Facilitator Version

Module #8 – Endocrine Emergencies

Adrenal Insufficiency

Objectives:By the end of this module, you should be able to:

1. Recognize signs and symptoms of adrenal insufficiency

2. Differentiate between primary vs secondary adrenal insufficiency

3. Understand and recognize relative 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 relative adrenal insufficiency

CASE

A 74 yom with past medical history of oxygen dependent COPD presents to the ER with fatigue, sob and productive cough present for three days. His outpatient medications are atrovent and albuterol MDIs and nebulizers. He has had four hospitalizations in the past year for COPD exacerbations. On review of systems, patient reports that he has lost ~15 lbs over the past 6 mos.

On physical examination, temperature 99.0 F, BP 88/52, 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.

Labs:Na 131, K 4.0, Cl 92, CO2 40, BUN 6, Cr 0.4, Glu 55WBC 12.1 (42% N, 46%L, 4%M, 6%E), Hgb 13m Hct 40, Plt 225Lactate wnl, Coags wnl, LFTs wnl, trop wnl

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 and started on atrovent and albuterol nebs Q6H, doxycycline, and prednisone 60mg taper. His breathing and oxygenation improves over the course of 3 days.

What is your differential diagnosis for his weight loss?Malignancy, chronic infections ie fungal, HIV, adrenal insufficiency and malnutrition

What lab values are abnormal and not explained by COPD exacerbation?Hyponatremia, lymphocytosis, eosinophilia and hypoglycemia

What diagnosis would explain the weight loss, hypotension and the abnormal lab findings?Adrenal insufficiency, given patient has a history of recurrent steroid treatment in the past year along with symptoms/signs of adrenal insufficiency (hypotension, weight loss, hyponatremia, lymphocytosis, eosinophilia and hypoglycemia).

Would you suspect this to be primary, secondary or relative adrenal insufficiency?Secondary adrenal insufficiency since we are suspecting that recurrent steroid treatment led to it.

Definitions:Primary adrenal insufficiency: Failure of adrenal glands resulting in insufficient production of BOTH glucocorticoids (cortisol) and mineralocorticoids (aldosterone).Etiologies: autoimmune adrenalitis (70%), bilateral adrenal hemorrhage, TB, Histoplasmosis, N. meningitides, medications (eg etomidate, ketoconazole), metastatic disease, Addison’s disease

Secondary adrenal insufficiency: Due to insufficient pituitary ACTH production resulting in decreased production of cortisol. Aldosterone production usually not affected.Etiologies: pituitary disease (adenoma, empty sella, tumors), chronic steroid use (i.e. prednisone), history of cranial irradiation

Relative adrenal insufficiency: Transient insufficiency of adrenal glucocorticoid (cortisol) production associated with critical illness/septic shock.Etiologies: critical illness, septic shock

How would you work it up?Cosyntropin stimulation is best test for the diagnosis of adrenal insufficiency and it can be done any time of day!!!

How do you perform Cosyntropin stimulation test?-Check baseline cortisol level-Give Cosyntropin 0.25 mg IV push-Check cortisol at 30 and 60 min post-Cosyntropin-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)

How is the interpretation of the results of cosyntropin stim test different in critically-ill patients vs non-critically ill patients?In non-critically ill patients: 60 min cortisol < 20 ug/dl after a cosyntropin stimulation is diagnostic of adrenal insufficiency.In critically-ill patients: baseline cortisol levels are already increased from being critically-ill, but the patient may still have diminished response and capacity to stress, referred to as relative adrenal insufficiency. Therefore a new reference has to be applied to diagnose relative adrenal insufficiency. Relative adrenal insufficiency is defined by an increase in cortisol ≤ 9 ug/dl following a 250 ug cosyntropin stim test. A cortisol increment ≤ 9 ug/dl suggests diminished adrenal reserve and diminished capacity to respond to stress. Diagnosing relative adrenal insufficiency in critically ill patients is important because probability of survival decreases in this population if not treated for the relative adrenal insufficiency.

