Anesthesia case management for the patient with pheochromocytoma – Flashcards

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Catecholamine synthesis occurs in...
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all adrenergic nerves and the adrenal medulla
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The rate-limiting step in the synthesis of catecholamines is the conversion of tyrosine to dopa by ...
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Tyrosine Hydroxylase.
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Tyrosine hydroxylase is subject to...
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feedback inhibition by dopamine and norepinephrine. For example, too much NE and Dopamine will inhibit tyrosine hydroxylase activity, thus decreasing catecholamine synthesis. The opposite will also occur, decreased levels of NE and Dopamine leads to increased Tyrosine Hydroxylase activity and increased production of catecholamines
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Norepinephrine and Epinephrine synthesis in the adrenal medulla __% is epinephrine, __% is norepinephrine.
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80;20
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Phenylalanine is converted into Tyrosine in the...
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LIVER.
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Tyrosine is then collected into the ..
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adrenergic nerve terminals.
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Release of Catecholamines process:
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-Catecholamines are accumulated in storage vesicles by active transport. -The vesicles become "docked" near the presynaptic plasma membrane. -After membrane depolarization, calcium influx occurs. -As a result of calcium influx, the vesicle fuses to the presynaptic plasma membrane wall and neurotransmitters are released by exocytosis into the synaptic cleft. This process is Ca++ and ATP dependent. CLNICAL EXAMPLE: Hypocalcemia would be a differential dx for a pt with neuromuscular weakness. -The empty vesicles are recycled.
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Number one way that catecholamines are removed from synaptic cleft is...
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reuptake.
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Pheo - reuptake info:
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A tremendous amounts of catecholamines throughout body, including NMJ. Concept of reuptake is important in pheo because it is the number one way catecholamines go back into storage vesicles. In this picture, instead of 4 NT molecules imagine 10-20. Therefore if a sympathetic response occurred you could imagine the degree of physiologic response that would occur. Therefore, in a patient with pheo, the storage vesicles are considered "loaded".
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The plasma half-life of catecholamines is ...
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less than one minute, broken down rapidly within the liver.
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Catecholamines are removed from the secretory site in three ways:
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1) Reuptake 2) Diffusion away from the synaptic junction 3) Enzymatic breakdown
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Reuptake: The #1 way in which catecholamines..
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...enter the storage vesicles. -50-80% of catecholamines are recycled via this method. It is an active transport process (ATP used). In a pt with Pheo vesicles are "loaded" with catecholamines.
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Diffusion of catecholamines away from synaptic junction into tissues and plasma: Diffusion after ...
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...unbinding from the postsynaptic receptors and will then diffuse into tissues and plasma, eventually being broken down by liver and/or kidneys
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Enzymatic breakdown of catecholamines occurs via:
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MAO and COMT
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Monoamine oxidase (MAO):
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**A pre-synaptic tissue based enzyme system. Breakdown occurs via deamination (removal of amine group from catecholamine), rendering it physiologically inactive.
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Catechol-O-methyltransferase (COMT):
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A blood borne enzyme, highest concentrations are located in kidneys and liver. COMT utilizes oxidation to break down catecholamines.
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Metabolites from catecholamine enzymatic breakdown can be measured ...
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in the blood and urine; this is used to diagnose a pheochromocytoma
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In the pre-synaptic membrane, MAO metabolizes epinephrine and norepinephrine into
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vanillymandelic acid (VMA).
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VMA is the ...
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common final product from the breakdown of catecholamines.
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In the liver, epinephrine is metabolized by...
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COMT into metanephrines and norepinephrine is metabolized by COMT into normetanephrines. Both end up as VMA as the final product. VMA, normetanephrine and metanephrine are measured in pts with pheo. -These end products of catecholamine metabolism are excreted in the urine and can also be found in the blood.
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MAO inhibitors are used to treat patients with...
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depression and other mental illnesses. -A decreased # of neurochemicals may be the cause of depression, specifically catecholamines in the brain. -Therefore, an MAO inhibitor is used to increase the amount of catecholamines available.
