Adrenal Insufficiency in the Critically Ill Patient

Published on 07/03/2015 by admin

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Last modified 07/03/2015

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Adrenal Insufficiency in the Critically Ill Patient

Adrenal diseases are infrequent primary admitting diagnoses to the intensive care unit (ICU). However, patients with unrecognized or previously diagnosed disease of the hypothalamic-pituitary-adrenal (HPA) axis may demonstrate severe decompensation in the setting of other critical illness.

Adrenal insufficiency (AI) is by far the most common adrenal disorder seen in the ICU and is the focus of this chapter. It occurs more frequently in critically ill patients than in general hospitalized patients and represents a true emergency that requires rapid diagnosis and treatment. If missed, the condition can be fatal. In addition, because critical illness is often the precipitant of overt AI, the intensivist may have the first and only chance to make the diagnosis.1

Primary AI results from a subtotal or complete destruction of the adrenal cortex (>90%) and results in cortisol, aldosterone, and androgen deficiency. Multiple causes of primary AI include autoimmune destruction (Addison’s disease), polyendocrine deficiency syndrome, infections (e.g., tuberculosis, fungus), vascular compromise, primary or metastatic cancer, amyloidosis, and surgical removal of the adrenal glands.

Secondary AI is much more common than primary AI and can be traced to a lack of adrenocorticotropic hormone (ACTH). Without ACTH to stimulate the adrenal glands, production of cortisol falls but aldosterone secretion remains intact. The most common cause of secondary AI is the inadvertent abrupt withdrawal of therapeutic exogenous corticosteroids. Another cause of secondary AI is the surgical removal of benign or noncancerous, ACTH-producing tumors of the pituitary gland (Cushing syndrome). In this case the source of ACTH is suddenly removed, and replacement hormones must be taken until normal ACTH and cortisol production resumes.

Less commonly, secondary AI occurs when the pituitary gland reduces or ceases production of ACTH. This can occur for a variety of reasons including tumors or infections of the area, loss of blood flow to the pituitary, radiation for the treatment of pituitary tumors, total or subtotal removal of the hypothalamus, and surgical removal of the pituitary gland.

The term relative adrenal insufficiency has been replaced in recent literature by critical illness–related corticosteroid insufficiency (CIRCI),2,3 which in simple terms is inadequate corticosteroid activity for the severity of the illness of a patient. Similar to type II diabetes (relative insulin deficiency), CIRCI is thought to arise because of corticosteroid tissue resistance and inadequate circulating levels of free cortisol.

Patients at risk of AI vary from young athletes on steroids to persons taking adrenal extracts for “adrenal fatigue syndrome.” Also at risk are those receiving chronic topical glucocorticoids for dermatologic disorders. Patients who are on glucocorticoids and inhibitors (such as itraconazole, diltiazem) of CYP3A4 are at risk as well.4 For all these reasons the intensivist must understand clinical problems associated with the HPA axis and the use of glucocorticoid hormones.

Incidence and Prevalence

The actual incidence of acute AI is unknown. The incidence of HPA axis failure varies depending on the criteria used to make the diagnosis and the patient population studied. The overall incidence of AI in critically ill patients is estimated to be as high as 60% in patients with severe sepsis and septic shock.5 At least 90% of both adrenal glands must be destroyed before clinical and biochemical manifestations of AI occur. Tissue hypoxia, a relatively common disorder in critically ill patients, has little effect on the synthesis of cortisol. Secondary AI may be more common than primary AI. The clinical presentation of secondary AI is relatively nonspecific and often resembles other conditions common in the ICU. Hence it is not uncommon to attribute the clinical features resulting from acute AI to commonly seen medical conditions in the ICU.6

Pathophysiology

To understand the pathogenesis of adrenal diseases one must understand the physiology of the adrenal glands and the causes that result in the disruption of the physiologic process.

The adrenal glands are pyramid-shaped, each weighing about 5 to 10 g, and located just superior to their respective kidneys. The left adrenal gland is usually slightly more cephalad than the right. Each adrenal gland is composed of an inner medulla and outer cortex. These layers are embryologically, anatomically, and physiologically distinct. The adrenal cortex is responsible for the secretion of multiple steroid hormones. The adrenal medulla is responsible for the secretion of catecholamines.

The adrenal cortex is composed of three zones: the outer zona glomerulosa, inner zona fasciculata, and zona reticularis. The zona glomerulosa secretes the mineralocorticoid aldosterone in response to angiotensin, ACTH, and a high circulating potassium concentration. The zona fasciculata and zona reticularis secrete glucocorticoids and adrenal androgens.

