Adrenal insuffiency in critical illness

Hypothamic-pituitary adrenal insufficiency in critical illness   7/20/2001

(Critical care clinics volume17 number1 January 2001)

INTRODUCTION

ü          Cortisol is the major glucocorticoid produced by the adrenal cortex and is required for normal function of all cell in the body. Deficiency of cortisol is associated with increased morbidity and mortality during critical illness.

ü          Cortisol is required for carbohydrate, protein, and lipid metabolism; immune function, synthesis and action of catecholamines and adrenergic receptors; cardiac contractility; wound healing; vascular tone, endothelial integrity, normal vascular permeability; and numerous other functions.

ü          Hemodynamic benefits of glucocorticoids also related to the action beta-adrenergic receptor desensitization/uncoupling, and inhibition of nitric oxide sythase. Mineralocorticoids are important in the maitenance of fluid and electrolyte balance.

Regulation

ü          Cortisol circulates in the blood in bound and unbound forms. The bound form is primarily carried on cortisol binding globulin(90%). It is unbound or free cortisol that is physiologically active and hemeostatically regulated.

ü          Although levels of free cortisol have not been well studied in critically ill patients, studies in critically ill patients suggest that there is a decreased in cortisol binding rather than an increased. The cause for this decrease in binding is not unknown, but it may increased cortisol availability to the cell during stress.

ü          The bioavailabilty of cortisol to its sites of action (i.e., nucleus) has not been well studied during critical illnesss. There are no clinically useful tests for assess cellular actions of cortisol (end-organ affects) during illness.

CAUSES OF ADRENAL INSUFFICIENCY

ü          Systemic inflammatory states such as sepsis are associated with primary and secondary adrenal insufficiency that is reversible with treatment of the inflammation.

ü          The adrenal insufficiency is believed to result from hypothalamic-pituitary-adrenal suppression by cytokines and other inflammatory mediators.<=The immune and endocrine systems share common mediators that are capable of regulating each other..

INCIDENCE

ü          The incidence of adrenal insufficiency in critically ill patients is variable and depends on the underlying disease and severity of the illness.

ü          The authors define adrenal insufficiency as an inappropriately low cortisol response to stress (i.e.,<25 a="a" acth="acth" cortisol="cortisol" dl="dl" endogenous="endogenous" exogenous="exogenous" for="for" is="is" mcq="mcq" of="of" p="p" secretion="secretion" stimulation="stimulation" stimulus="stimulus" stress="stress" superior="superior" tests.="tests." than="than" use="use">

ü          The incidence increased with severity of illness (critical illness and sepsis>elective surgery >ward admits) with most studies in critically ill patients reporting incidences of 25% to 40%

CLINICAL MANIFESTATIONS

ü          Adrenal insufficiency should be suspected in patients with clinical features or disease processes associated with adrenal dysfunction. These include sepsis, HIV infection, head trauma, bilateral flank pain, and DIC.

ü          Hypotension that is refractory to fluid and requires vasopressors is a common presentation. One should always suspect adrenal insufficiency in patients with unexplained hyponatremia, hypokalemia, hypoglycemia, or eosinophilia.

EVALUATION OF ADRENAL FUNCTION

ü          The best stimuli for testing adrenal function are endogenous stresses such as hypotension, hypoglycemia, and hypoxemia. The tests evaluate the integrity of the entire brain (the sensor), hypothalamus-pituitary-adrenal axis.Endogenous stresses such as hypotension, hypoxemia, and hypoglycemia are superior stimuli for cortisol secretion compared with ACTH testing.

ü          When the level of stress is low or uncertain, cortisol production can assessed by induction of hypoglycemia (i.e., insulin tolerance test) and injection of exogenous ACTH (i.e., corticotropin) . It is important to realize that administration of exogenous ACTH bypasses the brain-hypothalamic-pituitary axis and tests the integrity of the adrenal gland directly. Failure of the adrenal gland to secrete adequate cortisol in response to ACTH is diagnostic of primary or secondary adrenal insufficiency (high positive predictive power); however, a normal response to ACTH dose not rule out adrenal insufficiency (low negative predictive power).

