Corticosteroid Therapy in Acute illness Uptodate 2014-2015 ICU-Acquired Weakness and Recovery from Critical Illness, N Engl J Med 2014 Hydrocortisone Therapy for Patients with Septic Shock, n engl j, 2008

The following issues are discussed in this topic review: ●Effects of critical illness on the hypothalamic-pituitary-adrenal axis. ●Methods of evaluating adrenal reserve (random cortisol levels, synthetic adrenocorticotropic hormone [ACTH] stimulation tests, free cortisol levels). ●The concept of relative adrenal insufficiency. ●Clinical evidence from trials evaluating the effect of corticosteroid therapy in patients with septic shock, plus practical aspects of corticosteroid administration.

EFFECTS OF CRITICAL ILLNESS The hypothalamus continuously integrates stimuli and secretes corticotropin releasing hormone (CRH) whenever homeostasis is threatened. CRH stimulates the release of adrenocorticotropic hormone (ACTH) from the anterior pituitary, which induces cortisol secretion from the adrenal glands. Cortisol is the effector molecule of the hypothalamic-pituitary-adrenal (HPA) axis. Normal serum cortisol levels range between 5 and 24 mcg/dL , with significant variability depending upon the time of day . The HPA axis is activated and diurnal variation is lost during physiological stress (eg, major surgery , hypotension, severe infection) . Serum cortisol increases as a result, reaching levels as high as 40 to 50 mcg/dL .

cortisol metabolism and other aspects of critical illness: ●Reduced cortisol breakdown : suppressed expression and activity of cortisol-metabolizing enzymes. ●Renal dysfunction may prolong the half-life of circulating cortisol. ●Plasma concentrations of both cortisol binding globulin (CBG) and albumin, which bind >90 percent of circulating cortisol under normal circumstances, are frequently diminished. This results in an increase in the free cortisol. ●Inflammatory cytokines may increase glucocorticoid receptor affinity, disable glucocorticoid inactivation , and/or increase the peripheral conversion of precursors to cortisol .

Impairment of the HPA axis cortisol availability cannot be increased sufficiently to meet demand. drugs like ketoconazole, phenytoin, and etomidate may impair cortisol synthesis . Head injury , central nervous system depressants, pituitary infarction, adrenal hemorrhage, infections, malignancy, and previous corticosteroid therapy can also impair the HPA axis .

ASSESSING ADRENAL RESERVE Laboratory assays of plasma cortisol concentration and response to adrenocorticotropic hormone (ACTH) stimulation are likely unreliable in critically ill patients. Random serum cortisol Free cortisol In critically ill patients, loss of cortisol binding globulin (CBG) results in decreased protein-bound cortisol and increased free cortisol. free cortisol more accurately reflects HPA axis activation . The critically ill patients had total serum cortisol concentrations that were two to three times higher and free cortisol levels that were 7 to 10 times higher than healthy volunteers. total serum cortisol appeared lower in critically ill patients with hypoalbuminemia (albumin ≤2.5 g/dL) than in critically ill patients with preserved albumin concentrations, the free cortisol levels were similar. total and free plasma cortisol levels were compared to tissue levels of cortisol. during critical illness, blood levels of cortisol poorly reflect the amount of hormone available to target tissues.

ACTH stimulation tests synthetic ACTH (cosyntropin) administered intravenously and serum cortisol levels are drawn 30 and 60 minutes later. 250 mcg (high-dose ACTH stimulation test), and 1 mcg (low-dose ACTH stimulation test) High-dose ACTH test : a baseline serum cortisol level >34 mcg/dL and a maximum increase in cortisol of ≤9 mcg/dL were identified as risk factors for death. ●Good prognosis : Baseline plasma cortisol ≤34 mcg/dL and a cortisol increase >9 mcg/dL in response to cosyntropin. ●Poor prognosis : Baseline plasma cortisol >34 mcg/dL and a cortisol increase ≤9 mcg/dL in response to cosyntropin. ●Intermediate prognosis : Baseline plasma cortisol >34 mcg/dL and a cortisol increase >9 mcg/dL in response to cosyntropin. baseline cortisol level <15 mcg/dL or a cortisol increase ≤9 mcg/dL had a higher mortality, longer duration of shock, or shorter survival time.