What is the value of random cortisol level?The value of random cortisol level is very limited. Random cortisol level is seldom used to diagnose adrenal insufficiency because normal cortisol level fluctuates significantly throughout the day. Therefore there is no way of setting up normal parameters for random cortisol level since it depends on time of day it is drawn. Sometimes, 8am cortisol level is used because cortisol peaks in early morning so level <3 ug/dl may be suggestive but not diagnostic of adrenal insufficiency.

Results of Cosyntropin stimulation test are as follows:

Baseline: ACTH 5 (normal 10-65)Cortisol 16 ug/dl

30-minute stimulated cortisol: 22 ug/dl60-minute stimulated cortisol: 26 ug/dl

How do you interpret these values? Does the patient have adrenal insufficiency?

It is not clear whether patient has adrenal insufficiency because the cosyntropin stim test was done while the patient was taking prednisone. Prednisone and hydrocortisone cross-reacts with the assay for cortisol and can raise cortisol values and therefore the results cannot be interpreted. Dexamethasone does not cross-react with the cortisol assay and the results of a cosyntropin-stimulation test can be interpreted when dexamethasone is used.

What should you do now? Consult with Endocrinology so that a plan is in place after discharge for a repeat consyntropin stim test and the timing of that test relative to the prednisone taper.

Patient is seen by Endocrinology as outpatient and cosyntropin stim test is repeated, off prednisone. Results are as follows:Baseline cortisol: 10 ug/dl60-minutes stimulated cortisol: 16 ug/dl

Does the patient have adrenal insufficiency?

Yes. In non-critically ill patients, a peak cortisol < 20 ug/dl is diagnostic of adrenal insufficiency.

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. The patient is started on Hydrocortisone 15mg QAM and 5mg QPM.

Does this patient need fludrocortisone?

No. Fludrocortisone is a mineralocorticoid and is similar to aldosterone. In secondary adrenal insufficiency, secretion of aldosterone is preserved as the renin-angiotensin-aldosterone axis is still able to respond to increases in potassium. If the patient had primary AI, then fludrocortisone would probably be necessary.

Over the next 2 months, patient reports increased energy and weight gain of 3 lbs. He is seen in the Pulmonary Clinic for a follow-up of his recurrent COPD exacerbations (5 episodes in one year) and is started on Prednisone 10mg daily for his COPD.

What should you do with the hydrocortisone?

Stop 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 adrenal insufficiency, and the hydrocortisone can be stopped.

The patient is readmitted to the hospital 1 year later for RLL pneumonia. He is febrile, tachycardic, hypotensive, and requires 40% ventimask to maintain his oxygen saturation. The patient is diagnosed with community-acquired pneumonia and started on appropriate antibiotics. What would you do with his outpatient prednisone?

His outpatient prednisone should be discontinued and patient should be placed on stress dose steroids while he is critically ill. Don’t forget the patient has secondary adrenal insufficiency. Usually hydrocortisone IV is used, 200-300 mg/d in divided doses, 50mg IV Q6h or 100mg IV Q8h. Alternative to IV hydrocortisone is Dexamethasone 4mg IV qd.

When would you taper the stress dose steroids in this patient?Usually, stress dose steroids can be tapered slowly over the course of several days or weeks back to the patient’s maintenance dose.

Will the patient need steroids for life for his secondary adrenal insufficiency?No, the adrenals can recover in secondary adrenal insufficiency, but this may take months or years.

MKSAP 16:Question #25: Management of adrenal insufficiencyQuestion #39: Manage newly diagnosed adrenal insufficiencyQuestion #48: Evaluate adrenal function during critical illnessQuestion #55: Manage adrenal function during critical illnessQuestion # 60: Diagnose the cause of acute adrenal insufficiency

*****YOU MAY STOP HERE OR PROCEED TO THYROID STORM*****

Thyroid Storm

Objectives:By the end of this module, you should be able to:

1) Recognize three signs and symptoms of thyroid storm and why they occur

2) Be able to appropriately evaluate a patient with suspected thyroid storm

3) List three treatments for thyroid storm

CASE

A 19 yom was involved in a low speed motor vehicle accident. At the scene, he complained of neck pain. A C-collar was placed and he was transferred by ambulance to the local Emergency room. On exam, he was generally anxious, warm to touch, had mild tremor. Vitals show patient was tachycardic with heart rate of 125. Patient had tenderness over the c-spine, but no focal neurological deficits were noted. X-ray of the c-spine was ordered. Over the course of his ER stay he became progressively agitated, confused and combative. His heart rate increased to 160 and temperature rose to 40◦ C. He was visibly shaking and unable to sit still. He required sedation and restraints. He was intubated for airway protection and respiratory support and was transferred to a tertiary care center and admitted to an ICU bed.

