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William Harper, MD, FRCPC Endocrinology & Metabolism Assistant Professor of Medicine McMaster University
Pheochromocytoma
1. Catecholamine Physiology/Pathophysiology 2. Clinical Presentation
1. Epidemiology 2. Signs & Symptoms
3. Diagnosis
1. Biochemical 2. Localization
4. Management
1. 2. 3. 4. Preoperative Operative Postoperative Pregnancy
Chromaffin Cell
Ganglioneuroma
Behave like paraganglioma biochemically
Neuroblastoma
Common malignancy in children, adrenal or sympathetic chain Catecholamine humoral effects usually minor Rapid growth & widespread metastasis Some differentiate and spontaneously regress Rx complex (surgery, XRT, chemotherapy)
Catecholamines Tyrosine
TH
Metabolites Dopamine
DBH MAO, COMT
L-Dopa
NorepinephrineCOMT Normetanephrine
PNMT MAO COMT
Epinephrine
Metaneprine
MAO
Tumor Secretion:
Large Pheo: more metabolites (metabolized within tumor before release) Small Pheo: more catecholamines Sporadic Pheo: Norepi > Epi Familial Pheo: Epi > Norepi Paraganglioma: Norepi Cheodectoma, glomus jugulare: Norepi Gangioneuroma: Norepi Malignant Pheo: Dopamine, HVA Neuroblastoma: Dopamine, HVA
Adrenergic Receptors
Alpha-Adrenergic Receptors
E1: vasoconstriction, intestinal relaxation, uterine contraction, pupillary dilation E2: q presynaptic NE (clonidine), platelet aggregation, vasoconstriction, q insulin secretion
Beta-Adrenergic Receptors
F1: o HR/contractility, o lipolysis, o renin secretion F2: vasodilation, bronchodilation, o glycogenolysis F3: o lipolysis, o brown fat thermogenesis
Pheochromocytoma
1. Catecholamine Physiology/Pathophysiology 2. Clinical Presentation
1. Epidemiology 2. Signs & Symptoms
3. Diagnosis
1. Biochemical 2. Localization
4. Management
1. 2. 3. 4. Preoperative Operative Postoperative Pregnancy
Pheochromocytoma
0.01-0.1% of HTN population
Found in 0.5% of those screened
M=F 3rd to 5th decades of life Rare, investigate only if clinically suspicion:
Signs or Symptoms Severe HTN, HTN crisis Refractory HTN (> 3 drugs) HTN present @ age < 20 or > 50 ? Adrenal lesion found on imaging (ex. Incidentaloma)
Pheo: Hypotension!
Hypotension (orthostatic/paroxysmal) occurs in many patients Mechanisms:
ECFv contraction Loss of postural reflexes due to prolonged catecholamine stimulation Tumor release of adrenomedullin (vasodilatory neuropeptide)
CHF
HTN hypertrophic cardiomyopathy diastolic dysfn. Catechols induce dilated cardiomyopathy systolic dysfn.
Pheo: Rule of 10
10% extra-adrenal (closer to 15%) 10% occur in children 10% familial (closer to 20%) 10% bilateral or multiple (more if familial) 10% recur (more if extra-adrenal) 10% malignant 10% discovered incidentally
Familial Pheo
MEN 2a 50% Pheo (usually bilateral), MTC, HPT MEN 2b 50% Pheo (usually bilatl), MTC, mucosal neuroma, marfanoid habitus Von Hippel-Landau 50% Pheo (usually bilat), retinoblastoma, cerebellar hemangioma, nephroma, renal/pancreas cysts NF1 (Von Recklinghausen's) 2% Pheo (50% if NF-1 and HTN) Caf-au-lait spots, neurofibroma, optic glioma Familial paraganglioma Familial pheo & islet cell tumor Other: Tuberous sclerosis, Sturge-Weber, ataxia-telangectgasia, Carneys Triad (Pheo, Gastric Leiomyoma, Pulm chondroma)
Pheochromocytoma
1. Catecholamine Physiology/Pathophysiology 2. Clinical Presentation
1. Epidemiology 2. Signs & Symptoms
3. Diagnosis
1. Biochemical 2. Localization
4. Management
1. 2. 3. 4. Preoperative Operative Postoperative Pregnancy
24h Utotal metanephrines > 1.2 ug/d (6.5 umol/d) 24h UVMA > 3-fold elevation
ULN 35 umol/d for most assays
Plasma Catecholamines
Drawn with patient fasting, supine, with an indwelling catheter in place > 30 min Plasma total catechols > 11.8 nM (2000 pg/mL)
SEN 85% SPEC 80%
False positives: same as for 24h urine testing, also with diuretics, smoking CRF & ESRD:
Oliguric to Anuric 24h Urines inaccurate Plasma epinephrine best test for pheo in ESRD Plasma norepi and metanephrines falsely elevated in ESRD
Plasma Metanephrines
Not postural dependent: can draw normally Secreted continuously by pheo SEN 99% SPEC 89% False Positive: acetaminophen Assay not readily available in Canada
UVMA
Plasma catecholamines Plasma metanephrines
Suppression/Stimulation Testing
Clonidine suppression
May precipitate hypotensive shock! Unlike normals, pheo patients wont suppress their plasma norepi with clonidine
Glucagon stimulation
May precipitate hypertensive crisis! Pheo patients, but not normals, will have a > 3x increase in plasma norepi with glucagon
Localization: Imaging
CT abdomen
Adrenal pheo SEN 93-100% Extra-adrenal pheo SEN 90%
MRI
> SEN than CT for extra-adrenal pheo
Localization: Imaging
CT abdomen
Adrenal pheo SEN 93-100% Extra-adrenal pheo SEN 90%