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An herbal MAO inhibitor is ...
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St. Johns Wart. During surgical stimulus a pt on MAOIs may exhibit a hyperdynamic response resulting in a hypertensive crisis. Not prescribed often 2/2 this side effect. New MAOIs coming out that target sub-types to avoid these SEs.
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Alpha 1 Receptors:
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-Postsynaptic adrenoreceptors located in the smooth (vascular) muscle throughout the body.
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Agonism of alpha 1 receptors results in:
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increased BP by increasing vascular resistance example: Neosynephrine. Antagonism results in: vasodilation and decreased BP. -In pheo the majority of chemical released is NE, 90% of pheos are predominantly NE secreting tumors. One of the major signs of pheo is "incredibly" high blood pressure. Pre-operatively we treat these pts with alpha-1 blockers in attempt to normalize their BP.
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Alpha 2 Receptors:
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-Presynaptic adrenoreceptors located in the CNS. -Agonism results in: Decreased SNS outflow example: Clonidine. Later we will discuss Clonidine with the suppression test that works as an alpha-2 agonist.
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Beta 1 Receptors:
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-Postsynaptic adrenoreceptors located mainly in the heart. -Agonism results in: Increased HR, contractility, and chronotropy (increased rate of cardiac impulse conduction).
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Due to baroreceptor response pts frequently become ___________ after receiving alpha-1 blockade.
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tachycardic
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Beta 2 Receptors:
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-Postsynaptic adrenoreceptors located mainly in smooth muscle and glands. -Agonism results in: Relaxation of the bronchi and vasculature. Antagonism results in the opposite
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Lungs: In pheo ...
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NE will result in alpha 1 agonism and can result in increased bronchial tone and/or bronchoconstriction.
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Pancreas: in pheo
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Alpha-1 effect is to decrease insulin secretion.
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Liver: in pheo
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Alpha-1 effect is to increase the break down of glycogen to increase BS. -In a very active tumor the alpha-1 effects will greatly overshadow the B2 effects because NE is the main culprit. -Therefore net effect (decreased insulin, increased glycogen breakdown) increased BS (concern pre-op).
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**______ blockers MUST be given before ____ blockers (A before B)**
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alpha;beta -If we were to give beta blockers first ex. Propranolol (Inderal), which is not beta 1 specific, we would have unopposed alpha-1 constriction leading to a hypertensive crisis.
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How does upregulation or down regulation happen?
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-Catecholamines exert their pharmacological actions by causing a conformational change in an adrenergic receptor. -Receptor activation of G proteins then increases cAMP concentrations. This change increases phosphorylation within the cell and the main effect is typically increased amounts of intracellular Ca++, leading to a physiologic response. -The effector proteins cause changes in cellular dynamics. -Depending on the amount of catecholamines released, adrenergic receptors become sensitized (up-regulation) or desensitized (down-regulation). -There is an inverse relationship between receptor sensitization and amount of catecholamines.
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Remember when we talk about receptor up-regulation and down-regulation we're talking about....
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"functional tolerance"
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Increased catecholamines, receptor desensitization =
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down-regulation
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Decreased catecholamines, receptor sensitization =
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up-regulation
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Up-regulation of adrenoreceptors can occur very ...
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rapidly, for example research has shown it to occur as soon as 30 minutes after a spinal cord injury. CLINICAL EXAMPLE: This is why patients must be gradually weaned off of beta-blockers, to avoid a potential ischemic event. The beta-blocker that was being taken by the patient blocks adrenoreceptors. The tissue, specifically in the heart beta-1 receptors, gets used to little stimulation on beta-blockers and up-regulation occurs. Then if a pt stops cold turkey, you have the increased number of receptors PLUS the receptors no longer being blocked and you can have a patient that has a hypertensive crisis or ischemic event. SIMILAR TO PHEO: Pts with pheo are down-regulated 2/2 to the large amount of NE. When pheo is being removed the source of NE will be removed, however we have loaded these pts pre-operatively with alpha-1 blockers with long ½ lives. The combination of down-regulation, pheo removal, and alpha-1 blockade can render the pt hypotensive post-removal of the pheo.
