Speaker: Dr.KumarModerator : Dr. Prabhavati

Pheochromocytoma

Pheochromocytoma1. Catecholamine

Physiology/Pathophysiology2. Clinical Presentation

1. Epidemiology2. Signs & Symptoms

3. Diagnosis1. Biochemical2. Localization

4. Management1. Preoperative2. Operative3. Postoperative4. Pregnancy

Catecholamine Producing Tumors

Neural Crest

Sympathoadrenal Progenitor Cell(Neuroblasts)

Chromaffin Cell Sympathetic Ganglion Cell

Intra-adrenal Extra-adrenalPheochromocytoma

Ganglioneuroma

Neuroblastoma

Catecholamine Producing TumorsPheochromocytomaParaganglioma (extra-adrenal pheo)GanglioneuromaNeuroblastomaCheodectomaGlomus jugulare tumor

HISTORY First recognised by Von FrankelPheochromocytoma= dusky colored tumorName coined by Pick in 1912Successful surgery for excision of tumor-

Roux & Mayo ( 1926-27)

Pheochromocytoma Neuroendocrine tumour of the medulla

of the adrenal glandsOriginates from the chromaffin cells

along the paravertebral sympathetic chain extending from pelvis to base of skull

>95% are abdominal>90% in adrenal medullaSecretes excessive amounts of

adrenaline and noradrenaline80% occur unilateral

Pheo: ‘Rule of 10’10% extra-adrenal (closer to 15%)10% occur in children10% familial (closer to 20%)10% bilateral or multiple (more if familial)10% recur (more if extra-adrenal)10% malignant10% discovered incidentally

Tyrosine L-Dopa Dopamine

Norepinephrine

Epinephrine

Catecholamines

Normetanephrine

Metaneprine

PNMT

DBH

COMT

COMT

Metabolites

Homovanillic acid(HVA)

MAO, COMT

Vanillymandelic Acid(VMA)

MAO

MAO

TH

phenylethanolamine N-methyltransferase - PNMT

dopamine β-hydroxylase -DBH

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 ReceptorsAlpha-Adrenergic Receptors

1: vasoconstriction, intestinal relaxation, uterine

contraction, pupillary dilation2: presynaptic NE (clonidine), platelet

aggregation, vasoconstriction, insulin secretion

Beta-Adrenergic Receptors1: HR/contractility, lipolysis, renin secretion 2: vasodilation, bronchodilation, glycogenolysis3: lipolysis, brown fat thermogenesis

Pheochromocytoma

1. Clinical Presentation1. Epidemiology2. Signs & Symptoms

Pheochromocytoma

0.01-0.1% of HTN populationFound in 10% of those screened

M = F3rd to 10th decades of lifeRare, investigate only if clinically suspicion:

Signs or SymptomsSevere HTN, HTN crisisRefractory HTN (> 4drugs)HTN present @ age < 20 or > 50 ?Adrenal lesion found on imaging (ex. Incidentaloma)

Pheo: Signs & Symptoms

The five P’s:Pressure (HTN) 9%Pain (Headache) 80%Perspiration 71%Palpitation 64%Pallor 42%

oParoxysms (the sixth P!)The Classical Triad:

Pain (Headache), Perspiration, PalpitationsLack of all 3 virtually excluded diagnosis of pheo

Hypertension – commonest presenting complaint

Paroxysmalepisodic

Pheo: Paroxysms, ‘Spells’10- 17%10-60 min durationFrequency: daily to monthlySpontaneousPrecipitated:any activity that displaces abdominal

contentsDiagnostic procedures, I.A. Contrast Drugs (opiods, unopposed -blockade,

anesthesia induction, histamine, ACTH, glucagon, metoclopramide)

Strenuous exercise, movement that increases intra-abdo pressure (lifting, straining)

Micturition (bladder paraganlgioma)

Pheo: Paroxysms, ‘Spells’Sym depend upon the relative proportion of

epi & norepiExcessive secretion of epi & dopamineDue to epinephrine:Headache, profuse sweating, palpitations,

apprehension often with a sense of impending doom

Pallor/flushing d. t peripheral adrenergic response

Due to dopamine:Nausea & vomiting d .t. vasodilation in the GIT

Pheo: Hypotension!Hypotension (orthostatic/paroxysmal)

occurs in many patientsMechanisms:

ECF contractionLoss of postural reflexes due to prolonged

catecholamine stimulationTumor release of adrenomedullin (vasodilatory

neuropeptide)

