When Should Perioperative Glucocorticoid Replacement Be Administered?

INTRODUCTION

Glucocorticoids have been used as adjunctive therapy in the perioperative period for decades. They have immunosuppressant and antiinflammatory effects, improve cardiovascular sensitivity to catecholamines, restore adrenal cortical function, and maintain intravascular volume. Therefore steroids may be particularly beneficial in patients with sepsis, relative adrenal insufficiency caused by exogenous corticosteroid administration, acute respiratory distress syndrome (ARDS), and those undergoing cardiac surgical procedures. Perioperative steroid replacement remains controversial, however, because of heterogeneity among existing trials and ill-defined efficacy profiles in these populations. Potential adverse effects, including gastrointestinal bleeding, infection, impaired wound healing, hyperglycemia, fluid overload, hypernatremia, hypokalemia, and neuromuscular weakness, also limit systematic use. ^, Despite the lack of evidence supporting routine perioperative glucocorticoid replacement in these populations, steroids may be indicated in certain circumstances. They increase the rate of shock reversal and reduce short-term organ dysfunction in sepsis, decrease the risk of adrenal crisis in patients with exogenous steroid-induced adrenal suppression, and may shorten hospital stays and lower infection and pulmonary complication rates among cardiac surgery patients. Further examination is required to determine which patient populations benefit from glucocorticoid therapy in the perioperative period.

OPTIONS

Perioperative glucocorticoid replacement has been considered in a variety of circumstances, including sepsis, relative adrenal insufficiency caused by chronic exogenous glucocorticoid replacement, ARDS, and cardiac surgery.

EVIDENCE

The Hypothalamic-Pituitary-Adrenal Axis

The hypothalamic-pituitary-adrenal axis (HPAA) is regulated by positive and negative feedback. The hypothalamus secretes corticotropin releasing hormone (CRH), stimulating adrenocorticotropin (ACTH) excretion from the anterior pituitary. ^, The adrenal cortex releases hormones in response to ACTH; the zona glomerulosa produces mineralocorticoids, the zona fasciculata produces glucocorticoids, and the zona reticularis produces androgens. Rising cortisol levels inhibit CRH and ACTH release. Cortisol production is diurnal; levels peak in the morning and decline throughout the day. Only 10% to 20% of total cortisol is biologically active; the remaining 80% to 90% is bound to corticosteroid-binding globulin (CBG), albumin, and α-1 acid glycoprotein. ^, ^, Glucocorticoids are pleiotropic molecules that are instrumental in carbohydrate and protein anabolism and catabolism, gluconeogenesis, catecholamine production, antiinflammatory pathway activation, electrolyte and intravascular fluid regulation, and maintenance of cardiac output and contractility through modulation of β-receptors and vascular reactivity.

Inadequate cortisol release causes adrenal insufficiency (AI) and is classified by etiology. Primary AI is a result of adrenal cortex destruction from tumor metastasis, hemorrhage, infection, or autoimmune disease, the most common form of primary AI. Cortisol, aldosterone, and androgen deficiencies are present. ^, Pituitary dysfunction resulting in inadequate ACTH production produces secondary AI, and hypothalamic dysfunction causes tertiary AI. The most common cause of tertiary AI is exogenous steroid administration, whereby negative feedback suppresses CRH and ACTH release, the adrenal cortex involutes, and endogenous cortisol production declines. Patients with tertiary AI are unable to increase cortisol production in response to stress. The renin-angiotensin-aldosterone system (RAAS) remains intact in secondary and tertiary AI so aldosterone, sodium, and potassium levels are unaffected. ^, ^, ^,

AI is diagnosed when cortisol levels are low and the short corticotropin stimulation test fails to augment production. Cortisol concentration up to 18 mcg/dL after a large dose of synthetic ACTH is consistent with AI in nonphysiologically stressed patients. The diagnosis during critical illness is more complicated because HPAA dysfunction is common and hypocortisolemia during physiologic stress is poorly defined. ^, ^, Random cortisol levels do not necessarily reflect biologically active hormone in these patients and have not been proven useful in identifying relative AI among septic populations. CBG and albumin are negative acute phase reactants; their concentrations decrease in inflammatory states, resulting in increased biologically active cortisol. The short corticotropin stimulation test measures total cortisol, so it may overestimate the prevalence of AI in this population. Inability to increase cortisol concentration by at least 9 mcg/dL after ACTH stimulation or a random total cortisol of less than 10 mcg/dL may be consistent with adrenal suppression in critically ill patients. ^, ^,

HPAA dysfunction is ubiquitous during critical illness and may manifest as relative corticosteroid deficiency or excessive production. ^, Corticosteroid deficiency during physiologic stress has been recognized as a distinct entity known as critical illness related corticosteroid insufficiency (CIRCI). Suppressed ACTH synthesis, increased metabolic demand, altered cortisol metabolism, shock-mediated damage to neuroendocrine cells, and glucocorticoid resistance in peripheral tissues contribute to CIRCI. ^, ^, ^, It is associated with increased morbidity, mortality, intensive care unit (ICU) length of stay, and inflammatory and procoagulation markers. CIRCI is likely present in various critical illness states including sepsis, community-acquired pneumonia, ARDS, trauma, burns, cardiac arrest, and head injury. ^, Alternatively, acute physiologic stress may activate the HPAA, increasing cortisol levels up to sixfold and abolishing diurnal release. ^, ^, ^, ^, ^, Biologically active cortisol increases because of cytokine-mediated HPAA stimulation, impaired cortisol metabolism, and reduced CBG and albumin levels. HPAA activation occurs in 10% to 20% of critically ill patients and up to 60% of patients with septic shock. ^, ^, ^,

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