroid Insufficiency

Recommendation 1: Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis in critical illness is best described by the term critical illness–related corticosteroid insufficiency (CIRCI).

Recommendation 2: The terms absolute or relative adrenal insufficiency are best avoided in the context of critical illness.

Diagnosis of Adrenal Insufficiency

Recommendation 3: At this time, adrenal insufficiency in critical illness is best diagnosed by a delta cortisol (after 250 micrograms cosyntropin) of <9 micrograms/dL or a random total cortisol of <10 micrograms/dL.

Strength of Recommendation: 2B

Recommendation 4: The use of free cortisol measurements cannot be recommended for routine use at this time. Although the free cortisol assay has advantages over the total serum cortisol, this test is not readily available. Furthermore, the normal range of the free cortisol in critically ill patients is currently unclear.

Strength of Recommendation: 2B

Recommendation 5: The adrenocorticotrophic hormone (ACTH) stimulation test should not be used to identify those patients with septic shock or acute respiratory distress syndrome (ARDS) who should receive glucocorticoids (GCs).

Strength of Recommendation: 2B

Who to Treat with Glucocorticoids

Recommendation 6: Hydrocortisone should be considered in the management strategy of patients with septic shock, particularly those patients who have responded poorly to fluid resuscitation and vasopressor agents.

Strength of Recommendations: 2B

Recommendation 7: Moderate-dose GC should be considered in the management strategy of patients with early severe ARDS (partial pressure of arterial oxygen/fraction of inspired oxygen [PaO₂/FIO₂] of <200) and before day 14 in patients with unresolving ARDS. The role of GC treatment in acute lung injury and less severe ARDS (PaO₂/FIO₂ of >200) is less clear.

Strength of Recommendations: 2B

How to Treat

Recommendation 8: In patients with septic shock, intravenous hydrocortisone should be given in a dose of 200 mg/day in four divided doses or as a bolus of 100 mg followed by a continuous infusion at 10 mg/hr (240 mg/day). The optimal initial dosing regimen in patients with early severe ARDS is 1 mg/kg/day methylprednisolone as a continuous infusion.

Strength of Recommendation: 1B

Recommendation 9: The optimal duration of GC treatment in patients with septic shock and early ARDS is unclear. However, based on published studies and pathophysiological data, patients with septic shock should be treated for ≥7 days before tapering, assuming that there is no recurrence of signs of sepsis or shock. Patients with early ARDS should be treated for ≥14 days before tapering.

Strength of Recommendation: 2B

Recommendation 10: GC treatment should be tapered slowly and not stopped abruptly.

Strength of Recommendation: 2B

Recommendation 11: Treatment with fludrocortisone (50 micrograms orally once daily) is considered optional.

Strength of Recommendation: 2B

Recommendation 12: Dexamethasone is not recommended for the treatment of septic shock or ARDS.

Strength of Recommendation: 1B

Definitions:

None provided

The type of supporting evidence is identified and graded for each recommendation (see "Major Recommendations" field).

Appropriate diagnosis and management of corticosteroid insufficiency in critically ill adult patients

Adverse effects of steroids, including myopathy and superinfection

An implementation strategy was not provided.

Getting Better

Effectiveness
Timeliness

Not applicable: The guideline was not adapted from another source.

2008 Jun

Society of Critical Care Medicine - Professional Association

Society of Critical Care Medicine (SCCM)

Society of Critical Care Medicine Task Force

Primary Authors: 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

Dr. Marik has received lecture fees from Eli Lilly and Merck.

Dr. Keh has received grant support from the German Research Foundation and German Ministry of Education and Research (HYPRESS: Hydrocortisone for Prevention of Septic Shock).

Dr. Sprung has been a member of a data monitoring and safety committee for Artisan Pharma, Novartis Corporation, and Hutchinson Technology Incorporated. He has served as a consultant for AstraZeneca, Eisai Corporation, Eli Lilly, and GlaxoSmithKline. He has received grant support from the European Commission, Takeda, and Eisai Corporation. He has received lecture fees from Eli Lilly.

Drs. Sprung, Annane, Keh, Singer, and Briegel were investigators in the CORTICUS study, which was supported by the European Commission, the European Society of Intensive Care Medicine, the European Critical Care Research Network, the International Sepsis Forum, and the Gorham Foundation.

Dr. Annane has received grant support from the French Ministry of Health for the prognostic value of a adrenocorticotrophic hormone test in septic shock; the French multicenter, randomized, controlled trial on hydrocortisone plus fludrocortisone in septic shock; the ongoing French multicenter 2X2 factorial study that compares strict glucose control vs. conventional treatment for steroid-treated septic shock and hydrocortisone alone vs. hydrocortisone and fludrocortisone; and a French multicenter 2X2 factorial trial that compares hydrocortisone plus fludrocortisone, activated protein C, the combination of the two drugs, and placebos for the treatment of septic shock.

Dr. Pastores has received grant support from Eisai Medical Research (phase 3 trial of E5564 in severe sepsis), and Artisan Pharma (phase 2 sepsis with disseminated intravascular coagulation trial).

The remaining authors have not disclosed any conflicts of interest with respect to this article.

This is the current release of the guideline.

None available

None available

This NGC summary was completed by ECRI Institute on September 4, 2008. The information was verified by the guideline developer on October 20, 2008.

This NGC summary is based on the original guideline, which is subject to the guideline developer's copyright restrictions.