Glucocorticoids in sepsis: dissecting facts from fiction

An intact hypothalamic-pituitary-adrenal (HPA) axis with effective intracellular glucocorticoid anti-inflammatory activity is essential for host survival following exposure to an infectious agent. Glucocorticoids play a major role in regulating the activity of nuclear factorkappa- B, which has a crucial and generalized role in inducing cytokine gene transcription after exposure to an invading pathogen. Severe sepsis is, however, associated with complex alterations of the HPA axis, which may result in decreased production of cortisol as well as glucocorticoid tissue resistance.

Inadequate intra cellular glucocorticoid activity, referred to as critical illness-related corticosteroid insuffi ciency, typically results in an exaggerated proinfl ammatory response [1]. Patients with severe sepsis or septic shock are therefore frequently treated with exogenous glucocorti coids. While there are large geographic variations in the prescription of glucocorticoids for sepsis, up to 50% of intensive care unit patients receive such therapy [2]. Despite over 30 years of investigation and over 20 metaanalyses, the use of glucocorticoids in patients with sepsis remains extremely controversial and recommendations are confl icting.
Th e most important recent studies are that of Annane and colleagues [3] and the Corticosteroid Th erapy of Septic Shock (CORTICUS) study [4]. Both of these studies have important limitations: 24% patients received etomidate in the study by Annane and colleagues, whereas 19% received etomidate in the CORTICUS study. Th e benefi t of steroids in the study by Annane and colleagues may have been restricted largely to those patients who received etomidate [5]. Furthermore, only patients with 'refractory septic shock' were enrolled in the Annane study whereas, as a result of an overwhelming selection bias, only approximately 5% of eligible patients were enrolled in the CORTICUS study [6]. A more recent study found no benefi t from a 7-day course of 40 mg of prednisolone in patients hospitalized with communityacquired pneumonia [7].
In the study by Annane and colleagues [3], patients received 50 mg of hydrocortisone intravenously every 6 hours for 7 days, whereas in the CORTICUS study [4], patients received this dose for 5 days, followed by a tapering off over a further 5 days. Recently, two longi tudinal studies in patients with severe community-acquired pneumonia found high levels of circulating infl ammatory cytokines 3 weeks after clinical resolution of sepsis [8,9]. Th ese data suggest that patients with severe sepsis may have pro longed immune dysregulation (even after clinical recovery) and that a longer course of corticosteroids may be required. Th e use of a continuous infusion of hydrocortisone has been reported to result in better glycemic control with less variability of blood glucose concentration [10]. Th is may be clinically relevant as it has been demonstrated that an oscillating blood glucose level is associated with greater oxidative injury than sustained hyperglycemia [11]. Indeed, a number of reports indicate that glucose variability may be an independent predictor of outcome in critically ill patients [12]. A continuous infusion of glucocorticoid may, however, result in greater suppression of the hypothalamic-pituitary-adrenal axis. Furthermore, diff erent glucocorticoids diff erentially aff ect gene transcription and have diff ering pharma codynamic eff ects. Conse quently, the preferred glucocorticoid and the optimal dosing strategy in patients with septic shock remain to be determined.
Evidence-based medicine is defi ned as the use of the best current scientifi c evidence in making decisions about the care of individual patients. Owing to the dearth of high-level evidence, it is not possible to make strong evidence-based recommendations on the use of glucocorticoids in patients with sepsis. Th erefore, at this juncture, it is useful to summarize what we know, what we think we know, and what we do not know in order to

Abstract
An intact hypothalamic-pituitary-adrenal axis with eff ective intracellular glucocorticoid anti-infl ammatory activity is essential for host survival following exposure to an infectious agent. Glucocorticoids play a major role in regulating the activity of nuclear factorkappa-B, which has a crucial and generalized role in inducing cytokine gene transcription after exposure to an invading pathogen. Severe sepsis is, however, associated with complex, hypothalamic-pituitaryadrenal axis alterations, which may result in decreased production of cortisol as well as glucocorticoid tissue resistance.
lay the foundation for future scientifi c exploration; this information is summarized in Table 1.
In summary, the risk/benefi t ratio of glucocorticoids should be determined in each patient. A course (7 to 10 days) of low-dose hydrocortisone (200 mg/day) should be considered in vasopressor-dependent patients (dosage of norepinephrine or equivalent of greater than 0.1 μg/kg per minute) within 12 hours of the onset of shock [1]. Steroids should be stopped in patients whose vasopressor dependency has not improved with 2 days of glucocorticoids. While the outcome benefi t of low-dose glucocorti coids remains to be determined, such a strategy decreases vasopressor dependency and appears to be safe (no excess mortality, superinfections, or acute myopathy). Infection surveillance is critical in patients treated with corticosteroids, and to prevent the rebound phenomenon, the drug should be weaned slowly. At this time, glucocorticoids appear to have a limited role in patients who have sepsis or severe sepsis and who are at a low risk of dying.

Competing interests
The author declares that he has no competing interests.