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The adrenal glands are composed of the...
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outer cortex and inner medulla
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The adrenal cortex is responsible for ..
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synthesis and release of mineralocorticoids, glucocorticoids, and androgens.
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The adrenal medulla contains ...
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glandular cells of sympathetic origin, which are called chromaffin or pheochrome cells. (80% epi 20% NE)
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The adrenal glands sit ...
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on top of each kidney. (So you have two...)
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The adrenal glands are contained in...
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a thin fibrous capsule surrounded by fat.
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Blood flow is derived from the ...
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aorta, inferior phrenic artery, and renal artery. Per gram of tissue they have the highest blood flow in the body.
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The capillary endothelial lining is ...
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in direct contact with the pheochrome cells.
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Venous return flows from ...
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the right adrenal gland to the inferior vena cava, and from the left adrenal gland into the left renal vein.
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CATECHOLAMINE SURGE WITH
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SURGICAL MANIPULATION -Short adrenal veins are hyper-concentrated with catecholamines that enter directly into the central circulation, right up the inferior vena cava. -During surgical manipulation there is the potential for an enormous catecholamine surge into the central circulation and enormous physiologic responses.
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POTENTIAL FOR
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BLEEDING. -The area surrounding the adrenal glands is very vascular and there is the potential for rapid, uncontrolled bleeding. -This procedure can be performed via laparoscopy, however, if bleeding is encountered the potential for blood loss is tremendous before being able to convert to open.
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The adrenal medulla is innervated by...
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preganglionic fibers that bypass the paravertebral ganglia (T1-L2).
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Since the adrenal medullary tissue is embryologically derived from....
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neural tissue, the adrenal medulla acts (as its own) as group of postganglionic neurons (only place in the body where this occurs).
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The post-synaptic neurotransmitter at end organs for SNS is primarily __, however, for sweat glands it is ___.
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NE;Ach
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Remember that in both the PNS and SNS ___ is the primary pre-synaptic neurotransmitter.
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Ach
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Pheochrom=
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staining darkly with chrome salts
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-A catecholamine-secreting tumor derived from ...
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chromaffin cells, frequently located in the adrenal medulla. Incidence is low, 2 in 100,000 people. Thought to be 0.1 to 1% cause of HTN. 90% of pheos originate in the adrenal glands.
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Because adrenal tissues are embryologically derived from neural tissue, this catecholamine releasing tissue can be in other places (10% incidence) including ...
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**intra-abdominal (most common), pelvis, aorta, cervical neck region, mediastinum, vagina, spermatic cord, intrapericardial or intramyocardial, or lastly the bladder wall
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Organ of Zuckerkandl:
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Pheochrome tissue that exists at the bifurcation of the aorta and R/L iliac arteries.
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What are three locations of Pheos?
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-cervical -thoracic -abdominal (70-80%) - Upper Abdomen, Organ of Zuckerkandl, Bladder
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__% of pheochromocytomas are malignant
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10;2/2 genetic mutations and may run in families. If familial then typically (greater than 50% of the time) bilateral adrenal.
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Genetic predisposition:
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runs in families
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___ of pheos occur in children and most commonly male children. Usually only one adrenal in children.
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1/3
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Pheochromocytomas usually occur between ...
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30 and 50 years of age. Rare at age ; 60.
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Equal frequency between
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adult males and females.
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An association exists between pheochromocytomas and...
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multiple endocrine neoplasia 2 (MEN 2) and von Hippel-Landau syndrome (a familial/genetically pre-disposed syndrome where people develop CNS and visceral tumors). -Some pheos are not really active, they do not secret a tremendous amount of catecholamines, however, during a stressful period (pregnancy or even surgery), the catecholamine release can increase. Thus, the first s/sx of pheo can be un-masked during pregnancy and can be misdiagnosed as pre-eclampsia.
