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Pheochromocytoma

DR. SUVYL RODRICKS
DR. MEERA KHARBANDA


www.anaesthesia.co.in anaesthesia.co.in@gmail.com
Pheochromocytoma
1. Catecholamine Physiology/Pathophysiology
2. Clinical Presentation
1. Epidemiology
2. Signs & Symptoms
3. Diagnosis
1. Biochemical
2. Localization
4. Management
1. Preoperative
2. Operative
3. Postoperative
4. Pregnancy
Catecholamine Producing Tumors
Neural Crest
Sympathoadrenal Progenitor Cell
(Neuroblasts)
Chromaffin Cell
Sympathetic Ganglion Cell
Intra-adrenal Extra-adrenal
Pheochromocytoma
Ganglioneuroma
Neuroblastoma
 Pheochromocytoma
 Paraganglioma (extra-adrenal pheo)
 Originate in extra-adrenal sympathetic
chain/chromaffin tissue
 Ganglioneuroma
 Behave like paraganglioma biochemically
Catecholamine Producing Tumors
 Neuroblastoma
 Common malignancy in children, adrenal or
sympathetic chain.
 Rapid growth & widespread metastasis
 Some differentiate and spontaneously regress
 Rx complex (surgery, RT, chemotherapy)
 Cheodectoma
 Carotid body, behave like paraganglioma
biochemically
 Glomus jugulare tumor
 Intracranial branch of CN IX and X
 Behave like paragangliomoa biochemically
Catecholamine Producing Tumors
HISTORY
 First recognised by Von Frankel
 Pheochromocytoma= dusky colored tumor
 Name coined by Pick in 1912
 Successful surgery for excision of tumor-
Roux & Mayo ( 1926-27)

Pheochromocytoma
 Neuroendocrine tumour of the medulla of the
adrenal glands
 Originates from the chromaffin cells along the
paravertebral sympathetic chain extending from
pelvis to base of skull
 >95% are abdominal
 >90% in adrenal medulla
 Secretes excessive amounts of adrenaline and
noradrenaline
 80% occur unilateral


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
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
 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
 
1
: vasoconstriction, intestinal relaxation, uterine
contraction, pupillary dilation
 
2
:  presynaptic NE (clonidine), platelet aggregation,
vasoconstriction,  insulin secretion
 Beta-Adrenergic Receptors
 
1
:  HR/contractility,  lipolysis,  renin secretion
 
2
: vasodilation, bronchodilation,  glycogenolysis
 
3
:  lipolysis,  brown fat thermogenesis
Pheochromocytoma

1. Clinical Presentation
1. Epidemiology
2. Signs & Symptoms
Pheochromocytoma
 0.01-0.1% of HTN population
 Found in 10% of those screened
 M = F
 3
rd
to 10
th
decades of life
 Rare, investigate only if clinically suspicion:
 Signs or Symptoms
 Severe HTN, HTN crisis
 Refractory 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%
• Paroxysms (the sixth P!)
 The Classical Triad:
 Pain (Headache), Perspiration, Palpitations
 Lack of all 3 virtually excluded diagnosis of pheo in
a series of > 21,0000 patients
 Hypertension – commonest presenting
complaint
 Paroxysmal
 episodic
Pheo: Paroxysms, ‘Spells’
 10- 17%
 10-60 min duration
 Frequency: daily to monthly
 Spontaneous
 Precipitated:any activity that displaces abdominal contents
 Diagnostic procedures, I.A. Contrast (I.V. is OK)
 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 & norepi
 Excessive secretion of epi & dopamine
 D.t epinephrine:
 Headache, profuse sweating, palpitations, apprehension
often with a sense of impending doom
 Pallor/flushing d. t peripheral adrenergic response
 D .t dopamine:
 Nausea & vomiting d .t. vasodilation in the GIT



Pheo: Hypotension!
 Hypotension (orthostatic/paroxysmal)
occurs in many patients
 Mechanisms:
 ECF contraction
 Loss of postural reflexes due to prolonged
catecholamine stimulation
 Tumor release of adrenomedullin (vasodilatory
neuropeptide)
Cardiac manifestations
 Sinus tachy, bradycardia , SVT, ventricular ectopics,
V tach
 Catecholemine induced inc myocardial oxygen
consumption, coronary vasospasm
– Angina/MI
– Cardiomyopathy- hypertrophic Cardiomyopathy-
diastolic dysfn- norepi induced
– Dilated cardiomyopathy- systolic dysfn- epi induced
– CCF with myocarditis
– concentric hypertrophy/ assymetrical hypertrophy
– Rarely sinus node dysfunction