Cardiac manifestationsSinus tachy, bradycardia , SVT, ventricular

ectopics, V tachCatecholemine induced inc. myocardial

oxygen consumption, coronary vasospasmAngina/MICardiomyopathy- hypertrophic Cardiomyopathy-

diastolic dysfn- norepi inducedDilated cardiomyopathy- systolic dysfn- epi induced CCF with myocarditis concentric hypertrophy/ assymetrical

hypertrophyRarely sinus node dysfunction

Neurologic manifestations Hypertensive encephalopathy ( altered

mental status, focal neurological s/s, seizures )

Stroke – due to cerebral infarction/ embolus

Intracerebral bleed

Pheo: Signs (metabolic) Hypercalcemia

Associated MEN2 HPT PTHrP secretion by pheo

Mild glucose intolerance- supression of insulin secretion, glycogenolysis (↑ norepinephrine)

Epi causes stimulation of insulin release through B2 adrenoceptars- this is offset by the effects of circulation norepinephrine

polyuria Lipolysis- increased epinephrine secr

Weight-loss Ketosis > VLDL synthesis (TG)

Familial PheoMEN 2a

50% Pheo (usually bilateral)+ medullary Ca Thyroid + hyperparathyroidism

MEN 2b50% Pheo (usually bilatl) mucosal neuroma,

marfanoid habitusVon Hippel-Landau

50% Pheo (usually bilat), retinoblastoma, cerebellar hemangioma, nephroma, renal/pancreas cysts

Familial PheoNF1 (Von Recklinghausen's)

2% Pheo (50% if NF-1 and HTN)Café-au-lait spots, neurofibroma, optic glioma

Familial paragangliomaFamilial pheo & islet cell tumorOther: 1.Tuberous sclerosis,2. Sturge-Weber,3. ataxia-telangectgasia, 4.Carney’s Triad (Pheo, Gastric Leiomyoma, Pulm

chondroma)

PheochromocytomaDiagnosis

1. Biochemical2. Localization

24h Urine CollectionPositive results (> 2-3 fold elevation):

24h Ucatechols > 2-fold elevation 24h Utotal metanephrines > 1.2 ug/d 24h UVMA > 3-fold elevation

Detected by high performance liquid chromatography

24h Urine CollectionTest Characteristics:

24h urinary catechol Sen 83% Spec 88%24h U total metanephrines Sen 76% Spec 94%24h Ucatechols + Utotal metanephrines Sen 90% Spec 98%24h UVMA Sen 63% Spec 94%

Sensitivity increased if 24h urine collection begun at onset of a paroxysm

Serum creatinine measured for all collections of urine to determine adequacy of collection

Plasma free metanephrines sen 99% spec 89%

Plasma catecholamines sen 84% spec 81%

Biochemical Tests: SummarySEN SPEC

Ucatechols 83% 88%

Utotal metanephrines 76% 94%

Ucatechols+metaneph 90% 98%

UVMA 63% 94%

Plasma catecholamines 85% 80%

Plasma metanephrines 99% 89%

24h Urine: False PositiveDrugs: TCAs, MAO-i, levodopa, methyldopa,

labetalol, propanolol, clonidine (withdrawal), ilicit drugs (opiods, amphetamines, cocaine), ethanol, sympathomimetics (cold remedies)

Hold these medications for 2 weeks!

Major physical stress (hypoglycemia, stroke, raised ICP, etc.)

Plasma Catecholamines

Plasma total catechols > 2000 pg/mLSEN 85% SPEC 80%

False positives: same as for 24h urine testing, also with diuretics, smoking

Suppression/Stimulation TestingClonidine suppression

Usually they decrease catecholaminesUnlike normals, pheo patients won’t

suppress their plasma norepi with clonidine

Glucagon stimulationMay precipitate hypertensive crisisPheo patients, but not normals, will

have a > 3x increase in plasma norepi with glucagon

Localization: Imaging90% adrenal,

Extra- adrenal sites- organ of Zuckerlandl, bladder, myocardium, mediastenum, carotid & glomus jugulare bodies

CT abdomenAdrenal pheo SEN 93-100%Extra-adrenal pheo SEN 90%

MRI> SEN than CT for extra-adrenal pheo

MIBG ScanSEN 77-90% SPEC 95-100%

MIBG Scan123I or 131I labelled metaiodobenzylguanidine

Saved for cases where pheo diagnosed biochemically but no tumor on CT/ MRI

MIBG catecholamine precurosr taken up by the tumor

Inject MIBG, scan @ 24h, 48h, 72h

False negative scan:Drugs: Labetalol, reserpine, TCAs, phenothiazinesMust hold these medications for 4-6 wk prior to

scan

Pheochromocytoma1. Management

1. Preoperative2. Operative3. Postoperative4. Pregnancy

Pheo ManagementPrior to 1951, reported mortality for

excision of pheochromoyctoma 24 - 50 %HTN crisis, arrhythmia, MI, strokeHypotensive shock

