Severe sepsis and septic shock are major public health problems globally and are associated with substantial morbidity and mortality.1 No specific therapy exists apart from antibiotics and supportive care with intravenous (IV) fluids and vasopressors.(1) Recent large-scale clinical trials have failed to demonstrate improved outcomes with various treatment strategies for septic shock despite promising preliminary studies.(2-5) One of the first treatments studied in patients with septic shock was corticosteroids, based on the recognition of the role of excessive inflammation in the pathophysiology of multisystem organ dysfunction.(1,6) Studies published before 1995 demonstrated increased rates of adverse outcomes and complications with short courses of high-dose glucocorticoids in septic shock, so this practice was abandoned.(6-8)
Critical illness is characterized by complex abnormalities in hypothalamic-pituitary-adrenal axis (HPA) function, including reduced total serum cortisol levels (often with increased free cortisol levels due to reduced protein binding), reduced cortisol secretion in response to adrenocorticotropic hormone (ACTH), reduced metabolism of cortisol, and impaired tissue response to cortisol.(6,9-12) More than 50% of patients with septic shock have an impaired cortisol response to exogenous ACTH consistent with relative adrenal insufficiency, which is associated with adverse outcomes.(9,11,13-15) The definition and diagnosis of relative adrenal insufficiency in critically ill patients and its treatment are surrounded by controversy. Although lower “stress” doses of hydrocortisone have been used to supplement inadequate endogenous cortisol levels, the relationship between cortisol secretion, serum cortisol level and tissue cortisol effects can be unpredictable during critical illness.(6,9-11)
The American College of Critical Care Medicine published guidelines on critical illness-related corticosteroid insufficiency in 2008, emphasizing the complexity of HPA dysfunction in critical illness.(9) A delta cortisol <9 μg/dL after 250 μg of synthetic ACTH (cosyntropin) was recommended to diagnose relative adrenal insufficiency in critically ill patients.(9) A random cortisol level <10 μg/dL was suggested to define absolute adrenal insufficiency in critically ill patients, although the 2012 Surviving Sepsis Campaign guidelines recommended a higher random serum cortisol cutoff (<18 μg/dL) as defining adrenal insufficiency in septic shock.(9,16) The use of low-dose hydrocortisone (50 mg every six hours) was proposed only for vasopressor-dependent septic shock, and continuous hydrocortisone infusion (10 mg/h) was suggested to mitigate hyperglycemia.(9,17,18)
Use of a 1-μg ACTH stimulation test or free serum cortisol levels may improve the diagnosis of critical illness-related corticosteroid insufficiency, but these are not recommended.(9,12,19) Etomidate increases the risk of an impaired ACTH response by reversibly inhibiting adrenal cortisol synthesis. While use of etomidate has been associated with adverse outcomes in some studies, treatment with low-dose hydrocortisone does not consistently improve outcomes in such patients.(20-25) The combination of vasopressin and hydrocortisone is effective for reducing catecholamine requirements and may have synergistic effects in septic shock.(26,27)
Studies that have examined low-dose corticosteroids in patients with septic shock found conflicting results. The landmark 2002 multicenter study by Annane et al demonstrated a significant increase in 28-day survival in 300 critically ill patients with vasopressor-refractory septic shock and multiorgan dysfunction randomized to low-dose IV hydrocortisone (50 mg every six hours) plus low-dose fludrocortisone for seven days.(14) The mortality benefit was limited to patients with an impaired cortisol response to ACTH administration (hydrocortisone vs. placebo mortality, 53% vs. 63%; P=0.02). Subsequent meta-analyses found that longer courses (at least five days) of low-dose corticosteroids (hydrocortisone 200-300 mg/day) decreased mortality without a significant increase in complication rates.(28,29) The 2004 Surviving Sepsis Campaign guidelines recommended low-dose hydrocortisone in vasopressor-dependent septic shock after fluid resuscitation.(30)
In 2008, the multicenter Corticosteroid Therapy of Septic Shock (CORTICUS) study randomized 499 patients with septic shock to low-dose IV hydrocortisone (50 mg every six hours) or placebo.(15) This study found no reduction in 28-day mortality with hydrocortisone in patients with or without an impaired cortisol response to ACTH (hydrocortisone vs. placebo, 34.3% vs. 31.5%; P=0.51). In the hydrocortisone group, shock was reversed more quickly than the placebo group; patients were not required to have vasopressor-refractory shock for enrollment. More episodes of superinfection were seen in the hydrocortisone group, including new sepsis and septic shock.