Neurologic manifestations
 Hypertensive encephalopathy ( altered mental status, focal
neurological s/s, seizures )
 Stroke – d. t. 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 thro B2
adrenoceptars- this is offset by the effects of circ norepi
 polyuria
 Lipolysis- inc epinephrine secr
 Weight-loss
 Ketosis > VLDL synthesis (TG)




Pheo: malignant
 Increased dopamine secretion
 Causes inc outlet resistance of the prostatic urethra- pheo
of the bladder
 Accomp by hypertension , palpitation sweating , fainting

Familial Pheo
 MEN 2a
 50% Pheo (usually bilateral)+ medullary Ca Thyroid
+ hyperparathyroidism
 MEN 2b
 50% Pheo (usually bilatl) mucosal neuroma,
marfanoid habitus
 Von Hippel-Landau
 50% Pheo (usually bilat), retinoblastoma, cerebellar
hemangioma, nephroma, renal/pancreas cysts
Familial Pheo
 NF1 (Von Recklinghausen's)
 2% Pheo (50% if NF-1 and HTN)
 Café-au-lait spots, neurofibroma, optic glioma
 Familial paraganglioma
 Familial pheo & islet cell tumor
 Other: Tuberous sclerosis, Sturge-Weber, ataxia-
telangectgasia, Carney’s Triad (Pheo, Gastric Leiomyoma,
Pulm chondroma)

Pheochromocytoma
Diagnosis
1. Biochemical
2. Localization
24h Urine Collection
Positive results (> 2-3 fold elevation):
 24h U
catechols
> 2-fold elevation
• ULN for total catechols 591-890 nmol/d
 24h U
total metanephrines
> 1.2 ug/d (6.5 umol/d)
 24h U
VMA
> 3-fold elevation
• ULN 35 umol/d for most assays
 Detected by high performance liquid chromatography
24h Urine Collection
 Test Characteristics:
 24h urinary catechol

Sen 83% Spec 88%
 24h U total metanephrines

Sen 76% Spec 94%
 24h U
catechols
+ U
total metanephrines
Sen 90% Spec 98%
 24h U
VMA
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: Summary
SEN SPEC
U
catechols
83% 88%
U
total metanephrines
76% 94%
U
catechols+metaneph
90% 98%
U
VMA
63% 94%
Plasma catecholamines
85% 80%
Plasma metanephrines
99% 89%
24h Urine: False Positive
 Drugs: 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
 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
Plasma Catecholamines
 CRF & ESRD:
 Oliguric to Anuric  24h Urines inaccurate
 Plasma epinephrine best test for pheo in ESRD
 Plasma norepi and metanephrines falsely elevated in
ESRD
 Recurrent pheochromocytoma
– Besides others, Chromogranin A levels are done
– An acidic , monomeric protein , stored and secreted
with catecholamines
– Sen 84% spec 96%
Plasma Metanephrines
 Not postural dependent: can draw normally
 Secreted continuously by pheo
 SEN 99% SPEC 89%
 False Positive: acetaminophen

Suppression/Stimulation Testing
 Clonidine suppression
 May precipitate hypotensive shock!
 Unlike normals, pheo patients won’t 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
 90% adrenal,
 Extra- adrenal sites- organ of Zuckerlandl( origin of IMA),
bladder, myocardium, mediastenum, carotid & glomus
jugulare bodies
 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

123
I or
131
I 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
 Lugol’s 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
Localization: Nuclear medicine
 MIBG

