Corticosteroids exert effects on virtually every organ and tissue and are unquestionably essential for maintaining homeostasis. Cortisol plays a vital role in the maintenance of normal vascular tone, endothelial integrity and the regulation of fluid movements within the extravascular compartment. Cortisol also potentates the vasoconstrictor effects of catecholamines. Additionally, stimulation of the hypothalamic-pituitary axis resulting in elevated levels of cortisol is one of the most important hormonal reactions to severe illness, trauma, sepsis, anesthesia and surgery. However, the usefulness of exogenous corticosteroid administration in patients with shock is not as straight forward. Experimental animal studies showed favorable effects of early administration of a short course of "suprapharmacological" doses of glucocorticoids in models of sepsis. Based on theoretical grounds and the results of experimental studies glucocorticoids were given to many shock patients. Results of human clinical trials were mixed. In humans, the use of corticosteroids in patients with hypovolemic/ hemorrhagic shock was abandoned in the early 1970's in lieu of intravascular volume and red cells replacement to correct the primary problem.
The use of corticosteroids in septic shock has been a subject of continued debate for the ensuing 30 years. The controversy entered a quiet period following the publication of two meta-analyses in 1995. Each study concluded that glucocorticoids were not beneficial in sepsis and septic shock. The Cronin study actually suggested glucocorticoids might be harmful.
In the past few years, the interest in steroids in the management of septic shock has been renewed. Several trials using physiologic doses, for longer duration and later in the course of sepsis have shown improvement in reversal of shock and encouraging trends in 28-day mortality.
A number of theories have been proposed to explain why a low dose of glucocorticoids administered for a longer duration might be beneficial to patients in later stages of septic shock including increased catecholamine stimulation of myocardial contractility, increased vasomotor catecholamine response, prevention of desensitization of beta receptors and increased alpha adrenergic receptor density. However, the theory that has received the most attention is the concept of relative adrenal insufficiency.
Absolute adrenal insufficiency in critically ill patients is rare, however a number of investigators have detected a difference in basal plasma cortisol levels and diminished responses to corticotropin-releasing hormone in patients that died of septic shock as compared to those who survived. Annane et al. conducted a prospective clinical trial to characterize the cortisol level and cortical response to corticotropin in 189 patients with septic shock. They found an elevated basal cortisol level (>34 μg/dl) and a poor response to corticotropin (< 9 μg/dl elevation at 30 or 60 minutes) to be a predictor of the poorest survival in patients with sepsis.
Several recent prospective, randomized placebo-controlled trials have evaluated the use of low doses of steroids in "refractory" septic shock. In the Bollaert study, septic patients requiring vasopressor therapy (dopamine > 10 μg/kg/min or any dose of either epinephrine or norepinephrine) for more than 48 hours were randomized to receive either hydrocortisone (100 mg IV (1.4 mg/kg) 3x/day for 5 days) or placebo, with tapering over 6 days if shock reversal was achieved. They found a significant reduction in the time it took to reverse shock, and a trend towards decreased 28-day mortality. The treatment effect was present irrespective of hypothalamic-pituitary axis function as measured by baseline cortisol levels and after ACTH stimulation.
Briegel et al. enrolled septic shock patients with high output circulatory failure requiring vasopressor therapy (dopamine > 5 μg/kg/min or any dose of either epinephrine or norepinephrine) for no more than 72 hours. Patients were randomized to receive either a placebo or hydrocortisone (100 mg IV bolus, followed by a continuous infusion of 0.18 mg/kg/hr) until septic shock resolved. The length of time for which vasopressor support was required was significantly reduced in the hydrocortisone group (2 days vs 7 days). There was a trend toward earlier reversal of organ dysfunction. There was not, however, a mortality difference between the two groups.
Annane, et al demonstrated a relative risk reduction of almost 30% in patients with septic shock treated with low-dose corticosteroid and mineralocorticoid support. Three hundred adult patients in septic shock were randomized to receive either placebo or hydrocortisone (50 mg IV bolus every 6 hours) and fludrocortisone (50 μg tablet daily) for 7 days after undergoing a short corticotropin test. The survival benefit of combination therapy was significant only in patients with blunted response to ACTH stimulation.
The current evidence argues against high dose, short duration corticosteroid therapy in hypovolemic, hemorrhagic and septic shock. In the 2001 Guidelines for the Management of Severe Sepsis and Septic Shock created by the International Sepsis Forum (ISF), the use of short course, high dose steroids is strongly discouraged (Grade A evidence). The answer to the question concerning the use of low doses for longer duration in septic shock is not as straight forward. There are many unanswered questions about the optimal dosage and timing of therapy. Additionally, the patient population most likely to benefit from therapy has not been clearly defined. The ISF guidelines recommend low doses of corticosteroids for "refractory" shock but not during severe sepsis without shock or mild shock. Corticosteroids may have a role in the management of the most severely ill population, but the current evidence does not support it's use in all patients with sepsis and administration of steroids should not be a substitute for a careful search for other causes of unresponsive hypotension.
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