What is your differential diagnosis for his deterioration in mental status (initially anxious and mildly tremulous to agitation, confusion and combativeness) and increase in heart rate and temperature? Sepsis, intoxication, alcohol withdrawal, thyroid storm, organophosphate poisoning, autonomic insufficiency, psychosis, intracranial hemorrhage.

What is your next step in the work-up and management?A full metabolic panel, CBC, blood and urine cultures, toxicology screen, and thyroid panel were ordered. EKG, CXR, CT head. Manage with IVF.

Patient received IV fluids with no improvement in his heart rate. His labs were all WNL, white count wnl, no toxic granulation, no left shift. Tox screen was negative. UA was negative and blood culture was drawn, thyroid panel pending. EKG showed sinus tachycardia, CXR was negative, C-spine x-ray was difficult to interpret so a C-spine CT was ordered, head CT was negative.

Patient remained tachycardic at 160 and febrile to 41◦C, BP 160/90, with no obvious source of infection identified. What is the most likely diagnosis now? A diagnosis of thyroid storm should be made now and treatment started immediately, even when the thyroid panel results are still pending. The diagnosis of thyroid storm is made by clinical suspicion based on patient history, signs and symptoms and physical exam findings. Waiting for thyroid function tests to return leads to unnecessary treatment delays and can be catastrophic.

What are the clinical manifestations of thyroid storm?Thyroid storm is a medical emergency that includes hyperthyroidism, cardiovascular instability, thermogenic instability, and neurogenic instability. The diagnosis of thyroid storm is based on signs and symptoms and is a clinical diagnosis. Being able to recognize the manifestations of thyroid storm is essential to expedite treatment and prevent morbidity and mortality.

What would you look for in history if thyroid storm was suspected?Most patients will report a history of symptoms consistent with hyperthyroidism including unexplained weight loss, insomnia, heat intolerance, tremors, and palpitations.They will present with an acute worsening of those symptoms in addition to severe agitation.

T-4 Synthesis

T-4 release

T-4 T3

What would you look for in physical exam if thyroid storm was suspected?Significant physical exam findings include agitation and inability to sit still. Temperature is usually elevated, significant tachycardia is present and blood pressure is labile. Skin is moist and warm to touch. Eye examination may demonstrate stare, lid lag, or exopthalmos if Graves’ disease is present. Thyroid exam findings depend on the etiology of hyperthyroidism (Table 3). Muscle weakness and hyperreflexia may be present. Additionally, patients perform poorly on the mini mental status exam.

What is the mortality rate for this condition?Even with appropriate treatment mortality rates for thyroid storm remain high at 25%.

How would you treat this patient?Patients should be admitted to an intensive care unit. Treatment is multifactorial and includes supportive care and pharmacologic intervention. Pharmacologic treatment is aimed at blocking thyroid hormone synthesis, release, conversion to T3, and action on cells.

Fluid as patients are volume deplete Cooling blankets if hyperthermia is present Beta blockade to minimize catecholamine excess

o Propranolol 20-40 mg q 6 hours to decrease heart rate to < 100 bpm o Esmolol if concern regarding cardiac output (fast acting/short t ½ life.)

Thionamides: o Propothyouricil (PTU) 150 mg po q 6 hours if patient is able to take p.o.

Oro Methimazole 10-20 mg pr q 6 hours

SSKI or Lugol's solution: administer 1-2 hours following thionamide administration. Steroids: Dexamethasone 1 mg q 6-8 hours Treat underlying precipitating stressor if present If no response consider emergent thyroidectomy or plasmaphoresis. Aviod aspirin; it increases free thyroid hormone levels by competing with binding sites

on Thyroid binding globulin

Where do these pharmacologic agents work?