111
Indium-pentreotide
 Some pheo have somatostatin receptors
 PET

18
F-fluorodeoxyglucose (FDG)
 6-[
18
F]-fluorodopamine
Pheochromocytoma
1. Management
1. Preoperative
2. Operative
3. Postoperative
4. Pregnancy
Pheo Management
 Prior to 1951, reported mortality for excision of
pheochromoyctoma 24 - 50 %
 HTN crisis, arrhythmia, MI, stroke
 Hypotensive shock
 Currently, mortality: 0 - 2.7 %
 Preoperative preparation, -blockade?
 New anesthetic techniques?
• Anesthetic agents
• Intraoperative monitoring: arterial line, EKG monitor, CVP
line, Swan-Ganz
 Experienced & Coordinated team:
 Endocrinologist, Anesthesiologist and Surgeon
Preop W/up
 CBC, electrolytes, creatinine, INR/PTT
 CXR
 EKG
 Echo (r/o dilated CMY 2º catechols)
Preop Preparation Regimens
 Combined  +  blockade
 Phenoxybenzamine
 Selective 
1
-blocker (ex. Prazosin)
 Propanolol
 Metyrosine
 Calcium Channel Blocker (CCB)
 Nicardipine

 No Randomized Clinical Trials to compare various
regimens!
Preop: + blockade
 Start at least 10-14d preop
 Allow sufficient time for ECF re-expansion
 Phenoxybenzamine (Dibenzyline)
 Drug of choice
 Covalently binds -receptors (
1
> 
2
)
 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
 Phenoxybenzamine (cont’d)
 Side-effect: orthostasis with dosage required to
normalized seated BP, reflex tachycardia
 Drawback: periop hypotension/shock unlikely to
respond to pressor agents.
 Causes presynaptic inhibition of adrenergic control
thus leading to inc in beta adrenergic outflow
 Thus beta blockers needed to be given alongside

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
 Propanolol most studied in pheo prep
• Start 10 mg po bid  increase to cntrl HR
• Initial dose 80-120 mg/d
• IV 1-10 mg
Beta adrenergic blockers
 Propronolol ( contd)
– Side effects- may induce cardiac failure, bronchospasm
– Oral bioavailability 25% (extensive 1
st
pass
metabolism)
 Atenolol- selective B
1
– Dose 50- 100 mg/d PO
– Max 300 mg/d
– IV 2.5 to 10 mg/d
Beta adrenergic blockers
 Esmolol – selective B
1
for rapid intraop BP
control

– Bolus IV 500 µ/kg/min
– Infusion 50 to200 µ/kg/min
 Labetolol –mixed ɑ+Ɓ
– Dose- 50- 100 mg/d PO
– IV 0.25 mg/kg
– Not used as asole drug d.t unpredictable control of BP

Preop: + blockade
 If BP still not cntrl despite  +  blockade
 Add Prazosin to Phenoxybenzamine
 Prazosin (Minipress) –competitive, selective 
1
blockade
– T1/2- 2-3 Hrs
– Dose -1-5 mg PO BD
– Side effects- postural hypotension reflex tachycardia
– No  blockade required
 Not routinely used as incomplete -blockade
 Used more for long-term Rx (inoperable or malignant
pheo)
– Other selective 
1
blockers- terazosin, doxazocin


Other antihypertensives
 CCB-
– Diltiazem 60- 120mg/d, max 360mg/d
– T1/2- 3to 5 hrs
– Side effects- bradycardia, exacerbates cardiac
failure
– Nifedepine – 30mg/d PO Max. 360mg/d
– T1/2-1 to 2 hrs
– Side 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 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 -
blocked
Preop: CCB
 Cleveland Clinic:
 Only 10% received phenoxybenzamine
 CCB 1
st
line agents as preop po med
 Selective 
1
-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
Preop: + blockade
 Meds given on AM of surgery
 Periop HTN:
 IV phentolamine (Regitine)
– Short acting non-selective -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)
 Periop arrhythmia: IV esmolol
 Periop Hypotension: IV crystalloid +/- colloid
Pheo: Rx of HTN Crisis
 IV phentolamine
 IV NTP
 IV esmolol
 IV labetalol – combined  +  blocker
Preop: Metyrosine (Demser)
 Synthetic inhibitor of Tyrosine
Hydroxylase (TH)
 Start 250 mg qid  max 1 gm qid
 Severe 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
Evaluation of  adrenergic
blockade
 Roizens criteria
– Arterial 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