ü          The traditional approach to the short Corticotropin stimulation test (also known as the cosyntropin stimulation test) is to administer 250 mcg of synthetic corticotropin intravenously. Serum is obtained for cortisol analysis before and 30 and 60 minutes after corticotropin. A subnormal response (indicative of adrenal insufficiency) is a cortisol level less than 25 to 30 mcg/dL

ü          Importantly, a normal response to 250 mcg corticotropin(high dose) does not ru1e out adrenal insufficiency. This is amount of corticotropin is supraphysiologic (over one hundredfold greater than normal stress-induced ACTH levels). The very high levels of Corticotropin obtained with 25O mcg can override adrenal resistance to ACTH and result in a normal cortisol response (similar to the effect of insulin in patients with type 2 diabetes mellitus).These levels also can result in normal responses in patients with acute secondary adrenal insufficiency.

ü          Many patients with normal responses to high-dose(25O mcg) corticotropin fail to respond normally to stress or CRH.

ü          Patients with partial adrenal insufficiency and acute adrenal insufficiency can have normal responses to exogenous ACTH. It can take 10 to 14 days for the adrenal gland to atrophy enough so that responses are subnormal to ACTH after the acute onset of secondary adrenal insufficiency (as may be seen in patients with sepsis)．

ü          It is interesting that very high cortisol levels (markers of severe stress) and blunted increases in cortisol (lack of adrenal reserve) are associated with high mortality. Of course low cortisol response to stress also is associated with high mortality.

ü          The traditional high-dose (25O mcg) Corticotropin stimulation test administers supraphysiologic doses of Corticotropin, so many clinicians use the more physiologic low-dose (1 to 2mcg) Corticotropin stimulation test, which better approximates ACTH levels found in severe stress.

ü          Blood samples for cortisol analysis are obtained before and 30 and 60minutes after administration of 1to 2mcg of Corticotropin. An appropriate response is a circulating cortisol level greater than 25 to 30mcg/dL Using the low-dose Corticotropin stimulation test, the authors and other investigators have found that in most critical1y ill patients with stress-related cortisol levels 15mcg/dL cortisol levels do not increase higher than 20 mcg/dl following certicotropin. The authors believe that patients in whom Cortisol levels do not rise have adrenal insufficiency. Many affected patients wi1l have a normal cortisol response(25mcg/L) Using the high-dose Corticotropin stimulation test. Thus,it appears that the low-dose Corticotropin stimulation test is more sensitive than the high-dose test for detecting adrenal insufficiency

ü          In the authors’ experience, most patients with adrenal insufficiency diagnosed by the low dose corticotropin test improve clinically(i.e., improved blood pressure)with hydrocortisone treatment. In a recent study,³³ the authors reported that 40% of patients with hypotension and sepsis who require vasopressors and 30 of patients with HIV admitted to the ICU have adrenal insufficiency diagnosed with the low-dose corticotropin stimulation test.

ü          Endogenous ACTH levels range from 100 to300 pg/mL during severe stress. These levels produce maximal secretion of the adrenal gland. Postoperative ACTH levels average 100 to 125pg/mL. Critically ill patients typically have ACTH levels of 80 to 150 pg/mL. Normal ACTH levels in nonstressed individuals range from 9 to 50 pg/mL. Corticotropin levels (ACTH) can aid in the diagnosis of adrenal insufficiency. Low plasma cortisol levels in the face of high Corticotropin levels (i.e. 100 pg/mL or 22 pmol/L) suggest primary adrenal insufficiency. Normal or low Corticotropin levels m the presence of low cortisol levels suggest secondary adrenal insufficiency

ü          The adrenal axis can be evaluated using Corticotropin releasing hormone (CRH). After administration of CRH, corticotropin(ACTH) peaks at 15to 30minutes and cortisol peaks at 30to 60minutes.This test can distinguish between corticotropin deficiency and deac1ency of CRH. The authors have noted an occasional patient in the ICU who fails to respond normally to CRH but does respond normally to high-dose (250 mcg) corticotropin. These patients have secondary adrenal insufficiency.．

ü          There is much controversy regarding levels of cortisol that are considered an adequate stress response. Many textbooks and published manuscripts state that the normal cortisol response to stress is a level＞18to 2O mcg/dL. .The choice of 18to 20 mcg／dL is based primarily on the response to exogenous ACTH（25O mcg）in patients who are not stressed or critically ill. When the physician examines the cortisol  response to severe stress （i.e., critical illness，hypotension，hypoxemia）, the majority of patients are found to achieve levels in excess of 25to 30mcg/dL* An uncomplicated cholecystectomy in a normal person increases cortisol concentrations to 27 to 34mcg/dL at 30minutes after the start of surgery and to 46 to 49mcg/dL at 5 hours after surgery. Melby and colleagues ³⁷ reported a mean cortisol level of 63mcg/dL in 2O patients with hypotension and sepsis (range 30 to 160 mcg/dL). Thus, many critical care metabolism experts believe that the cortisol response to critical illness should exceed these levels. The authors use 25mcg/dL as the lower normal response to stress. It is not necessary to obtain cortisol levels at a specific time of the day because most critically ill patients lose the diurnal variation in their cortisol levels. The level should be obtained during the stress(i.e., hypotension，hypoglycemia， hypoxemia).