MRI
> SEN than CT for extra-adrenal pheo
MIBG Scan
SEN 77-90% SPEC 95-100%
MIBG Scan
123I or 131I labelled metaiodobenzylguanidine MIBG catecholamine precurosr taken up by the tumor Inject MIBG, scan @ 24h, 48h, 72h Lugols 1 gtt tid x 9d (from 2d prior until 7d after MIBG injection to protect thyroid) False negative scan:
Drugs: Labetalol, reserpine, TCAs, phenothiazines Must hold these medications for 4-6 wk prior to scan
PET
18F-fluorodeoxyglucose (FDG) 6-[18F]-fluorodopamine
Pheochromocytoma
1. Catecholamine Physiology/Pathophysiology 2. Clinical Presentation
1. Epidemiology 2. Signs & Symptoms
3. Diagnosis
1. Biochemical 2. Localization
4. Management
1. 2. 3. 4. Preoperative Operative Postoperative Pregnancy
Pheo Management
Prior to 1951, reported mortality for excision of pheochromoyctoma 24 - 50 %
HTN crisis, arrhythmia, MI, stroke Hypotensive shock
Preop W/up
CBC, lytes, creatinine, INR/PTT CXR EKG Echo (r/o dilated CMY 2 catechols)
Preop: E + F blockade
Start at least 10-14d preop
Allow sufficient time for ECFv re-expansion
Phenoxybenzamine
Special pharmacy access only (no DIN) Drug of choice Covalently binds E-receptors (E1 > E2) Start 10 mg po bid increase q2d by 10-20 mg/d Increase until BP cntrl and no more paroxysms Maintenance 40-80 mg/d (some need > 200 mg/d) Salt load: NaCl 600 mg od-tid as tolerated
Preop: E + F blockade
Phenoxybenzamine (contd)
Side-effect: orthostasis with dosage required to normalized seated BP, reflex tachycardia Drawback: periop hypotension/shock unlikely to respond to pressor agent.
Selective E1-blockers
Prazosin, Terazosin, Doxazosin Some experience with Prazosin for Pheo preop prep Not routinely used as incomplete E-blockade Less orthostasis & reflex tachycardia then phenoxybenzamine Used more for long-term Rx (inoperable or malignant pheo)
Preop: E + F blockade
F-blockade
Used to control reflex tachycardia and prophylaxis against arrhythmia during surgery Start only after effective E-blockade (may ppt HTN) If suspect CHF/dilated CMY start low dose Propanolol most studied in pheo prep
Start 10 mg po bid increase to cntrl HR
Preop: E + F blockade
If BP still not cntrl despite E + F blockade
Add Prazosin to Phenoxybenzamine Add CCB, ACE-I Avoid diuretics as already ECFv contracted Metyrosine
Preop: E + F blockade
Meds given on AM of surgery Periop HTN:
IV phentolamine
Short acting non-selective E-blocker Test dose 1 mg, then 2-5 mg IV q1-2h PRN or as continuous infusion (100 mg in 500cc D5W, titrate to BP)
IV Nitroprusside (NTP)
Preop: Metyrosine
Tyrosine
TH
L-Dopa
Dopamine
Synthetic inhibitor of Tyrosine DBH Hydroxylase (TH) Norepinephrine Special pharm access, no DIN PNMT Start 250 mg qid max 1 gm qid Severe S/Es: sedation, extrapyramidal, diarrhea,Epinephrine nausea/vomit, anxiety, renal/chole stones, galactorrhea Alone may insufficiently cntrl BP and reported HTN crises during pheo operation Restrict use to inoperable/malignant pheo or as adjunct to E + F blockade or other preop prep
Preop: CCB
Cleveland Clinic Experience
Only 6 cardiovascular complications All occurred in patients with preop E-blockade 30% received no medications preop if no HTN Patients not receiving phenoxybenzamine required less fluids (956 cc intraop, 479 cc POD#1)
CCB
Block norepi mediated Ca transport into vascular smooth muscle
Preop: CCB
Nicardipine (France Study)
Started po 24h to few weeks preop to cntrl BP and allow ECFv restoration After intubation IV Nicardipine gtt (start 2.5 ug/kg/min) IV Nicardipine adjusted to SBP Stopped prior to ligation of tumor venous drainage Tachycardia Rx with concurrent IV esmolol
Advantage: periop hypotension may still respond to pressor agents as opposed to those patients who are completely E-blocked
Preop: CCB
Cleveland Clinic:
Only 10% received phenoxybenzamine CCB 1st line agents as preop po med Selective E1-blockers (Prazosin, Terazosin, Doxazosin) added to CCB if BP still high Periop arrythmia: IV esmolol Periop HTN: IV NTP Periop hypotension:
IV crystalloid or colloid Dopamine, norepi, epi, phenylephrine
O.R.
Admit night before for overnight IV saline Arterial line, EKG monitor, CVP line Known CHF: consider Swan-Ganz Regardless of preop medications:
Have ready: IV phentolamine, IV NTP, IV esmolol Rx hypotension with crystalloid +/- colloid 1st Aim for CVP 12 or Wedge 15 Inotropes may not work!
O.R.
Anesthetic choice:
Enflurane or isoflurane: dont sensitized myocardium to catecholamines Halothane: may sensitize heart arrhythmia
Postop
Most cases can stop all BP meds postop
Postop hypotension: IV crystalloid HTN free: 5 years 74% 10 years 45%
3rd trimester:
Phenoxybenzamine + Fblocker prep When fetus large enough: cesarian section followed by tumor resection