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Attending Version Adrenal Insufficiency Module Created by Dr. Hemanth Pai Objectives: By the end of this module, you should be able to: 1. Differentiate between primary vs secondary adrenal insufficiency 2. Give a definition of relative adrenal insufficiency (RAI) 3. Recognize signs and symptoms of adrenal insufficiency 4. Understand the utility and limitations of diagnostic tests in adrenal insufficiency 5. Understand reasons for different treatment regimen in primary vs secondary vs RAI References: 1. Krieger et al 2. Vermes et al. J Clin Endocrinol Metab 1995 3. Annane et al. JAMA 2000 ADRENAL INSUFFICIENCY Definitions: Primary adrenal insufficiency (AI): Failure of adrenal glands resulting in insufficient production of BOTH glucocorticoids (GC)- cortisol and mineralocorticoids (MC)-aldosterone. Secondary AI: Due to insufficient pituitary ACTH production resulting in decreased production of adrenal GC. MC production usually not affected. Relative AI: Transient insufficiency of adrenal GC (ie cortisol) production associated with critical illness/septic shock. Etiologies: Primary AI: autoimmune adrenalitis (70%), bilateral adrenal hemorrhage, TB, Histoplasmosis, N. meningitides, medications (eg etomidate, ketoconazole), metastatic disease, Addison’s disease Secondary AI: pituitary disease (adenoma, empty sella, tumors), chronic steroid use (i.e. prednisone), history of cranial irradiation Relative AI: critical illness, septic shock Symptoms: Nausea, vomiting, abdominal pain, anorexia and weight loss, myalgias (flu-like symptoms), arthralgias, dizziness, orthostasis. Salt-craving may also be present in primary AI Signs: Physical examination: o Primary AI: Hypotension, hyperpigmentation of skin folds and palmar creases, generalized tanned skin o Secondary AI: Hypotension, decreased visual acuity or visual field cuts or diplopia (seen with pituitary disease) Laboratories: o Electrolytes: hyponatremia, hyperkalemia (only in primary AI), azotemia, hypoglycemia o Hematologic: lymphocytosis, eosinophilia Diagnosis of Primary & Secondary Adrenal Insufficiency: Random Cortisol Level is seldom used to diagnose adrenal insufficiency because normal cortisol level fluctuates significantly throughout the day, see Figure 1. i.e. a serum cortisol level of 3 ug/dl may be normal in the afternoon, although would be considered low at 8am. Therefore there is no way of setting up normal parameters for random cortisol level since it depends on time of day it is drawn. Figure 1. Variation in normal serum cortisol and ACTH levels (Krieger et al) 8am cortisol Level is sometimes used because cortisol peaks in early morning so level <3 ug/dl may be suggestive but not diagnostic of adrenal insufficiency Cosyntropin (ACTH)-stimulation test is best for the diagnosis of adrenal insufficiency Can be done any time of day Check baseline cortisol level Give Cosyntropin 0.25 mg IV push Check cortisol at 30 and 60 min post-Cosyntropin 60 min cortisol < 20 ug/dl diagnostic of adrenal insufficiency Check baseline ACTH level only if trying to determine/distinguish primary vs secondary adrenal insufficiency (ACTH high in primary AI and low in secondary AI) o o o o o o Pitfalls of Cosyntropin-stimulation test: Sensitivity is decreased in diagnosing partial secondary AI as adrenal glands may only be partially atrophied and respond normally to exogenous ACTH Cannot be used immediately following pituitary injury as adrenal glands do not atrophy for at least ~8 wks (for example, cosyntropin stimulation test may be normal immediately following surgery as adrenal glands respond normally to ACTH administration) No reference ranges for baseline cortisol in critically ill (ie ICU) patients Serum cortisol is dependent on albumin and cortisol-binding globulin (CBG); conditions that decrease albumin and CBG will decrease serum cortisol Diagnosis of Relative Adrenal Insufficiency (RAI): o o Normal reference range for primary or secondary adrenal insufficiency (< 20 ug/dl) does not apply in the critically ill population (Figure 2) as baseline cortisol levels are increased in critically ill subjects. 60 min cortisol < 20 ug/dl after a cosyntropin stimulation test is diagnostic of adrenal insufficiency in most settings; although it does not apply in the critically ill population, because baseline cortisol levels are already increased, see Figure 2. Although, patients in this population may still have diminished response and capacity to stress, referred to as relative adrenal insufficiency. Therefore a new reference has to be applied to the critically ill patients. RAI is defined by an increase in cortisol ≤ 9 ug/dl following a 250 ug cosyntropin/ACTH stim test (Figure 3). A cortisol increment ≤ 9 ug/dl suggests diminished adrenal reserve and diminished capacity to respond to stress, termed relative adrenal insufficiency. Diagnosing relative adrenal insufficiency in critically ill patients is important because probability of survival decreases in this population as shown in Figure 3 below. Treatment for RAI/AI Hydrocortisone 50mg IV Q6h or 100mg IV Q8h