Currently, mortality: 0 - 2.7 %Preoperative preparation, -blockadeNew anesthetic techniques

oAnesthetic agentso Intraoperative monitoring: arterial line,

EKG monitor, CVP line, Swan-GanzExperienced & Coordinated team:

Endocrinologist, Anesthesiologist and Surgeon

Preop W/upCBP, electrolytes, creatinine, INR/PTTCXRECGEcho (dilated CMY 2º catechols)

Preop Preparation RegimensCombined + blockade

PhenoxybenzamineSelective 1-blocker (ex. Prazosin)Propanolol

Metyrosine

Calcium Channel Blocker (CCB)Nicardipine

Preop: + blockade

Start at least 10-14d preopAllow sufficient time for ECF re-expansion

Phenoxybenzamine Drug of choiceCovalently binds -receptors (1 > 2)Start 10 mg po bid increase q2d by 10-20

mg/dIncrease until BP cntrl and no more

paroxysmsMaintenance 40-80 mg/d (some need > 200

mg/d)

Phenoxybenzamine (cont’d)Side-effect: orthostasis with dosage required to

normalized seated BP, reflex tachycardiaDrawback: periop hypotension/shock unlikely to

respond to pressor agents.Causes presynaptic inhibition of adrenergic control

thus leading to inc in beta adrenergic outflowThus beta blockers needed to be given alongside

Evaluation of adrenergic blockade

Roizens criteriaArterial BP < 160/95 mm Hg in the last 48 hrs

prior to surgery. Recommended to measure in stressful environment

Mild orthostatic hypotension indicates optimal adrenergic blockade but not < 80/45.

ECG- free of ST changes for > 2 wks

Ventricular ectopic < 1 over 5 min

Preop: + blockade-blockade

Used to control reflex tachycardia and prophylaxis against arrhythmia during surgery

Start only after effective -blockade (may ppt HTN)

If suspect CHF/dilated CMY start low dose Propranolol Dose

oStart 40 mg po bid increase to cntrl HR

oUp to 480 mg/day in divided dosesoIV 1-2 mg bolus

Beta adrenergic blockersPropronolol ( contd)

Side effects- may induce cardiac failure, bronchospasm

Oral bioavailability 25% (extensive 1st pass metabolism)

Atenolol- selective B1

Dose 50- 100 mg/d POMax 300 mg/dIV 2.5 to 10 mg/d

Beta adrenergic blockersEsmolol – selective B1 for rapid intraop BP

controlBolus IV 250-500 µ/kg/minInfusion 25 to 250 µ/kg/min

Labetolol –mixed ɑ+ƁDose- 50- 200 mg/d POIV 0.25 mg/kgNot used as asole drug due to unpredictable

control of BP

Preop: + blockadeIf BP still not cntrl despite + blockadeAdd Prazosin to PhenoxybenzaminePrazosin (Minipress) –competitive, selective 1

blockade T1/2- 2-3 HrsDose -1-5 mg PO BDSide effects- postural hypotension reflex

tachycardiaNo blockade required

Not routinely used as incomplete -blockadeUsed more for long-term Rx (inoperable or malignant

pheo)Other selective 1 blockers- terazosin, doxazocin

Other antihypertensivesCCB-

Diltiazem 60- 120mg/d, max 360mg/dT1/2- 3to 5 hrs Side effects- bradycardia, exacerbates

cardiac failure

Nifedepine – 30mg/d PO Max. 360mg/dT1/2-1 to 2 hrsSide effects- hypotension, peripheral edema

ACE-I- Ramipril

Avoid diuretics as already ECF contracted

Preop: CCB

Nicardipine Started po 24h to few weeks preop to cntrl BP and

allow ECF restorationAfter intubation IV Nicardipine gtt (start 2.5

ug/kg/min)IV Nicardipine adjusted to SBPStopped prior to ligation of tumor venous drainageTachycardia Rx with concurrent IV esmolol

Advantage: periop hypotension may still respond to pressor agents as opposed to those patients who are completely -blocked

Preop: + blockadeMeds given on morning of surgeryPeriop HTN:

IV phentolamine (Regitine)Short acting non-selective -blocker

IV Nitroprusside (NTP)Periop arrhythmia: IV esmololPeriop Hypotension: IV crystalloid +/-

colloid

Pheo: Rx of HTN CrisisIV phentolamineIV NTPIV esmololIV labetalol – combined + blocker

Preop: Metyrosine (Demser)

Synthetic inhibitor of Tyrosine Hydroxylase (TH)Start 250 mg qid max 1 gm qidSevere S/E’s: sedation, extrapyramidal,

diarrhea, 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 + blockade or other preop prep