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MEN Type 2A Manifestation
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Medullary thyroid cancer, Parathyroid adenoma, Pheochromocytoma
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MEN Type 2B Manifestation
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Medullary thyroid cancer, Mucosal adenomas, Marfan appearance, Pheochromocytoma
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Von Hippel-Lindau Syndrome Manifestation
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Hemangioblastoma involving the CNS, Pheochromocytoma
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Familial pheochromocytoma occurs bilaterally in __% of cases and is rarely malignant or extra-adrenal.
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50
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Familial pheos=
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rarely cancerous
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5 year survival rate after adrenalectomy for nonmalignant pheochromocytoma is ;__%.
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95
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5 year survival rate after adrenalectomy for malignant pheochromocytoma is ;__%.
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-50 The high mortality rate for malignant tumors is attributed to the fact the adrenals receive high blood flow and therefore at great risk for metastasis
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What are the best tests for pheo?
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1) plasma free metanephrines 2) 24 hr urine for catecholamines/metanephrines
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95% of patients with pheochromocytomas have increased levels of ...
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metanephrines ; normetanephrines.
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VMA screening is the...
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least reliable screening.
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Why is the VMA screening least reliable?
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-Many things can increase the amount of circulating catecholamines for example extreme exercise, thus VMA screening is not the best test for the diagnosis of pheo. -If metanephrine levels are elevated, then three 24-hour urine samples are tested for free catecholamines. If all three samples are within normal limits, the patient is not considered to have a pheochromocytoma.
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What is one disadvantage of urine tests for the dx of pheo?
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The tumor may secrete catecholamines intermittently, leading to high and low peaks of catecholamine metabolites. To prevent a potential false negative a 24-hour urine sample tests is utilized.
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According to Stoelting's Co-Ex Dx, the best screening test is...
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urinary metanephrines, the most sensitive is free NE in urine
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MOST SENSITIVE TEST ....
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FREE NOREPINEPHRINE IN THE URINE
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Plasma catecholamines levels are...
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...poor indicators for the diagnosis of pheochromocytoma and should not be used as an initial screening tool. -This is due to the large variability in catecholamine levels with daily activities.
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What is the suppression test?
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-The release of catecholamines from a pheochromocytoma is not mediated by the central nervous system, so the pt may be in bed relaxing. Infection could also cause a surge of catecholamines. -Clonidine (alpha 2 agonist) is administered (0.3 mg) PO. (Decreasing sympathetic output from CNS) If in three hours hypertension is not present, then a pheochromocytoma does not exist. If in three hours hypertension is present a pheochromocytoma may be present.
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A CT scan can...
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...localize 95% of tumors, it can detect adrenal masses as small as 1 cm and if extra-adrenal it can detect masses as small as 2 cm.
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Signs and symptoms are caused by ...
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excessive catecholamine release.
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Hypertension may be....
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sustained or paroxysmal.
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The triad of________, ________, and __________ may be the most reliable indicator of the presence of a pheochromocytoma.
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**headache, diaphoresis, and tachycardia
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Exacerbations may be caused by a variety of factors including:
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psychological stress, infection, physiologic stress (decreased BP, hypothermia, surgical trauma, intubation).
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During an acute episode the following symptoms may occur:
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Think NE. Hypertension, HA, pallor (especially in periphery b/c NE potent vasoconstrictor), palpitations, stroke, MI, ischemic changes.
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Orthostatic hypotension due to...
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plasma fluid deficit associated with polycythemia. (All d/t high SVR). Pheo associated with increased secretion of erythropoietin.
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Hyperglycemia 2/2 ...
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pancreatic response (decreased insulin production/increased glycogen breakdown in liver).
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Paresthesia and ischemia in ...
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extremities.
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As a result of excess catecholamine levels, the following changes can occur to the heart:
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INCREASED SVR -Left ventricular hypertrophy -Ischemia -MI -Cardiomyopathy/CHF -Rhythm disturbances (PVCs)- catecholamines sensitize myocardium to arrhythmias
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Only __-__% of patients with pheo develop these symptoms. The symptom of bradycardia is rare (3%), however is thought to occur 2/2....