The CORTICUS study population differed from that in the earlier study by Annane et al in several ways.(14,15) First, CORTICUS patients had lower severity of illness (mean Simplified Acute Physiology Score [SAPS] II score, 49±17) than the patients studied by Annane et al (mean SAPS II score, 59±21). The risk of 28-day mortality in the placebo arm of the CORTICUS study was 32% compared with 61% in the Annane study. Second, in the CORTICUS study, patients were enrolled if the systolic blood pressure remained <90 mm Hg despite adequate fluid replacement or if vasopressors were needed for at least one hour. In contrast, in the study by Annane et al, patients were required to have systolic blood pressure <90 mm Hg for more than one hour despite fluids and vasopressors. Third, the CORTICUS study allowed patient enrollment up to 72 hours after the onset of shock, whereas the Annane study allowed enrollment up to eight hours after onset. Fourth, hydrocortisone was used only for five days in the CORTICUS study and seven days in the Annane study. Fifth, fludrocortisone was not used in the CORTICUS study, and a subsequent trial excluded benefit of fludrocortisone.(31) Sixth, post hoc subgroup analysis of CORTICUS patients who met the inclusion criteria used by Annane et al showed a lower 28-day mortality with hydrocortisone (hydrocortisone vs. placebo, 45% vs. 56%). Finally, care of patients with septic shock was markedly different in the two studies. The sepsis bundles and the Surviving Sepsis Campaign guidelines were developed after the Annane study; their application could have resulted in the overall improved mortality rates observed in the CORTICUS study, reducing any potential marginal benefit of corticosteroids.
Subsequent meta-analyses included both of these studies and found variable results, although methodological differences may have played a role in the findings.(9,28,29,32-36) Overall, the mortality benefit of low-dose hydrocortisone rose as the severity of illness increased. Prolonged (≥5 days) treatment with low-dose (≤300 mg/day) hydrocortisone was associated with reduced duration of vasopressor dependency in septic shock but was associated with increased risk of hyperglycemia, hypernatremia and possibly infection. ACTH stimulation testing did not consistently predict the benefit of hydrocortisone therapy, and corticosteroid weaning provided no clear benefit over abrupt discontinuation.(16)
The 2012 Surviving Sepsis Campaign guidelines recommend “not using intravenous hydrocortisone to treat adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability.” It continues, “In case this is not achievable, we suggest intravenous hydrocortisone alone at a dose of 200 mg per day (grade 2C).”(16) These guidelines recommend against using an ACTH stimulation test to identify patients with septic shock who should receive hydrocortisone (grade 2B) and not using corticosteroids to treat sepsis in the absence of shock (grade 1D).(16) Tapering hydrocortisone when vasopressors are no longer required (grade 2D) and using continuous infusion when hydrocortisone is given (grade 2D) are suggested.(16)
We eagerly await the results of the upcoming Adjunctive Corticosteroid Treatment in Critically Ill Patients with Septic Shock (ADRENAL) study (NCT01448109), a multicenter trial randomizing 3,800 mechanically ventilated patients with vasopressor-dependent septic shock to hydrocortisone (200 mg/day) or placebo for seven days.(37) The patients enrolled in this study are expected to have a higher severity of illness than those in the CORTICUS study, helping to resolve the controversy regarding effects of low-dose hydrocortisone. Until the results of the ADRENAL investigation become available, clinicians could consider using empiric low-dose IV hydrocortisone (200 mg/day) for critically ill patients with septic shock who require multiple high-dose vasopressors and/or who remain hypotensive despite vasopressors and adequate fluid resuscitation (vasopressor-refractory shock).(16,32-36,38) Any potential benefit of corticosteroids in such patients is likely to outweigh the risks of steroid therapy.
Examining ACTH response or random cortisol levels prior to starting hydrocortisone is unlikely to be helpful in clinical decision making, unless other clinical features suggest the presence of absolute adrenal insufficiency.(9,15) Low-dose hydrocortisone can be continued for five to seven days and at least for 24 hours after cessation of vasopressors, with tapering doses if the patient exhibits any decompensation after steroid withdrawal. It is important to prevent complications of corticosteroid therapy, such as hyperglycemia, peptic ulcers and secondary infections.
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