ü          The acute and chronic responses to ACTH differ. The acute response may not always predict the chronic response. Thus, patients with chronic critical illnesses or stresses should be re-evaluated at intervals to determine if their adrenal function is adequate (even if initial adrenal function was adequate for the level of stress)．The authors call the failure to maintain cortisol secretion in the face of chronic stress the adrenal exhaustion syndrome. Chronically elevated cytokine levels or persistent or recurrent infections may contribute to adrenal exhaustion．

ü          The initial step is to determine whether the patient has primary or secondary adrenal insufficiency. This determination can be accomplished using ACTH levels or prolonged ACTH infusion. The next step is to image the brain (secondary adrenal insufficiency)or adrenals (primary adrenal insufficiency). Magnetic resonance(MR) imaging is the most sensitive test for detecting abnormalities m the hypothalamic-pituitary-adrenal axis. Disease in the adrenal glands is best imaged with computed tomography(CT) scanning. Enlarged adrenal glands suggest tuberculosis (unless long standing), fungal disease, cancer, hemorrhage, and AIDS. Small adrenal glands suggest autoimmune adrenal atrophy or long-standing infectious or vascular disease. A biopsy specimen from the involved area may be required for definitive tissue diagnosis. Patients with secondary adrenal insufficiency should be evaluated for loss of other hormones such as thyroid hormone.

TREATM ENT

1.          Supportive care and treatment underlying disease: It includes administration of fluids, electrolytes, nutrition, needed medications such as antibiotics and organ support (i.e., respiratory  cardiovascular support). It is important to maintain body temperature and glucose levels(With dextrose and normal saline solutions).

2.          Hydrocortisone replacement

ü          Adrenalectomy in animals increases mortality after septic and hypovolemic shock. Glucocorticoid replacement improves survival in these models. Thus it is believed that hydrocortisone treatment is lifesaving in patients with adrenal insufficiency ; however, most of this belief is based on pathophysiologic reasoning and case studies.For example, Soni and colleagues identified and treated thee patients with septic shock and adrenal insufficiency with glucocorticoids. All thee were weaned off pressor support within several hours of receiving steroid.

ü          Survival was not improved Mckee and colleagues reported that the mortality from critical illness increased from 27 in patients with stress cortisol levels 125mcg/dL  and 97 to 100m patients with stress cortisol level 125rncg/dL n 36.

ü          Beishuizen and colleagues diagnosed adrenal insufficiency in 10 of 40 medical-surgery ICU patients. Treatment with hydrocortisone improved hemodynamics in seven of eight patients.

ü          Mark and colleagues diagnosed adrenal insufficiency in seven patients. In all of them blood pressure improved with hydrocortisone treatment

=>There are a few studies in the literature that have compared treatment of patients with adrenal insufficiency with glucocorticoids versus placebo.

ü          Mckee and colleagues randomized18 critically ill patients with adrenal insufficiency (stress cortisol 125mcg/dL and no response to corticotropin) to glucocorticoid treatment or placebo. One of eight(13) steroid-treated patients died compared with nine of ten (9) of patients given placebo.

ü          Evidence for high mortality from untreated adrenal insufficiency in critically ill patients also comes from the report of Ledingham andWatt , who reported increased mortality from use of etomidate(a sedative agent that causes adrenal insufficiency) in multiple trauma patients (44 etomidate versus 27 other sedatives).

ü          Bollaert and colleagues randomized 41 critically ill patients with septic shock to hydrocortisone (100 mg every 8hours)or placebo. The glucocorticoid-treated patients had a greater reversal of shock at 7and 28days and reduced 28-day mortality compared with the placebo group.

ü          In a recent study Bnegel and colleagues randomized 40 critically ill patients with sepsis and hypotension who required vasopressor support to hydrocortisone or placebo. Hydrocortisone treatment was associated with improved shock reversal and decreased days of vasopressor support. There also was earlier resolution of organ dysfunction, shorter ventilator time and shorter ICU stay. Mortality was 4of 20 of the steroid-treated patients versus 6 of 20 of the placebo group. The authors of this study did not evaluate the patients for the presence of adrenal insufficiency; however, this group reports an incidence of adrenal insufficiency of 40 to 50. These studies used stress doses of glucocorticoids (300 mg hydrocortsone per day) in contrast, a number of large multicenter studies that used massive doses of glucocorticoids (30 mg/kg methylprednisolone) failed to and benefit in patients with sepsis.