O.R.
 Admit night before for overnight IV saline
 Arterial line, EKG monitor, CVP line
 Known CHF, CAD, low EF(<30): consider Swan-Ganz
 Spo2, ETCO2, temperature monitoring
 preop medications:
– Anxiolytic sedative- benzodiazepine helps dec
catecholamines release
– Opoids- morphine preferably avoided as causes
histamine release
– Fentanyl, sufentanyl safe
Premedication
 Atropine to be omitted- causes tachycardia
 Droperidol- antiemetic, blocks  adrenoceptor and inhibit
catecholamine uptake & promotes catecholamine release
Anaesthetic technique
 General anaesthesia
 Regional anaesthesia- mid to low thoracic
 Combined regional and general anaesthesia
 Preferred- combined regional and general anaesthesia
technique
– Here 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 alomg with
close monitoring of HR and arterial pressure
 Thiopentone / propofol widely used
 Etomidate –causes pain/ involuntary movt
 Ketamine – not recommended
 Multimodal – benzodiazapines+ opoid+ induction agent
Attenuate pressor response
 Important for laryngoscopy and tracheal intubation
 2% lignocaine – 1-1.5mg/kg
 Esmolol – 50- 100 µg/kg/min
 During laryngoscopy catecholamine levels ↑
– Normally- 200- 2000 pg/ml
– In pheo- 2000- 20,000 pg/ml



Neuromuscular blockade
 Non depol neuromusc blocking drugs
– DOC-Vecuronium
 Suxamethonium- 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
maintenance
 Inhalational agent- isoflurane used extensively coz does
not sensitize the myocardium to catecholamines
 Halothane undesirable ……arrhythmogenic properties
 Sevoflurane used successfully (fast onset …..fast offset)
O.R
 Have ready: IV phentolamine, IV NTP, IV esmolol
 Other alternatives tried- MgSO4 ,40-60 mg/kg bolus
foll by 2 gms/hr
 Very high uncontrolled BP- surgeons to stop
 Ligation of adrenal vein- sudden hypotension
 Rx hypotension with crystalloid +/- colloid 1
st
 may need dopamine/ noradrenaline/ phenylephrine

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

Adverse perioperative effects
 Large tumor size
 Prolonged duration of surgery
 Inc levels of preoperative urinary catecholamines and
catecholamine metabolites
Laparoscopic adrenalectomy.
 If tumor < 8cm
 Slow CO2 insufflation….. Not > 12 mm Hg


Postop
 Post op ventilation / ICU stay- depends upon the
haemodynamic status…. Preferably ICU stay for 24 hrs
 Hypoglycemia post op d. t disinhibition of B cell
supression….. Inc insulin secretion
 Glucose supplementation at end of surgery

Post op
 Most cases can stop all BP meds postop
 Postop hypotension: IV crystalloid
 HTN free: 5 years 74% 10 years 45%
 24h urine collection 2 wk postop
 Surveillance:
 24h urine collections q1y for at least 10y
 Lifelong f/up
 5 yr survival- non malignant pheo- 95%
– Malignant- < 50 %

Pheo: Unresectable, Malignant
 -blockade
 Selective 
1
-blockers (Prazosin, Terazosin,
Doxazosin) 1
st
line as less side-effects
 Phenoxybenzamine: more complete -blockade
 -blocker
 CCB, ACE-I, etc.
 Nuclear Medicine Rx:
 Hi dose
131
I-MIBG or
111
indium-octreotide
depending on MIBG scan or octreoscan pick-up
 Sensitize tumor with Carboplatin + 5-FU

Pheo & Pregnancy
 Grave prognosis ,mortility: maternal - 48%, fetal 55%
 Diagnosis with 24h urine collections and MRI
 No stimulation tests, no MIBG if pregnant
 Never spontaneous labour
 1
st
& 2
nd
trimester (< 24 weeks):
 Phenoxybenzamine + blocker prep
 Resect tumor laprascopically
 3
rd
trimester:
 Phenoxybenzamine + blocker prep…..2-3 wks
 When 37 weeks: cesarian section followed by tumor
resection

Conclusion
 Long term outlook very good
 Managed by an experienced team of anaesthesiologist,
surgeon, endocrinologist &cardiologist
 Principles of anaesthetic management
– Good adrenergic blockade preop
– Vigilent intraop monitoring and treatment of hyper/
hypotension
– Post op ICU care
 Antihypertensive for a prolonged period



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