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Endocrine Emergencies
Adrenal Insufficiency
Adrenal physiology
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Cortisol functions at target tissues to maintain
vascular resistance, cardiac output, hepatic glucose
production and free water excretion
Cortisol concentration normally demonstrates
diurnal variation and increases during times of
medical stress
Adrenal physiology
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The hypothalamus secretes CRH which in turn
stimulates ACTH production from the pituitary
ACTH stimlates cortisol production from the adrenal
glands
The hypothalamus and pituitary are influenced by
negative feedback from cortisol
Adrenal physiology
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Aldosterone is controlled primarily by angiotensin II
and circulating potassium levels; ACTH stimulates
aldosterone secretion only transiently
Aldosterone stimulates sodium exchange for
potassium in the distal nephron
Autoimmune Adrenal Insufficiency
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The most common cause of adrenal insufficiency in
industrialized countries
May occur alone or associated with other autoimmune
disorders
– Schmidt’s syndrome or type II autoimmune polyglandular
syndrome. Type I diabetes and autoimmune thyroid
disease
– Type I autoimmune polyglandular syndrome or APECED
(autoimmune polyendocrinopathy-candidiasis-ectomdermal
dystrophy) with chronic mucocutaneous candidiasis and
hypoparathyroidism.
Adrenal Hemorrhage
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Increasingly recognized as a cause of adrenal
insufficiency
Meningococcemia (Waterhouse-Friderichsen
syndrome) and other forms of sepsis
Anticoagulation therapy and coagulation disorders
including antiphospholipid antibody syndrome
Severe illness and stress; ACTH-induced increases
in adrenal blood flow that exceeds the capacity for
venous drainage
Infections
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Tuberculosis
Histoplasmosis
Cryptococcus
Blastomycosis
Paracocciciomycosis
Cytomegalovirus associated with HIV
Adrenoleukodystrophy and
Adrenomyeloneuropathy
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X-linked peroxisomal disorders of imparied very long chain fatty
acid oxidation
In adrenoleukodystropy the neurological features begin in
childhood and progress to coma and death
Adrenomyeloneuropathy neurological features (central
demyelination, cortical blindness, neuropathies) begin in
adolescence or young adulthood, progress more slowly and
involve peripheral nerves
Diagnosis made by measuring high concentrations of VLCFA
Young men with adrenal insufficiency should be screened for
this disorder
Congenital Adrenal Hyperplasia
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A family of autosomal recessive disorders caused by
deficiency of one of the multiple enzymes in the cortisol
synthesis pathway
The enzyme deficiency causes inadequate cortisol
production and a compensatory increase in ACTH
ACTH stimulates adrenal hyperplasia and increased
production of precursors proximal to the block in cortisol
synthesis
Bilateral Adrenal Metastases
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Metastases to the adrenal are common
Breast 54%
Bronchogenic 44%
Renal 31%
Adrenal insufficiency from metastases is very rare
Medications
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Accelerate metabolism
of cortisol
Thyroid hormone
Rifampin
Phenytoin
Phenobarbital
Mitotane
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Inhibit cortisol synthesis
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Ketoconazole (but not
fluconazole or itraconazole)
Etomidate
Metyrapone
Mitotane
Aminoglutethimide