for 7 days (remember that once hydrocortisone is started, you cannot do cosyntropin stim test since hydrocortisone cross reacts with assay for cortisol and so does prednisone; Alternative to IV hydrocortisone is Dexamethasome 4mg IV qd). Outpatient dose is usually Hydrocortisone 15mg qam and 5pm or 20mg qam and 10mg qpm. o Fludrocortisone generally not necessary due to mineralcorticoid properties of hydrocortisone o Glucocorticoid treatment associated with improvement in 28-day mortality, ICU mortality, hospital mortality, and time to vasopressor withdrawal. Figure 2. Baseline Cortisol levels in normal subjects and the critically ill (adapted from Vermes et al. J Clin Endocrinol Metab 1995) Figure 3. Outcomes of septic shock associated with relative adrenal insufficiency and baseline cortisol level (adapted from Annane et al. JAMA 2000) CASE A 74 yo man veteran presents to the ER with fatigue, SOB, and productive cough. A diagnosis of COPD is present in the chart. He is on chronic home oxygen. He reports that he has lost ~15 lbs over the past 6 mos. Looking over his chart, his medical history is significant for COPD, BPH. PFTs done by his PCP reveal a FEV1 of 1.1 L. His outpatient medications are atrovent and albuterol MDIs and nebulizers. He has had three hospitalizations in the past year for COPD exacerbations. Each time, he was discharged home with antibiotics and a prednisone taper. On physical examination, temperature 99.0 F, BP 98/60, HR 114 (after Duoneb was given), RR 20 with O2 sat 88% while on 4L of oxygen. Weight is 115 lbs, BMI 21. Physical examination is significant for a thin man with globally diminished breath sounds without any crackles or wheezing. He is breathing with pursed lips with contraction of accessory respiratory muscles. Remainder of the exam is normal. Laboratories reveal the following: Na 133, K 4.0, Cl 92, CO2 40, BUN/Cr 6/0.4, Glu 138 WBC 12.1 (42%N, 46%L, 4%M, 6%E), H/H 13/40, Plt 225,000 Coags, LFTs, and a cardiac panel are normal. Imaging: PA/LAT CXR reveals no evidence of infiltrate or nodules. There is flattening of the diaphragms bilaterally. Hospital Course: A diagnosis of COPD exacerbation is made. The patient is admitted to the hospital started on atrovent and albuterol nebs Q6H, doxycycline, and prednisone 40mg taper. He improves over the course of 3 days. 1. Is there anything else you would consider prior to discharge? With a history of recurrent steroid treatment in the past year along with symptoms/signs of AI (hypotension, weight loss, hyponatremia, lymphocytosis, eosinophilia), suspicion for adrenal insufficiency, in this case secondary AI, must be high. Prior to hospital discharge, a cosyntropin stimulation test is performed to evaluate for adrenal insufficiency with the following results: Baseline: ACTH 5 (normal 10-65), baseline cortisol 16 ug/dl 30-minute stimulated cortisol: 22 ug/dl 60-minute stimulated cortisol: 26 ug/dl 2. Does the patient have adrenal insufficiency? Based on the actual numbers, the patient does not have adrenal insufficiency as his peak cortisol > 20 ug/dl. However, prednisone (as well as hydrocortisone) cross-reacts with the assay for cortisol and can raise cortisol values. Dexamethasone does not cross-react with the cortisol assay and the results of a cosyntropin-stimulation test can be interpreted when dexamethasone is used. The patient is discharged and the prednisone is tapered off over 10 days. The patient’s PCP sees the results of the cosyntropin-stimulation test, and after consultation with an endocrinologist, repeats the test 8 weeks later with the following results: Baseline cortisol: 10 ug/dl 60-minutes stimulated cortisol: 16 ug/dl 3. Does the patient have adrenal insufficiency? Yes. In non-critically ill patients, a peak cortisol < 20 ug/dl is diagnostic of adrenal insufficiency. 4. How would you treat this patient now? The average daily cortisol secretion is about 15-25 mg/day with peaks in secretion in the early morning and early evening (see Figure 1). The patient is started on Hydrocortisone 15mg QAM and 5mg QPM. Over the next 2 months, he reports increased energy and weight gain of 3 lbs. 5. Does this patient need fludrocortisone? No. Fludrocortisone is a mineralocorticoid and is similar to aldosterone. In secondary AI, secretion of aldosterone is preserved as the renin-angiotensinaldosterone axis is still able to respond to increases in potassium. If the patient had primary AI, then fludrocortisone would probably be necessary. Follow-up The patient is seen in the Pulmonary Clinic 3 months after hospital discharge and is started on Prednisone 10mg daily for his COPD. 6. What would you do with the hydrocortisone? Prednisone is a more potent steroid than hydrocortisone. It is thought that prednisone is ~4-5x more potent than hydrocortisone. In this patient, a dose of prednisone of 10mg would be about equivalent to a hydrocortisone dose of 40mg daily. Thus, the prednisone would be sufficient to treat his secondary AI, and the hydrocortisone can be stopped. Just remember that patient cannot be off steroids completely as long as he has secondary AI. So when doing prednisone taper for COPD exacerbations, when prednisone is tapered to about 5mg/d or less, then patient needs to be switched back to previous hydrocortisone dose. Also, adrenals can recover in secondary AI, but this may take months or years The patient is readmitted 1 year later with fever, SOB, and productive cough. On physical exam, T 100.3 F, BP 98/60, HR 112, RR 22, O2 sat 86% on 40% ventimask. A PA/Lat CXR this time shows a RLL infiltrate. The patient is diagnosed with community-acquired pneumonia and started on appropriate antibiotics. 