ü          Annane and colleagues evaluated adrenal function in 189 patients with septic shock. Interestingly, compared with survivors/nonsurvivors had significantly higher basal plasma cortisol levels and lower cortisol response to high-dose (0.25mg) Corticotropin(decreased adrenal reserve) The increased basal cortisol levels and lower response to corticotropin may reflect a higher degree of illness in the nonsurvivors. The relative lack of a serum Cortisol response to Corticotropin insome critically ill patients may be related to the fact that the hypothalamic-pituitary-adrenal axis is already maximally stimulated. Similar observations have been noted by other investigators, Thus, patients with low stress cortisol values(adrenal insufficiency)and those with high values (severe stress or illness) have increased morta1ity.

THERAPEUTIC APPROACH TO ADRENAL INSUFFICIENCY

ü          Patients with diseases known to cause adrenal insufficiency and clinical features of adrenal insufficiency should be evaluated for adrenal dysfunction . Patients with hypotension refractory to fluids and who require vasopressors are at very high risk. Hyponatremia, hyperkalemia, hypoglycermia, and eosinophilia also suggest the diagnosis of adrenal insufficiency.

ü          A stress serum cortisol sample should be obtained for analysis. The patient should be started on hydrocortisone (100 mg every 8hours) empirically pending results of testing. If the serum cortisol level is found to be less than 25mcg/dL the hydrocortisone should be continued. In addition, if the patient has improved clinically with hydrocortisone, the author favor continuing the hydrocortisone for a few days (unless there is a specific contraindication). The authors and other believe that some patients may have cellular resistance or deficiency of glucocorticoids despite high serum levels. Until there is an adequate end-organ assay for glucocorticoid actions,they recommend continuing glucocorticoid treatment in patients who improve on thesteroid, despite adequate circulating levels. The does of hydrocortisone should be tapered down toward maintenance doses as the patient’s clinica1status improves.

ü          If the level of stress is uncertain and adrenal insufficiency is suspected, the authors favor adrenal testing with the low-dose (1 to 2mcg) corticotropin stimulation test. The authors usually treat the patient with hydrocortisone empirically pending results. If the corticotropin stimulation test can not be performed immediately, dexamethasone (2mg) should be administered, and the test should be performed within the next 12 hours. Dexamethasone does not significantly cross-react with cortisol in the assay for cortisol l and can be given to patients spending the results of adrenal testing.

ü          There is debate regarding whether asymptomatic patients with borderline adrenal insufficiency should be treated with hydrocortisone. The authors believe that all critically ill patients are symptomatic and warrant treatment because many of the clinical features of adrenal insufficiency are nonspecific and easily masked by critical illness.

ü          Once their conditions are stable, patients should be tapered to maintenance does of hydrocortisone appropriate to their levels of stress. In nonstressed patients 15mg hydrocortisone in the morning and 10mg in the afternoon are usually adequate for replacement. Definitive adrenal testing should wait until the patient is well. Most critically ill patients with acquired adrenal insufficiency recover adrenal function after recovery from illness and will not require life-long replacement of adrenal hormones.

ü          Patients with primary adrenal insufficiency develop both glucocorticoid and mineralocorticoid hormones. Mineralocorticoids can be replaced with fludrocortisone(50 to 200 mcg/d)

SUMMARY

ü          Adrenal insufficiency is a common and underdiagnosed disorder that develops in critically ill patients. Most forms are acquired and will resolve with treatment of the underlying disease. Hypotension that is refractory to fluids and requires vasopressors is the most common presentation of adrenal insufficiency in the ICU. It is important to make the diagnosis of adrenal insufficiency, because current data suggest that treatment with glucocorticoids improves outcome.

ü          Diagnosis usuallv can be made on the basis of a stress cortisol level. Occasionally, when the level of stress is uncertain,the low-dose corticotropin stimulation test will be required for definitive diagnosis. A therapeutic trial with hydrocortisone should be started in patients with suspected adrenal insufficiency pending results of diagnostic testing．

Lesson 1: Inflammation causes adrenal insufficiency
Lesson 2: This is mediated by cytokines
Lesson 3: Endocrine health is intimately linked with immune health. You can't have one without the other.




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