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Secondary Adrenal Insufficiency
 Pituitary tumors due to mass or treatment of tumor
 Metastases to pituitary
 Craniopharyngioma
 Meningioma
 Infiltrative disorders (histiocytosis X, lymphocytic
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hypophysitis,sarcoidosis, hemochromatosis)
Postpartum pituitary necrosis (Sheehan’s syndrome)
Iatrogenic from exogenous steroids
High doses of megestrol acetate
Clinical Presentation
Finding
Primary
Secondary
Anorexia and weight loss
Yes (100%)
Yes (100%)
Fatigue and weakness
Yes (100%)
Yes (100%)
Nausea/diarrhea
Yes (50%)
Yes (50%)
Muscle,joint,abdominal pain
Yes (10%)
Yes (10%)
Orthostatic hypotension
Yes
Yes
Hyponatremia
Yes (80%)
Yes (60%)
Hyperkalemia
Yes (60%)
No
Hyperpigmentation
yes
No
Secondary deficiencies of
testosterone, GH, thyroid, ADH
No
Yes
Associated autoimmune diseases
Yes
No
Adrenal Crisis
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Dehydration, hypotenstion, shock out of proportion to severity
of current illness, nausea, vomiting with anorexia, weight loss,
unexplained fever, hyponatremia, hyperkalemia, azotemia,
hypercalcemia, eosinophilia, and hypoglycemia
Often precipitated by intercurrent illness in patient with
unrecognized adrenal insufficiency or in a patient with known
disease who did not increase cortisol replacement appropriately
or patient who recently had glucocorticoid therapy withdrawn, or
in patient with bilateral adrenal hemorrhage
Laboratory Testing
 In acute emergencies “treat first, test later”
 In the acutely ill patient draw serum cortisol
and ACTH then treat with dexamethasone 2-4
mg IV q12 hours or hydrocortisone 100 mg
q6 hours then switch to dexamethasone for
testing
Laboratory Testing
 Static testing not very useful
 If cortisol between 8-9 am if less than or
equal to 3 ug/dl adrenal insufficiency likely
 If cortisol greater than 19 adrenal
insufficiency ruled out
Dynamic Testing: Cortrosyn
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A serum cortisol of 20 ug/dl or more 1 hour following 250 ug of
cortrosyn IM or IV excludes primary adrenal insufficiency
Some have suggested a value of 18 is an adequate respone
Difference between baseline and stimulated cortisol no longer
used
Does not exclude the presence of secondary adrenal
insufficiency
Dynamic Testing: Cortrosyn
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Low dose cortrosyn 1 ug IV followed by cortisol
measurement in one half hour.
There is evidence for and against the utility of this
test
ACTH Measurements
 In untreated primary adrenal insufficiency
ACTH is greater than 100 pg/ml
 Not useful for judging adequacy of therapy
Insulin Tolerance Test
 Performed fasting in morning
 IV administration of 0.1-0.15 units regular insulin/kg
 Cortisol >18 to 20 during hypoglycemia is normal
 Contraindicated in patients with severe illness, coronary artery

disease, seizures, psychiatric disease
In patients with pituitary disease growth hormone is measured
simultaneously
Metyrapone Test
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Metyrapone activates the HPA axis by blocking cortiosl
production at the 11-hydroxylase step, the last step in cortisol
synthesis
This leads to cortisol deficiency which should activate ACTH
production and production of precursors proximal to the block
Metyrapone is given at midnight with a light snack
Cortisol and 11-deoxycortisol are measured at 8 am. The test
is considered normal if cortisol is less than 5 and 11deoxycortisol is at least 7 ung/dl.
Once the diagnosis is made a search for the
underlying cause is indicated if not immediately
obvious
For primary adrenal insufficiency adrenal imaging
is indicated
For secondary disease MRI imaging of
pituitary/hypothalamus may be needed.