The principal mineralocorticoid is aldosterone, which is regulated not only by ACTH but also by serum sodium and potassium levels and by the renin-angiotensin system.7,8 Mineralocorticoids exert their primary effect on distal renal tubule cells, resulting in renal sodium retention at the expense of potassium loss in the urine. A third major class of adrenal steroids is the sex hormones: dehydroepiandrosterone (DHEA), DHEA-sulfate, and androstenedione. Like the glucocorticoids, ACTH primarily regulates these steroid hormones. They function mainly as precursors for the primary circulating androgen, testosterone, and also may undergo separate conversion to estrogen hormones. In critically ill patients, glucocorticoids are the steroid hormones of greatest concern and therefore remain the focus of the remainder of this discussion.

Glucocorticoid Synthesis

Glucocorticoid synthesis is regulated by (1) a negative feedback mechanism involving cortisol and adrenal steroids, (2) a diurnal rhythm, and (3) stress. The hypothalamus and the pituitary gland closely regulate adrenal hormone production. Corticotropin-releasing hormone (CRH) is produced in the hypothalamus and acts on specialized cells in the pituitary, stimulating production of ACTH, which serves, in turn, to stimulate adrenal cortical cells to produce numerous steroid hormones, including cortisol. Adrenal hormones have a negative influence at the level of the hypothalamus and the pituitary, inhibiting CRH and ACTH release. The adrenal gland in turn ceases its secretory activity until the cortisol concentration returns to normal. When serum cortisol levels are below normal, secretion of CRH and ACTH increases, stimulating the adrenal glands to produce cortisol until its level normalizes. Therefore, abnormalities in circulating serum levels of adrenal steroid hormone can be caused by either adrenal or hypothalamic pituitary disease. Because ACTH possesses α-melanocyte-stimulating hormone activity, excessive production of ACTH is associated with hyperpigmentation.

Cortisol is normally secreted in a diurnal pattern. The circulating cortisol level is increased in the morning hours, at approximately 8 AM. Serum cortisol concentrations decrease throughout the remainder of the day.9 Similarly, the serum cortisol response to ACTH stimulation also varies in a circadian rhythm. Afternoon responsiveness is much greater because of the decreased circadian level of cortisol at that time. In addition, cortisol is secreted in a series of pulses rather than in a continuous fashion. These factors contribute to make interpretation of a random cortisol level and the ACTH-stimulated value difficult.

“Stress” (exemplified by sepsis, major surgery, or trauma) also affects glucocorticoid synthesis.10-12 The stress response is characterized by continuous ACTH secretion despite a high serum cortisol concentration. Stress overrides all other regulatory mechanisms of cortisol secretion by the adrenal cortex and increases cortisol secretion irrespective of the time of day or the current serum cortisol concentration. The mechanism by which the HPA axis is regulated during stress is not clearly understood. Periventricular neurons in the hypothalamus respond to stress by increasing the levels of CRH messenger ribonucleic acid (mRNA).13,14 It has been shown that production of the cytokines interleukin 1 (IL-1), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α) also plays an important role in the regulation of the HPA axis.1519 The cortisol secretion that occurs because of the activation of the HPA axis causes an inhibitory effect not only on the secretion of CRH and ACTH but also on the liberation of interleukins.20 Thus, there is a functional loop between immune activation and regulation of the HPA axis during stress.

The stress response is biphasic, consisting of an early phase in which both ACTH and cortisol are elevated and a late phase in which the serum cortisol level is elevated but the serum ACTH level is paradoxically low.8 This is explained by the fact that endothelin and atrial natriuretic peptide are both elevated in severe illnesses. Endothelin increases cortisol production by the adrenals, whereas the atrial natriuretic peptide inhibits ACTH production by acting at the hypothalamic-pituitary level. Vasopressin and angiotensin II can increase ACTH secretion during stress conditions, such as sepsis and septic shock

Acute respiratory failure causes a 50% to 100% rise in serum cortisol concentration. A twofold to sixfold rise occurs with septic shock and following surgical procedures and trauma. The rise in serum cortisol correlates positively with severity of illness6 and negatively with survival.7

The normal daily output of cortisol by the adrenal glands is 20 to 30 mg. The normal adrenal gland secretes about 10 to 12 times the normal daily output of cortisol when under maximal physiologic stress. Hence approximately 200 to 300 mg of hydrocortisone or its equivalent is considered a daily “stress dose” of glucocorticoid.

Glucocorticoid Actions

After uptake of free hormone from the circulation, the effects of cortisol and aldosterone are mediated by binding to intracellular receptors termed the glucocorticoid receptor and the mineralocorticoid receptor.