Low-dose ACTH test Some investigators believe that 250 mcg of cosyntropin is supraphysiologic and stimulates adrenal secretion of cortisol even when adrenal dysfunction exists Use of low-dose (1 mcg) cosyntropin has been proposed as an alternative . adrenal insufficiency detected by low-dose ACTH stimulation was superior to that detected by high-dose ACTH stimulation in predicting hemodynamic responsiveness to corticosteroids. A positive response to ACTH stimulation was defined as a serum cortisol increase >9 mcg/dL. more likely to survive than those who did not respond to either dose.

ACTH stimulation tests may be unreliable in critically ill patients for several reasons: ●Some critically ill individuals have spontaneous increases in their serum cortisol of ≥9 mcg/dL WITHOUT cosyntropin stimulation . ●Altered metabolism of cortisol appears to be partly responsible for hypercortisolemia observed in critically-ill patients . ●Etomidate , which suppresses the HPA axis , if used for intubating patients with septic shock, could potentially interfere with the results of ACTH stimulation.

●A maximum increase of serum cortisol ≤9 mcg/dL following intravenous synthetic adrenocorticotropic hormone (ACTH) stimulation is associated with increased mortality from septic shock . ●Baseline and post-ACTH serum cortisol <23.7 mcg/dL predict responsiveness to exogenous steroids in septic shock, where responsiveness is defined by the ability to maintain a mean arterial blood pressure >65 mmHg without norepinephrine infusion within 24 hours after starting hydrocortisone . Suboptimal cortisol production during septic shock has been termed "functional" or "relative" adrenal insufficiency . This condition has also been called “critical illness-related corticosteroid insufficiency (CIRCI)” .

CORTICOSTEROID THERAPY Interest in the possible therapeutic role of corticosteroids in severe infections has existed for at least 50 years . The major theoretical purpose of corticosteroids in sepsis is to restore balance to the altered HPA axis with the goal of improved outcomes such as mortality ●Among all patients, hydrocortisone administration decreased 28-day mortality . ●Among patients defined as having inadequate adrenal reserve, hydrocortisone administration decreased 28-day mortality , ICU mortality , and hospital . septic shock was defined as a systolic blood pressure <90 mmHg despite adequate fluid resuscitation, or the need for vasopressor administration for more than one hour. All meta-analyses confirmed improved shock reversal with low-dose corticosteroid use .

Conclusions ●In patients without shock, or patients with less severe septic shock , corticosteroid therapy does not appear to be beneficial. ●corticosteroid therapy is most likely to be beneficial in patients who have severe septic shock. ●ACTH stimulation testing is not clinically useful in distinguishing responders from not responders.

Administration Hydrocortisone is a pharmacologic form of cortisol. Compared to hydrocortisone, other pharmacologic corticosteroids bind cortisol-binding globulin (CBG) poorly, resulting in more free, physiologically active corticosteroid and greater potency at any given dose. The different preparations vary widely in anti-inflammatory and mineralocorticoid potency. Dose : administer 200 to 300 mg per day of hydrocortisone intravenously in divided doses (50 mg every six hours or 100 mg every eight hours).

Type Hydrocortisone is the most commonly used corticosteroid in large randomized trials. we do not typically add fludrocortisone because we believe that hydrocortisone alone has sufficient mineralocorticoid effect . Duration administer five to seven days of therapy and a tapered approach to withdrawal that is guided by the clinical response .

اسلايدهاي سيستم هموويژلانس- ويژه پزشكان THANK YOU اسلايدهاي سيستم هموويژلانس- ويژه پزشكان 18