Treatment
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For primary adrenal crisis: hydrocortisone 100 mg
q6 hours if diagnosis established or dexamethasone
2-4 mg q12 hours if diagnostic testing needed
For secondary adrenal crisis: dexamethasone may
be preferred to avoid fluid retention and
hypokalemia
Intravenous saline to support volume and treat
hyperkalemia
Specific mineralocorticoid is usually not necessary
while using high dose hydrocortisone
Maintenance Therapy
 Hydrocortisone 10-20 mg in am, 5-10 mg in early pm
 Prednisone 5 mg in am, 0-2.5 mg in pm
 Florinef 0-0.1 mg per day
 Adequacy of glucocorticoid judged by patient well-being,
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decrease in pigmentation, electrolytes, blood pressure
Adequacy of mineralocorticoid judged by blood pressure,
edema, potassium and plasma renin activity
All patients with adrenal insufficiency should have MedicAlert
bracelet or carry documentation of this disorder
Acute Illness Coverage
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Mild to moderate illness: double or triple usual glucocorticoid
dosage
Severe illness or vomiting: dexamethasone or solucortef IM
self-administered by patient then seek prompt medical help
Moderately stressful procedures such as endoscopy:
hydrocortisone 100 mg one hour before procedure
Major surgery: hydrocortisone 100 mg IV before induction of
anesthesia and repeated q6 hours. Dose then tapered
depending on patient’s rate of recovery, usually 50% decrease
per day until maintenance dose achieved
Thyroid Storm
Thyroid Storm
 Severe and life-threatening thyrotoxicosis
 Exaggeration of the typical symptoms of hyperthyroidism
 Tachycardia with rate often>140
 CHF
 Fever
 Change in mental status: delirium, psychosis, stupor, coma
 Nausea, vomiting, diarrhea, abdominal pain
 Hepatic failure, jaundice, abnormal liver function tests
Precipitants
Usually precipitated by an acute event in a patient with untreated
hyperthyroidism
 Thyroid or nonthyroidal surgery
 Trauma
 Infection
 Acute iodine load or radioactive iodine
 Poor compliance with specific therapy
 Low socioeconomic status
Preoperative preparation of patients undergoing thyroidectomy for
hyperthyroidism has led to dramatic reduction in prevalence of
surgically-induced thyroid storm
Treatment
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IV Fluid
Acetominophen
Beta blockade to control adrenergic symptoms
Thionamide - methimazole or PTU
Iodine solution to block release of thyroid hormone
Iodinated contrast agent to inhibit the peripheral
conversion of T4 to T3
Glucocorticoids to reduce T4 to T3 conversion and
to treat potential coexistent adrenal insufficiency
Beta Blockers
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Use with caution in patients with CHF or other
contraindication
Propranolol is frequently selected as it can be given
intravenously and reduces the conversion of T4 to
T3
Esmolol - loading dose of 250-500 ug/kg IV followed
by infusion of 50-100 ug/kg/min. This permits rapid
titration of drug and minimizes adverse reactions
Thionamides
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Block de novo thyroid hormone synthesis within 1-2 hours of
administration but have no effect on preformed thyroid
hormone stored in the gland
PTU blocks conversion of T4 to T3 but since other drugs
given in storm are usually coadministered it is okay to use
methimazole which has a longer duration of action
High doses needed: Methimazole 30 mg q6 or PTU 200 mg
q4 hours
Both drugs can be suspected in liquid for rectal
administration
Iodine
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Iodine blocks release of T4 and T3 from the gland
SSKI 5 drops every 6 hours or Lugol’s solution 10
drops tid
Delay administration of at least one hour after
thionamide administration to prevent iodine being
used as a substrate for new hormone synthesis
If iodine allergic, lithium has been used for the same
purpose
Iodinated Radiocontrast Agents
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Iopanoic acid used for oral cholecystography
Potent inhibitors of T4 to T3 conversion
Dose 0.5 to 1 gm qd
Give at least one hour after thionamide to prevent
iodine from being used as a substrate for new
hormone synthesis
Glucocorticoids
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Reduce T4 to T3 conversion
May have a direct effect on underlying autoimmune
process if storm is due to Graves disease
Use of glucocorticoids has improved outcome in
one series
Hydrocortisone 100 mg IV q8 hours
Myxedema Coma
Myxedema Coma
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Severe hypothyroidism due to severe long-standing
untreated hypothyroidism
Precipitating acute event almost always present: infection,
myocardial infarction, cold exposure, sedative drugs
Older women affected most frequently