7. Is there anything else you would do? Yes! Don’t forget the patient has secondary AI. He should receive stress dose steroids (hydrocortisone 200-300 mg/d in divided doses, 50mg IV Q6h or 100mg IV Q8h). Stress dose steroids can be tapered slowly over the course of several days or weeks back to the patient’s maintenance dose. QUESTION A woman was admitted this morning in the medical intensive care unit for elective cholecystectomy. Before surgery, her physical exam, including vital signs, was normal. The procedure went well, and there were no noticeable complications. However, three hours after returning to her room, she was noted to be unresponsive, and her blood pressure was barely palpable. She was intubated for respiratory failure. Her blood pressure has been refractory to intravenous fluids and pressors. You are consulted to help in the workup of suspected adrenal insufficiency. Which of the following statements regarding adrenal insufficiency is true? A. The most common cause of adrenal insufficiency in the US is tuberculosis B. The critical test for the diagnosis of chronic adrenal insufficiency is the cosyntropin test C. Chronic secondary adrenal insufficiency is treated with hydrocortisone and fludrocortisone, whereas chronic primary adrenal insufficiency is treated with hydrocortisone alone D. In idiopathic or autoimmune adrenal insufficiency, CT of the abdomen shows enlarged adrenal glands (Answer B) Key concept/Objective: To understand the diagnosis and treatment of adrenal insufficiency Primary adrenal insufficiency results from destruction of the adrenal cortex. The list of causes of primary adrenal insufficiency is long. In the industrialized nations, idiopathic or autoimmune adrenal destruction is the most common cause. Secondary adrenal insufficiency results from disruption of pituitary secretion of ACTH. By far the most common cause of secondary adrenal insufficiency is prolonged treatment with exogenous glucocorticoids. The acute syndrome is closely analogous to cardiogenic or septic shock and involves reduced cardiac output and a dilated and unresponsive vascular system. Symptoms include prostration, as well as all of the signs and symptoms of the shock syndrome. With both chronic and acute syndromes, the diagnosis should be suspected on clinical grounds but requires laboratory confirmation. The critical test for the diagnosis of chronic adrenal insufficiency is the cosyntropin stimulation test. Synthetic ACTH (cosyntropin) is administered in a 250Ug intravenous bolus, and plasma cortisol levels are measured 45 and 60 minutes afterward. Values greater than 20ug/dl exclude adrenal insufficiency as a cause of the clinical findings. Values less than 20ug/dl suggest that adrenal compromise could be a contributing factor. In this situation, treatment with a glucocorticoid is mandatory until the clinical situation is clarified with more precision. The differential diagnosis of adrenal insufficiency requires the discrimination of primary and secondary causes. The most useful test of this is measurement of the circulating plasma ACTH level. ACTH levels greater than normal define primary disease; values in the normal range or below define secondary disease. Primary chronic adrenal insufficiency is treated with 12 to 15 mg/m2 of oral hydrocortisone a day. Hydrocortisone is best given as a single daily dose with breakfast. Fludorocortisone is given at a dose of 0.1 mg/day. Chronic secondary adrenal insufficiency is treated in the same way as chronic primary disease but with replacement of hydrocortisone only, not aldosterone. Post Module Evaluation Please place completed evaluation in an interdepartmental mail envelope and address to Dr. Wendy Gerstein, Department of Medicine, VAMC (111). 1) Topic of module:__________________________ 2) On a scale of 1-5, how effective was this module for learning this topic? _________ (1= not effective at all, 5 = extremely effective) 3) Were there any obvious errors, confusing data, or omissions? Please list/comment below: ________________________________________________________________________ ________________________________________________________________________ ________________________________________________________________________ ________________________________________________________________________ 4) Was the attending involved in the teaching of this module? Yes/no (please circle). 5) Please provide any further comments/feedback about this module, or the inpatient curriculum in general: 6) Please circle one: Attending Resident (R2/R3) Intern Medical student