Cardiovascular Effects

Glucocorticoids help to maintain vascular tone and cardiac contractility. The presence of glucocorticoids is important to the physiologic effects of catecholamines on vascular smooth muscle. Glucocorticoids affect blood pressure by different mechanisms including direct action of glucocorticoids on the vasculature, permissive effects of the glucocorticoids on the vasopressor action of catecholamines, and glucocorticoid-induced decrease in the levels of prostaglandin E2 and kallikrein (vasodilators). Angiotensinogen synthesis is increased by glucocorticoids.21 Glucocorticoids increase the synthesis of β-adrenergic receptors, reverse β2-adrenergic receptor dysfunction, and increase the coupling of the receptor with the second messenger system.22

Two hemodynamic states have been described during acute AI:

1. Low cardiac output, high systemic vascular resistance shock is caused by both decreased myocardial contractility and decreased preload.

2. High cardiac output, low systemic vascular resistance shock mimics septic shock.23 It appears that patients with AI present initially with a combination of cardiogenic shock and hypovolemic shock. Intravascular volume expansion with intravenous fluids results in an increase in cardiac output and a lowering of systemic vascular resistance. The hemodynamic profile that one sees depends on the timing of pulmonary artery catheter placement during the course of treatment in an individual patient. Thus, the hypotension of AI can mimic cardiogenic, hypovolemic, or septic shock (depending on when the hemodynamic assessment was made) and may be poorly responsive or unresponsive to treatment with fluids and vasopressors in the absence of glucocorticoid therapy.

Metabolic Effects

Glucocorticoid hormones have profound influence on carbohydrate metabolism. A major action is on gluconeogenesis. Glucocorticoids increase hepatic glycogen and glucose by inducing the synthesis of hepatic enzymes and increasing the availability of gluconeogenic substrates. This is because of glucocorticoid-induced proteolytic activity on peripheral tissues, which causes mobilization of glycogenic amino acid precursors from peripheral supporting structures such as bone, skin, muscle, and connective tissue because of protein breakdown and inhibition of protein synthesis. Glucocorticoids decrease the peripheral uptake and utilization of glucose. They have a permissive effect on other hormones such as glucagon and catecholamines, thus serving to increase the circulating glucose concentration, which in turn increases insulin secretion.

Glucocorticoids also affect fat and protein metabolism. They increase lipolysis both directly and indirectly by action on other hormones. Glucocorticoids regulate fatty acid mobilization by enhancing activation of cellular lipase by lipid-mobilizing hormones (e.g., catecholamines, pituitary peptides). They elevate free fatty acid levels in the plasma and enhance any tendency to ketosis. Glucocorticoids stimulate peripheral protein metabolism, using the amino acid products as gluconeogenic precursors. Glucocorticoids inhibit RNA synthesis in most body tissues, but in the liver they stimulate RNA synthesis.

Immunologic Effects

Glucocorticoids suppress immunologic responses, and this is the basis for their use in the treatment of autoimmune and inflammatory disorders. In the peripheral blood, they redistribute lymphocytes from the intravascular compartment to the lymphoid pool in the spleen, lymph nodes, and bone marrow. They therefore decrease lymphocyte counts, but neutrophil counts increase after glucocorticoid administration. Eosinophil counts fall, due to eosinophil apoptosis. The immunologic actions of glucocorticoids are mediated through T and B lymphocytes. Glucocorticoids inhibit immunoglobulin synthesis and cytokine production from lymphocytes. Glucocorticoids also inhibit monocyte differentiation into macrophages and plasminogen activators.21

Glucocorticoids mediate anti-inflammatory effects by stabilizing lysosomal membranes. They also decrease the release of inflammatory mediators such as histamine, cytokines, and prostaglandins.

The immunologic actions of glucocorticoids are only significant in circumstances in which they are present in supraphysiologic amounts such as markedly increased endogenous production or exogenous administration.

Other Effects

Glucocorticoids have many other effects, including the ability to produce significant mood changes and even psychosis in some patients. Glucocorticoids have an association with cataract formation and increased intraocular pressure both by increasing aqueous humor production and decreasing drainage. They also affect the production and action of a number of other hormones including insulin, thyroid hormones, and gonadal hormones.

Aldosterone secretion is regulated mainly by the renin-angiotensin system. The most potent modulator of this system is renal perfusion. Hyperkalemia inhibits production of renin but increases the synthesis of aldosterone. Aldosterone increases sodium reabsorption in the collecting tubules and at the same time causes potassium and hydrogen ion excretion. This is mediated by the Na+/K+ pump in the presence of the enzyme Na+/K+-ATPase and results in sodium and water retention and an increase in intravascular volume.21

Hyperkalemia, hyponatremia, non–anion gap metabolic acidosis, hemoconcentration, and hypovolemia provide important clinical clues to the diagnosis of primary AI. Because ACTH is not a potent regulator of aldosterone secretion, secondary AI is usually not associated with hyperkalemia. Hyponatremia and hypovolemia may be present in secondary AI but not to the degree found in primary AI. The renin-angiotensin system is activated during AI and serves as a defense mechanism to improve the low intravascular volume and the altered vasomotor tone that results from aldosterone and cortisol deficiency.25,26