May result from any of the usual causes of hypothyroidism
Important clues in a poorly responsive patient include
presence of thyroidectomy scar or history of radioiodine
treatment or known hypothyroidism
Mortality rate is high 30-40%
Clinical Presentation
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Hypothermia
Decreased mental status
Hypotension
Bradycardia
Hyponatremia
Hypoglycemia
Hypoventilation
Diagnosis
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History, physical exam, and exclusion of other causes of
coma
Treat before waiting for lab confirmation but draw TSH, free
T4, cortisol before treatment
Most patients will have primary hypothyroidism with high
TSH and low free T4; rare patients have low free T4 and low
TSH consistent with secondary hypothyroidism due to
hypothalamic or pituitary disease
Cortisol measurement will help exclude coexistent adrenal
insufficiency
Treatment: Thyroid Hormone
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Optimal mode of thyroid hormone therapy is controversial
Increasing serum thyroid hormones rapidly carries some risk
of precipitating MI or atrial arrhythmia but this risk must be
accepted given high mortality rate of myxedema coma
Levothyroxine 0.2-0.4 mg IV initial dose
.05 to 0.1 mg IV qd thereafter
Switch to oral when feasible
T3 can be given 5-20 ug initially, then 2.5-10 ug q8 hours
Stop T3 when clinical improvement occurs
Supportive Measures
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Avoid dilute fluids
Severe hypotension that does not respond to fluids
should be treated with vasopressors until T4 has
had time to act
Passive rewarming with heating blanket (active
rewarming carries risk of vasodilatation)
Empiric antibiotics until appropriate cultures are
proven negative
Pheochromocytoma
Catecholamine -Secreting Tumors:
Pheochromocytoma and Paragangliomas
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Arise from chromaffin cells of adrenal medulla and
sympathetic ganglia
Rare: incidence 2-8 cases per million; prevalence
estimates 0.01% to 0.1% of hypertensive population
Occurs equally in men and women, primarily in 3rd
through 5th decades
Curable with surgical removal of tumor
Potential for lethal paroxysm
Symptoms
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Usually present and are due to pharmacologic
effects of excess circulating catecholamines
The five P’s:
 Pressure- sudden major increase in BP
 Pain- abrupt onset of throbbing headache, chest and/or
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abdominal pain
Perspiration- profuse generalized diaphoresis
Palpitations
Pallor
Spells
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Extremely variable in presentation
Spontaneous
Precipitated by diagnostic procedures, postural
changes, anxiety, exercise, or maneuvers that
increase intra-abdominal pressure
Duration 10-60 minutes and may occur daily to
monthly
Additional symptoms: constipation, attacks of
hypotension and shock, tremor, anxiety, epigastric
and chest pain
Clinical Signs
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Hypertension - paroxysmal in half, may be severe and resistant
to conventional therapy
Orthostatic hypotension
Pallor
Grade II-IV retinopathy
Tremor
Weight loss
Fever
Café au lait spots in neurofibromatosis
Painless hematuria and paroxysmal attacks induced by
micturition in pheo of bladder
Hyperglycemia
Hypercalcemia
Erythrocytosis
Rule of 10
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10% are extradrenal
10% occur in children
10% are multiple or bilateral
10% recur after surgical removal
10% are malignant
10% are familial
Differential Diagnosis
Endocrine
 Thyrotoxicosis
 Menopausal syndrome
 Hypoglycemia
 Mastocytosis
Cardiac
 Essential hypertension
 Cardiovascular deconditioning
 Paroxysmal arrhythmia
 Withdrawal of adrenergic inhibiting medications (clonidine)
 MAO-inhibitor treatment and ingestion of tyramine or
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decongestant
Angina
Differential Diagnosis
Psychoneurologic
 Anxiety and panic attacks
 Hyperventilation
 Migraine headaches
 Amphetamine, phenylpropanolamine, or cocaine use
 Diencephalic epilepsy
Factitious
 Sympathomimetic ingestion
Familial Syndromes
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Familial pheochromocytoma
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MENII a
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Pheochromocytoma
Medullary thyroid carcinoma
Hyperparathyroidism
MENII b
Pheochromocytoma (bilateral in >70%)
Medullary thyroid carcinoma
Mucosal neuromas
Thickened corneal nerves
Intestinal ganglioneuromatosis
Marfanoid body habitus
Familial Syndromes
 Neurofibromatosis (von Recklinghausen’s disease)
1% develop pheochromocytoma
 Von Hippel-Lindau (retinal angiomatosis and cerebellar
hemangioblastoma)
 Additional pheochromocytoma-related neurocutaneous syndromes:
Ataxia telangiectasia
Tuberous sclerosis
Sturge-Weber
 Other known associations without familial basis
 Carney’s triad
Gastric leiomyosarcoma
Pulmonary chondroma
Extra-adrenal pheochromocytoma
 Cholelithiasis
 Renal artery stenosis
Paragangliomas
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Para-aortic sympathetic chain
Organs of Zuckerkandl at origin of inferior
mesenteric artery
Wall of urinary bladder
Sympathetic chain in the neck or mediastinum
Other Endocrine Manifestations of
Pheochromocytoma
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GHRH- acromegaly
ACTH/CRH - Cushing’s syndrome
VIP- watery diarrhea
PTH-RP- hypercalcemia
Diagnostic Evaluation
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Biochemical documentation should precede any imaging
studies
24 hour urine collection for catecholamines, metanephrine and
VMA
24 hour urine collection should start with the onset of a spell in
pateints with episodic hypertension
Usually more than 2 fold increase above the upper normal limit
No role for provocative testing with histamine or glucagon
Medications Interfering with Assessment
Increase values
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Tricyclic antidepressants
Labetolol
Levodopa
Decongestants
Amphetamines, busipirone and most psychoactive medications
Sotalol
Methyldopa
Ethanol
Benzodiazepines
Decrease values
 Metyrosine
 Methylglucamine
Plasma Catecholamines
Plasma catecholamines
 must be obtained from fasting supine patient with indwelling
catheter in place for 20 minutes
 affected by diuretics, smoking, renal insufficiency
Plasma metanephrines
 Recent report shows accuracy for diagnosis
Chromogranin A
 Costored and secreted with catecholamines and increased in
80-90% of patients with catecholamine secreting tumors
Neuropeptide Y increased in 87%
Measurements of urinary catecholamines and metabolites,
chromogranin A, plasma norepi and dopamine are invalid In
advanced renal insufficiency. Plasma epi levels more reliable
Localization Studies
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90% of tumors are found in the adrenal and 98% are in the
abdomen
Pheo’s have a characteristic T2-weighted appearance on MRI
Common locations of extradrenal paragangliomas are superior
para-aortic region in 46%, inferior para-aortic in 29%, urinary
bladder in 10%, thorax in 10%, head and neck 3%, pelvis 2%
If results of imaging studies are negative an MIBG scan can be
performed. Sensitivity 88%, specificity 99%
Treatment of Pheochromocytoma
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Surgical resection after careful pre-op alpha and
beta adrenergic blockade
Controls blood pressure and prevents intraoperative
hypertensive crisis
Alpha blockade started at least 10 days preop to
allow for contracted blood volume
Encourage high salt intake during this time
Alpha blockade
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Phenoxybenzamine 10 mg bid and increased 10-20
mg every 2 days until BP and spells controlled
Average dosage 0.5-1.0 mg/kg daily
Orthostatic hypotension increased, tachycardia,
miosis, nasal congestion, diarrhea, fatigue
Beta blockade
 Administer only after alpha inhibition is effective because beta
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blockade alone may result in more severe hypertension due to
unopposed alpha adrenergic stimulation
Indicated to control tachycardia associated with high circulating
catecholamines and alpha blockade
Use cautiously and at low dose as chronic circulating
catecholamines may cause a cardiomyopathy and beta
blockers can result in pulmonary edema
Labetolol is a combined beta blocker and alpha blocker but
instances of paradoxic hypertensive crisis (due to incomplete
alpha blockade) have been reported; safety as primary agent is
controversial
Catecholamine Synthesis Inhibitor:
Metyrosine
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Useful in patients with persistent catecholamine
producing tumors that cannot be treated with
combined alpha and beta blockade
Inhibits tyrosine hydroxylase
Side effects: diarrhea, sedation, anxiety,
nightmares, urolithiasis, galactorrhea,
extrapyramidal manifestations
Acute Hypertensive Crises
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Phentolamine test dose of 1 mg followed by repeat
5 mg IV boluses
Response maximal in 2-3 minutes and lasts 10-15
minutes
100mg/500 cc 5% dextrose can be infused IV and
titrated to BP control
Postoperative Course
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Hypotension may occur after surgery: treat with fluids and
colloid
Less frequent in patients who have had adequate alpha
blockade preoperatively
Hypoglycemia
BP usually normal prior to discharge
Some patients remain hypertensive for up to 4-8 weeks
2 weeks after surgery 24 hour urine obtained to insure cure
then every 5 years