Thionamides Iodine PTU β-blockersPropranolol SteroidsSteroid

T3 activity

Patient received: Propranolol 60 mg iv q 6 hours, PTU 150 mg po q 6 hours, Dexamethasone 1 mg iv q 6 hours. SSKI 6 drops po q 6 hours (started 2 hours after the first dose of PTU). The following day, his thyroid panel results were available and showed TSH was undetectable and his Free T4 was >6 mg/do. A diagnosis of thyroid storm was confirmed. Once his c-spine was cleared by CT scan, the c-collar was removed. A diffusely enlarge thyroid gland was visible on gross inspection. Three days after admission the patient’s heart rate was 92, Temp was 37.3, he was mentating normally, and was able to report a 20 pound weight loss over the preceding 3-months, insomnia and heat intolerance.

What precipitated this patient into thyroid storm?Patient’s motor vehicle accident caused an acute catecholamine surge, in the presence of untreated hyperthyroidism lead to thyroid storm. Thyroid storm typically occurs in a patient with underlying hyperthyroidism, either previously known or unknown, who develops a second illness or stressor. The second stressor results in an acute catecholamine surge. The catecholamine surge in the presence of hyperthyroidism leads to tachyarythmias, high output cardiac failure and cardiovascular instability. Elevated catecholamine in the setting of hyperthyroidism causes hyperthermia leading to thermodynamic instability. The combination also causes tremors, hyperreflexia, mania, concentration and memory disturbances and culminates in neuropsychiatric instability.

What are common precipitants of thyroid storm?

Table 1. Causes of hyperthyroidism Table 2. Precipitants of Thyroid StormGraves’ DiseaseToxic Multinodular GoiterToxic AdenomaThyroiditisExogenous Thyroid HormoneThyroiditisJod BasedowTSH Secreting Pituitary AdenomaMolar PregnancyStruma Ovarii

PregnancyTraumaInfectionMyocardial InfarctionSurgeryIntoxication ETOH Cocaine AmphetaminesIodine ( in MNG, Toxic adenoma) Radioactive Iodine IV Contrast Amiodarone

MKSAP 16:Question #72: Diagnose thyroid storm

*****YOU MAY STOP HERE OR PROCEED TO MYXEDEMA COMA*****

Severe hypothyroidism/Myxedema Coma

Objectives:By the end of this module, you should be able to:

1) Recognize three signs and symptoms of severe hypothyroidism/myxedema coma and why they occur

2) Be able to appropriately evaluate a patient with suspected of severe hypothyroidism/myxedema coma

3) List three treatments for severe hypothyroidism/myxedema coma

CASE

72 yo obese female with history of overactive thyroid gland s/p radioactive iodine therapy and hypertension is brought in to the ED by her husband for cough productive of green sputum, lethargy and confusion. Husband reports that cough started about a week ago, but patient has been really weak, unable to get out of bed much and sleeping a lot for the past month. Outpatient medications are levothyroxine and losartan, although patient has not been taking these for at least several months. Patient does not take any over the counter medications, herbs or supplements. Vitals, T 35.2, BP 80/55, HR 70, rr 9, O2 sat 80% on RA. Exam shows an obese female, arouses intermittently but falls back asleep again, unable to answer questions appropriately, appears lethargic and has dry skin and dry mucous membranes. Lungs with bibasilar diminished breath sounds and crackles most notably on R side mid-lung fields. Abdominal exam is normal. Extremities with mild bilateral edema. Neuro exam, patient unable to follow commands, moves all 4 extremities spontaneously, and has slow reflexes.

Labs: WC 21, 000, 90% neutrophils, h/h 15/43, plts 230Na 131, K 3.5, Cl 102, bicarb 25, bun 8, cr 0.7, Glucose 45

CXR shows RLL consolidation and small bilateral pleural effusions. CT head without contrast is negative. Urine toxicology is negative.