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10-30; the baroreceptor response.
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Treatment includes ...
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surgical removal of the pheochromocytoma
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The goals of preoperative preparation are to...
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establish alpha and beta blockade, restore blood volume, assess end organ damage, control hypertension and treat cardiac dysrhythmias.
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_____ BLOCKADE MUST BE ACCOMPLISHED BEFORE ____ BLOCKADE
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alpha; beta
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Why alpha before beta?
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This is done to avoid CHF; if we give a beta-blocker to a pt. with a very high vascular resistance they can develop CFH. Also, "remember that the beta-2 effects have an overall vasodilating effect, therefore if you give a beta-blocker, which is not beta-1 specific, which is also a beta-2 antagonist, you can have unopposed alpha constriction and can make their BP climb higher than it was before pharmacologic therapy was started".
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Which alpha blockers are given?
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Phenoxybenzamine, Prazosin, Doxazosin
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Phenoxybenzamine:
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-The drug of choice. -Given 10-14 days pre-op. -It is both an alpha 1 & 2 antagonist. -It is a non-competitive blocking agent, irreversible bond with adrenergic receptor. ½ life is long (24 hours). -Should be continued all the way up to the day of surgery. Because of alpha blockade a hypotensive event would necessitate higher amounts of pressors, the normal response to pressors is altered when taking phenoxybenzamine. The biggest undesirable effect of phenoxybenzamine is that normal vascular function takes two weeks to return. Other alpha-blockers are not typically used for pheo because they are competitive blocking, these agents would not work effectively with the large amounts of catecholamines competing for the adrenergic receptors.
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Prazosin:
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Alpha-1 competitive blocker with a ½ life of 2-3 hrs.
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Doxazosin:
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Alpha-1 competitive blocker with a longer duration of action. Normal vascular function returns in 24-36 hrs. Some experts suggest that Doxazosins works just as well as phenoxybenzamine while allowing for normal vascular function to return faster.
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If you alpha block someone who is volume depleted the baroreceptor response is.....
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tachycardia, beta blockade must then be initiated.
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Beta Blockers:
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No one beta blocker has been proven to be best for pheo. However, the most commonly used is Inderal (Propranolol) 2/2 to the long duration of action. With the use of beta-blockers you must be vigilant for the risk of CHF, especially with this population
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Calcium Channel Blockers:
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The added effect from this group of drugs is coronary artery dilation
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Metyrosine:
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Inhibits tyrosine hydroxylase and can decrease catecholamine production by 40-80%.
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Optimal Preoperative Preparation
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-**The following criteria must be met prior to surgical intervention** -No BP should exceed 160/90 for 24-48 hrs pre-operatively. -Orthostatic hypotension with BP > 85/45 should be present. -ECG without evidence of ST and/or T wave abnormalities for one week. If present, further work up must be completed (ie ECHO) -No more than one PVC q 5 mins. -HCT should be decreased by 5%, indicating re-hydration. According to Nagelhout & Plaus patients will be less labile if this can be achieved.
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Goals For Intraoperative Anesthetic Management
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-Avoid drugs that cause sympathetic nervous stimulation. -Attempt to decrease sympathetic nervous stimulation without causing hypotension. -Use of vasopressors and vasodilators when necessary. -Direct acting pressors such as Phenylephrine is the pressor of choice. -Use of invasive monitoring. A-line, CVP, if significant cardiac dx then PA cath & CO monitoring
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**The nurse anesthetist must be aware of the possibility of extreme hypertension during the following 3 times**
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1.) During intubation 2.) During manipulation of tumor 3.) Ligation of the venous drainage
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Preoperative factors that increase the incidence of morbidity/mortality for patients with a pheochromocytoma include:
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-A large tumor, they tend to be more active. -Prolonged duration of surgery/anesthesia. -Increased pre-operative catecholamine levels.
