Critical illness-related corticosteroid insufficiency (CIRCI) was first introduced in 2008 by a task force convened by the Society of Critical Care Medicine (SCCM) to describe the impairment of the hypothalamic-pituitary-adrenal (HPA) axis during critical illness (Marik PE, et al. Crit Care Med. 2008;36(6):1937).
CIRCI is characterized by dysregulated systemic inflammation resulting from inadequate cellular corticosteroid activity for the severity of the patient’s critical illness. Signs and symptoms of CIRCI include hypotension poorly responsive to fluids, decreased sensitivity to catecholamines, fever, altered mental status, hypoxemia, and laboratory abnormalities such as hyponatremia and hypoglycemia. CIRCI can occur in a variety of acute conditions, such as sepsis and septic shock, acute respiratory distress syndrome (ARDS), severe community-acquired pneumonia, and non-septic systemic inflammatory response syndrome (SIRS) states associated with shock, such as trauma, cardiac arrest, and cardiopulmonary bypass surgery. Three major pathophysiologic events are considered to constitute CIRCI: dysregulation of the HPA axis, altered cortisol metabolism, and tissue resistance to glucocorticoids (Annane D, Pastores SM, et al. Crit Care Med. 2017;45(12):2089; Intensive Care Med. 2017;43(12):1781). Plasma clearance of cortisol is markedly reduced during critical illness, due to suppressed expression and activity of the primary cortisol-metabolizing enzymes in the liver and kidney. Furthermore, despite the elevated cortisol levels during critical illness, tissue resistance to glucocorticoids is believed to occur because of insufficient glucocorticoid receptor alpha-mediated anti-inflammatory activity.
Reviewing the Updated Guidelines
Against this background of recent insights into the understanding of CIRCI and the widespread use of corticosteroids in critically ill patients, an international panel of experts of the SCCM and the European Society of Intensive Care Medicine (ESICM) recently updated the guidelines for the diagnosis and management of CIRCI in a two-part guideline document (Annane D, Pastores SM, et al. Crit Care Med. 2017;45(12):2078; Intensive Care Med. 2017;43(12):1751; Pastores SM, Annane D, et al. Crit Care Med. 2018;46(1):146; Pastores SM, Annane D, et al. Intensive Care Med. 2018;44(4):474). For this update, the multidisciplinary task force used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology to formulate actionable recommendations for the diagnosis and treatment of CIRCI. The recommendations and their strength (strong or conditional) required the agreement of at least 80% of the task force members. The task force spent considerable time and spirited discussions on the diagnosis of CIRCI and the use of corticosteroids for clinical disorders that most clinicians associate with CIRCI: sepsis/septic shock, ARDS, and major trauma.
The task force was unable to reach agreement on a single test that can reliably diagnose CIRCI. However, they acknowledged that a delta cortisol less than 9 µg/dL at 60 minutes after administration of 250 µg of cosyntropin and a random plasma cortisol level of less than 10 µg/dL may be used by clinicians. They also suggested against the use of plasma-free cortisol or salivary cortisol level over plasma total cortisol. Unequivocally, the panel acknowledged the limitations of the current diagnostic tools to identify patients at risk for CIRCI and how this may impact the way corticosteroids are used in clinical practice.
Sepsis and Septic Shock
Despite dozens of observational studies and randomized controlled trials (RCTs) over several decades, the benefit-to-risk ratio of corticosteroids to treat sepsis and septic shock remains controversial with systematic reviews and meta-analyses either confirming (Annane D, et al. Cochrane Database Syst Rev. 2015;12:CD002243) or refuting (Volbeda M, et al. Intensive Care Med. 2015;41:1220) the survival benefit of corticosteroids. Based on the best available data, the task force recommended the use of corticosteroids in adult patients with septic shock that is not responsive to fluids and moderate-to-high vasopressor therapy but not for patients with sepsis who are not in shock. Intravenous hydrocortisone less than 400 mg/day for at least greater than or equal to 3 days at full dose was recommended rather than high dose and short course. The panel emphasized the consistent benefit of corticosteroids on shock reversal and the low risk for superinfection with low dose corticosteroids.
Since the publication of the updated CIRCI guidelines, two large RCTs (more than 5,000 combined patients) of low-dose corticosteroids in patients with septic shock were reported: The Adjunctive Corticosteroid Treatment in Critically Ill Patients with Septic Shock (ADRENAL) trial (Venkatesh B, et al. N Engl J Med. 2018;378:797) and the Activated Protein C and Corticosteroids for Human Septic Shock (APROCCHSS) trial (Annane D, et al. N Engl J Med. 2018;378:809). The ADRENAL trial included 3,800 patients in five countries and did not show a significant difference in 90-day mortality between the hydrocortisone group and the placebo group (27.9% vs 28.8%, respectively, P=.50). In contrast, the APROCCHSS trial, involving 1,241 patients in France, reported a lower 90-day mortality in the hydrocortisone-fludrocortisone group compared with the placebo group (43% vs 49.1%, P=.03). Both trials showed a beneficial effect of hydrocortisone in the number of vasopressor-free and mechanical ventilation-free days. Blood transfusions were less common in the in the hydrocortisone group than among those who received placebo in the ADRENAL trial. Besides hyperglycemia, which was more common in the hydrocortisone group in both trials, the overall rates of adverse events were relatively low.
It is important to highlight the key differences in study design between these two RCTs. First, in the APROCCHSS trial, oral fludrocortisone (50-μg once daily for 7 days) was added to hydrocortisone to provide additional mineralocorticoid potency, although a previous study had shown no added benefit (Annane D, et al. JAMA. 2010;303:341). Second, hydrocortisone was administered as a 50-mg IV bolus every 6 hours in APROCCHSS and given as a continuous infusion of 200 mg/day for 7 days or until death or ICU discharge in ADRENAL. It is noteworthy that the subjects in the ADRENAL trial had a higher rate of surgical admissions (31.5% vs 18.3%), a lower rate of renal-replacement therapy (12.7% vs 27.6%), lower rates of lung infection (35.2% vs 59.4%) and urinary tract infection (7.5% vs 17.7%), and a higher rate of abdominal infection (25.5% vs 11.5%). Patients in the APROCCHSS trial had high Sequential Organ Failure Assessment (SOFA) scores and Simplified Acute Physiology Score (SAPS) II values suggesting a sicker population and probably accounting for the higher mortality rates in both hydrocortisone and placebo groups compared with ADRENAL. In view of the current evidence, the author believes that survival benefit with corticosteroids in septic shock is dependent on several factors: dose (hydrocortisone greater than 400 mg/day), longer duration (at least 3 or more days), and severity of sepsis. “The more severe the sepsis, the more septic shock the patient is in, the more likely it is for corticosteroids to help these patients get off vasopressors and mechanical ventilation. I consider the addition of fludrocortisone as optional.”