Patient is admitted for SIRS/Sepsis, and started on appropriate antibiotics for the pneumonia and receives IVF to support blood pressure. Patient’s pneumonia appears to be improving over the next 24 hours as WC decreases to 9,000 and oxygenation improves to 89% on RA. You initially thought that patient’s altered mental status was due to sepsis and or delirium, and therefore expected it to improve over the next 24 hours, although it has not. Patient remains really sleepy, confused and lethargic and this is not a waxing and waning pattern.

What is your differential diagnosis for her confusion, sleepiness, delayed reflexes, low BP, low respiratory rate, low sodium, and low glucose?Severe hypothyroidism/myxedema coma

What studies would you send to work this up?TSH, Free T4 and Total T3

Results return as follows:TSH 155Free T4 0.2 (nl range Total T3 <20

What is your diagnosis?Severe hypothyroidism/myxedema coma. The clinical picture is often that of an elderly obese female who has come increasingly withdrawn, lethargic, sleepy and confused. The presentation

is one of severe hypothyroidism, with or without coma (the term myxedema coma, may therefore, be a misnomer)

What precipitated this patient’s presentation?In this patient’s case the precipitating event was the pneumonia. Myxedema coma is most frequently associated with discontinuation of thyroid hormone therapy and rerely is the first manifestation of hypothyroidism. Myxedema coma may be precipitated by an illness such as a CVA, infection, GI bleeding acute trauma, excessive hydration, or administration of a sedative, narcotic, or potent diuretic drug.

What is the most appropriate initial treatment of this patient?Myxedema coma/severe hypothyroidism is considered a medical emergency, and appropriate supportive measures (treatment of precipitating factor ie infections or AMI, ventilator support if necessary, and assessment and treatment of cardiac issues) are very important. Typically, the patient is severely ill and usually is admitted to the ICU for intubation and ventilator support.

No consensus exists about the most efficacious thyroid hormone replacement regimen to use for myxedema coma. Oral medications are poorly absorbed (due to ileus), and all medications should be given intravenously (IV). Typically, a loading dose of 200 to 500 ug of T4 IV is given initially to saturate T4 binding sites in plasma binding proteins. The patient is then maintained on 50ug to 100ug of IV T4 daily until oral administration is feasible. The high doses of levothyroxine are recommended to replenish the depleted tissue stores of thyroid hormone. However, high doses of levothyroxine may be associated with cardiac irregularities and should be used cautiously, especially in patients with known or suspected cardiac disorders.

Decreased intracellular T3 leads to change in fluid balance with increased water retention due to impaired renal perfusion as well as increased vascular permeability. These changes result in effusions and hyponatremia, which in turn contributes to coma. Water restriction is necessary to correct the hyponatremia and avoid fluid overload.

IV glucose to treat the hypoglycemia.

The use of hydrocortisone is prudent because patients may have hypopituitarism or autoimmune polyglandular failure that can lead to secondary adrenal insufficiency. Patients with myxedema coma should be checked for possible adrenal insufficiency and treated with a stress-dose glucocorticoid, such as hydrocortisone, until adrenal insufficiency is excluded and appropriate adrenal function confirmed. Usually hydrocortisone IV is used, 200-300 mg/d in divided doses, 50mg IV Q6h or 100mg IV Q8h. Alternative to IV hydrocortisone is Dexamethasone 4mg IV qd. This is usually tapered over the next 5-7 days.

Once myxedema coma is suspected in a hypothermic patient, external rewarming should be avoided, because this may cause redistribution of blood flow to subcutaneous tissues and cardiovascular collapse.

What is the mortality rate in treated vs untreated myxedema coma?Prior to recognition of the need for IV T4 and for respiratory support, the mortality from myxedema coma was about 80%. Currently, the mortality is about 20% and is mostly due to the underlying or precipitation illness. Higher mortality is associated with increased age, cardiac complications and high-dose thyroid hormone replacement (> 500ug/d of levothyroxine). Persistent hypothermia and bradycardia, despite therapy, are associated with a poor prognosis.

MKSAP 16:Question #49: Treat myxedema coma

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