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DRUGS TO AVOID IN A PATIENT WITH PHEOCHROMOCYTOMA
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Desflurane Pancuronium Atracurium Succinylcholine Morphine Droperidol Metoclopramide Phenothiazines Ephedrine Ketamine Atropine Narcan
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General surgical considerations:
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-They are working at the level of the 12th rib; the incision is made in the flank. -Whenever they are working at this high of a level the risk of a pneumothorax is possible. -If they are working on the right side it is very close to the liver and if they are working on the left they are very close to the pancreas and the spleen. -The average EBL (open) is 200-300 cc with insensible loses of 10-15 cc/kg/hr. -T&C with blood available and a fluid warmer are essential.
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Preoperative Medications
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Benzodiazepines
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The goal of induction is to ...
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achieve an adequate depth of anesthesia before laryngoscopy and at the same time avoiding hypotension (slow induction- beta-blockers and vasodilators drawn up and readily available)
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Combined technique with epidural and GA (adv vs disadv)
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Advantage: help with post-op pain and BP control prior to tumor removal Disadvantage: once tumor out may have hypotension that is difficult to control
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Induction meds:
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-Sodium pentothal, propofol, or etomidate for induction. -All induction agents would be appropriate except for Ketamine (for obvious reasons)
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Lidocaine 1-1.5 mg/kg to
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decrease SNS response
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Narcs for induction:
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Fentanyl/sufentanil preinduction.
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For induction and introperative maintenance:
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-Vasodilators: The dilator of choice is Nipride because it acts primarily on arteries. -Vasopressors: Direct acting preferred, Neosynephrine.
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maintance of anesthesia:
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-Nitrous oxide and Isoflurane/Sevoflurane. MAC of 1.5-2 may be used if healthy heart. Some people say no nitrous because of potential for pneumo -Narcotics -Non-histamine release inducing muscle relaxants. -Esmolol drip may be desirable 2/2 large and labile swings in BP. -Hypertension with release of catecholamine from tumor manipulation. -If extreme HTN with PVCs develops the recommendation is not to give an antiarrhythmic but to lower the BP in attempt to decrease the work of the heart. -Hypotension after tumor venous ligation is best treated with decreasing depth of anesthesia/increasing fluid administration/direct acting vasopressor. -Hypoglycemia can occur quickly after tumor removal and during post-op period.
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Factors that can contribute to postoperative hypotension include:
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-Volume depletion (along with alpha blockade) -Ischemia/MI -Bleeding -Sepsis
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Factors that can contribute to postoperative hypertension include:
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-Pain -Volume overload -Hypoxia, consider pneumothorax (according to Jaffe it can occur up to 20% of the time). -Hypoglycemia -Residual pheo
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75% of patients become normotensive within ...
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10 days
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In the remaining 25% of patient's, blood pressure is...
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controlled on antihypertensive drug regimen.
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Alternative Approaches:
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Laparoscopic removal of pheochromocytoma has been performed. -Advantages: Small incision site without thoracotomy (decreased post-op pain), Decreased insensible loses and maintenance of their temperature. -Disadvantages: Pneumoperitoneum for 2-3 hours (can pts cardiac status tolerate this?), Ability and time to convert to open procedure if needed. Will not be done via lap if pheo ;10 cm pheo or pheo is known to be cancerous.
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-Regional anesthesia has been used with success, however disadvantages include:
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-Need for a continuous high block. -Difficulty breathing and with positioning (prone or lateral) -Profound hypotension after tumor removal.
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What is a CT guided percutaneous ethanol injection (This is being done in China):
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-A needle bx of the pheo is taken, they will make sure it is not cancerous, infiltrate with LA, and then inject ethanol into the medulla of the adrenal gland. Vascular embolization will occur by ceasing blood flow to the tumor and causing pheo cell death.
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Alternative Intraoperative Diagnosis:
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-If a pheochromocytoma is undetected and a patient is undergoing surgery for another problem, then surgical stress can cause a catecholamine release. -The clinical picture of extreme hypertension, tachycardia, and dysrhythmias may be misdiagnosed as malignant hyperthermia.
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