By Kathryn Radigan, MD

Attending Physician, Division of Pulmonary and Critical Care, Stroger Hospital of Cook County, Chicago

Dr. Radigan reports no financial relationships relevant to this field of study.

SYNOPSIS: For critically ill patients with sepsis, septic shock, acute respiratory distress syndrome, and major trauma, a multispecialty task force of 16 international experts developed evidence-based recommendations for the diagnosis of corticosteroid insufficiency and use of corticosteroids in the ICU.

SOURCE: Annane D, Pastores SM, Rochwerg B, et al. Guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in critically ill patients (Part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017. Crit Care Med 2017;45:2078-2088.

Although there was a 2008 consensus statement for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in adult and pediatric patients, there has been a growing need to further update the concept, diagnosis, and management of CIRCI. A multispecialty task force of 16 international experts in critical care medicine, endocrinology, and guideline methods from the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM) were chosen to update the recommendations. Experts reviewed the 2008 recommendations and examined an updated systematic review of pertinent studies from 2008-2017. Experts formulated recommendations using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. The strength of each recommendation was classified as strong or conditional. Furthermore, the evidence was rated from very low to high and based on study design, risk of bias within the study, the consistency of the results, and the directness and precision of the evidence. An approved recommendation required the agreement of 80% of the members of the task force.

The experts were not able to reach an agreement on a single test that would consistently diagnose CIRCI. Although the team made no recommendation regarding whether to use a delta cortisol (change in baseline cortisol at 60 minutes of < 9 μg/dL) after cosyntropin 250 μg administration or a random plasma cortisol of < 10 μg/dL, it did not recommend using plasma-free cortisol or salivary cortisol level (conditional, low quality of evidence). The team recommended that treatment should include intravenous (IV) hydrocortisone < 400 mg/day for ≥ 3 days in patients with septic shock who are not responsive to fluid and needing moderate to high doses of vasopressor support (conditional, low quality of evidence). The team also recommended the use of IV methylprednisolone 1 mg/kg/day in patients with moderate to severe acute respiratory distress syndrome (ARDS; i.e., PaO2/FiO2 < 200) within at least 14 days of onset (conditional, moderate quality of evidence). Corticosteroids were not recommended for adult patients with sepsis without shock (conditional recommendation, moderate quality of evidence) or patients with major trauma (conditional, low quality of evidence).

COMMENTARY

CIRCI is widely recognized as a disorder of dysregulated systemic inflammation that results from inadequate intracellular glucocorticoid-mediated anti-inflammatory activity that is out of proportion to the severity of a patient’s critical illness. This systemic inflammation is due to dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, altered cortisol metabolism, and tissue resistance to corticosteroids and is thought to lead to increased morbidity, ICU length of stay, and mortality.1,2 As there remains substantial controversy over the diagnosis and treatment of CIRCI, the SCCM and the ESICM have updated the 2008 guidelines.

Accurately diagnosing adrenal insufficiency or relative adrenal insufficiency in critically ill patients has been a challenge. In 2016, the Surviving Sepsis Campaign guidelines suggested not using the adrenocorticotropic stimulation test to assess appropriateness for treatment with hydrocortisone and recommended IV hydrocortisone at a dose of 200 mg per day if adequate fluid resuscitation and vasopressor therapy are unable to restore hemodynamic stability.3 After a detailed review of all the data, the multispecialty task force also remained in disagreement regarding a single test to diagnosis CIRCI but suggested that a delta cortisol (change in baseline cortisol at 60 minutes of < 9 μg/dL) after cosyntropin administration and a random plasma cortisol of < 10 μg/DL may be considered. They also suggested that patients with septic shock who are not responsive to fluid and needing moderate to high doses of vasopressor support be treated with IV hydrocortisone < 400 mg/day for ≥ 3 days at full dose.

Shortly after these recommendations were released, results from the ADRENAL trial were published.4 In this international, pragmatic, double-blind, parallel-group, randomized, controlled study, investigators assigned patients with septic shock who were undergoing mechanical ventilation to either continuous infusion of hydrocortisone 200 mg daily or placebo for seven days or until death or discharge from the ICU. It should be noted that this particular study required less stringent enrollment criteria and included all ventilated patients who had been treated with vasopressors or inotropic agents for four hours or more. Although there was no difference in 90-day mortality, patients who received hydrocortisone experienced a more rapid resolution of shock, shorter time to ICU discharge, earlier cessation of the initial episode of mechanical ventilation, and a lower incidence of blood transfusion compared to placebo.

The task force also recommended considering IV methylprednisolone 1 mg/kg/day in early ARDS patients (within seven days of onset of ARDS with PaO2/FiO2 of < 200) and methylprednisolone 2 mg/kg/day in late ARDS patients (after day 6 of onset) with slow tapering over the following 13 days. This recommendation was affected by a relatively recent individual patient data analysis of four of the largest trials evaluating prolonged methylprednisolone in early and late ARDS, which revealed a benefit to corticosteroids with improved survival and decreased duration of mechanical ventilation without concerning side effects.5 Since glucocorticoids may blunt the febrile response, it also was recommended to maintain optimal infection surveillance to ensure prompt identification and treatment of infection for patients undergoing glucocorticoid treatment. Despite this recommendation, many practitioners are not strong proponents of the routine administration of glucocorticoids in ARDS until there is an adequately powered, randomized, placebo-controlled trial demonstrating a mortality benefit and further detailing the indication, timing, duration, and appropriate dosing of corticosteroids in this setting. Currently, this recommendation from the team likely would benefit from further ongoing investigation. In conclusion, there is no single test that can consistently diagnose CIRCI. Although the task force recommends against use of corticosteroids in patients with sepsis but without shock, treatment with IV hydrocortisone < 400 mg/day for ≥ 3 days at full dose should be considered in patients with septic shock who are not responsive to fluid and needing moderate- to high-dose vasopressor support. Although mortality benefits are not seen consistently across the literature in these situations, there may be other benefits, such as faster resolution of shock and shorter ICU lengths of stay. The task force also recommends the use of IV methylprednisolone 1 mg/kg/day in patients with moderate to severe ARDS (PaO2/FiO2 < 200) within 14 days of onset, but consideration should be made on a case-by-case basis, strongly weighing the benefits and risks of such a therapy.

REFERENCES

  1. Annane D, Pastores SM, Arlt W, et al. Critical illness-related corticosteroid insufficiency (CIRCI): A narrative review from a Multispecialty Task Force of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM). Intensive Care Med 2017;43:1781-1792.
  2. Annane D. Corticosteroids for severe sepsis: An evidence-based guide for physicians. Ann Intensive Care 2011;1:7.
  3. Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med 2017;43:304-377.
  4. Venkatesh B, Finfer S, Cohen J, et al. Adjunctive glucocorticoid therapy in patients with septic shock. N Engl J Med 2018;378:797-808.
  5. Meduri GU, Bridges L, Shih MC, et al. Prolonged glucocorticoid treatment is associated with improved ARDS outcomes: Analysis of individual patients’ data from four randomized trials and trial-level meta-analysis of the updated literature. Intensive Care Med 2016;42:829-840.