Tyrosine L-Dopa Dopamine

Norepinephrine

Epinephrine

PNMT

DBH

TH

O.R.Admit night before for overnight IV salineArterial line, EKG monitor, CVP lineKnown CHF, CAD, low EF(<30): consider Swan-

GanzSpo2, ETCO2, temperature monitoringpreop medications:

Anxiolytic sedative- benzodiazepine helps dec catecholamines release

Opoids- morphine preferably avoided as causes histamine release

Fentanyl, sufentanyl safe

Premedication Atropine or Glyco pyrolate to be omitted-

causes tachycardia

Droperidol- antiemetic, blocks adrenoceptor and inhibit catecholamine uptake & promotes catecholamine release

Anaesthetic technique

General anaesthesiaRegional anaesthesia- mid to low thoracic Combined regional and general anaesthesiaPreferred- combined regional and general

anaesthesia techniqueHere although regional anaesthesia protects

against stresses of surgery, it cannot prevent catecholamine surges due to tumor manipulation.

In extensive sympathetic blockade, severe hypotension after tumor removal,

INDUCTION Essentially imp to give induction agents slowly

along with close monitoring of HR and arterial pressure

Thiopentone / propofol widely usedEtomidate –causes pain/ involuntary movementKetamine – not recommended Multimodal – benzodiazapines+ opoid+

induction agent

Attenuate pressor responseImportant for laryngoscopy and tracheal

intubation 2% lignocaine – 1-1.5mg/kgEsmolol – 50- 100 µg/kg/minDuring laryngoscopy catecholamine levels ↑

Normally- 200- 2000 pg/mlIn pheo- 2000- 20,000 pg/ml

Neuromuscular blockadeNon depolarising neuromusc blocking drugs

DOC-VecuroniumSuxamethonium- avoided causes

fasciculations and rise in intra abdominal pressure

Atracurium/ mivacurium- best avoided d. t release of histamine

Cisatracurium/ rocuronium- safe cardio stable and least histamine release

maintenanceInhalational agent- isoflurane used

extensively coz does not sensitize the myocardium to catecholamines

Halothane undesirable ……arrhythmogenic properties

Sevoflurane used successfully (fast onset …..fast offset)

O.RHave ready: IV phentolamine, IV NTP, IV

esmololOther alternatives tried- MgSO4 ,40-60 mg/kg

bolus foll by 2 gms/hrVery high uncontrolled BP- surgeons to stopLigation of adrenal vein- sudden hypotensionRx hypotension with crystalloid +/- colloid 1st

may need dopamine/ noradrenaline/ phenylephrine

Aim for CVP 12 or Wedge 15Inotropes may not work!

Adverse perioperative effects

Large tumor sizeProlonged duration of surgeryInc levels of preoperative urinary

catecholamines and catecholamine metabolites

Laparoscopic adrenalectomy.If tumor < 8cmSlow CO2 insufflation….. Not > 12 mm Hg

PostopPost op ventilation / ICU stay- depends

upon the haemodynamic status…. Preferably ICU stay for 24 hrs

Hypoglycemia post op due to disinhibition of B cell supression….. Increased insulin secretion

Glucose supplementation at end of surgery

Post opMost cases can stop all BP meds postop

Postop hypotension: IV crystalloidHTN free: 5 years 74% 10 years 45%

24h urine collection 2 wk postopSurveillance:

24h urine collections q1y for at least 10yLifelong f/up

5 yr survival- non malignant pheo- 95%Malignant- < 50 %

Pheo: Unresectable, Malignant-blockade

Selective 1-blockers (Prazosin, Terazosin, Doxazosin) 1st line as less side-effects

Phenoxybenzamine: more complete -blockade

-blockerCCB, ACE-I, etc.Nuclear Medicine Rx:

Hi dose 131I-MIBG or 111indium-octreotide depending on MIBG scan or octreoscan pick-up

Sensitize tumor with Carboplatin + 5-FU

Pheo & PregnancyGrave prognosis ,mortility: maternal - 48%, fetal

55%Diagnosis with 24h urine collections and MRINo stimulation tests, no MIBG if pregnantNever spontaneous labour1st & 2nd trimester (< 24 weeks):

Phenoxybenzamine + blocker prepResect tumor laprascopically

3rd trimester:Phenoxybenzamine + blocker prep…..2-3 wksWhen 37 weeks: cesarian section followed by tumor

resection

Conclusion Long term outlook very goodManaged by an experienced team of

anaesthesiologist, surgeon, endocrinologist &cardiologist

Principles of anaesthetic managementGood adrenergic blockade preopVigilent intraop monitoring and treatment of

hyper/ hypotensionPost op ICU care

Antihypertensive for a prolonged period

THANK YOU