Pheochromocytoma

DR. SUVYL RODRICKS

DR. MEERA KHARBANDA

www.anaesthesia.co.in

anaesthesia.co.in@gmail.com

Pheochromocytoma
1.
2.

Catecholamine Physiology/Pathophysiology
Clinical Presentation
1.
2.

3.

Diagnosis
1.
2.

4.

Epidemiology
Signs & Symptoms
Biochemical
Localization

Management
1.
2.
3.
4.

Preoperative
Operative
Postoperative
Pregnancy

Catecholamine Producing Tumors

Neural Crest
Sympathoadrenal Progenitor Cell
(Neuroblasts)

Chromaffin Cell

Neuroblastoma

Sympathetic Ganglion Cell

Intra-adrenal Extra-adrenal
Pheochromocytoma

Ganglioneuroma

Catecholamine Producing Tumors

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

HISTORY
First

recognised by Von Frankel

Pheochromocytoma= dusky colored tumor
Name coined by Pick in 1912
Successful surgery for excision of tumorRoux & 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

Catecholamines

Metabolites

Tyrosine TH L-Dopa Dopamine

MAO, COMT

DBH

Homovanillic acid
(HVA)

COMT
Norepinephrine
Normetanephrine
PNMT

EpinephrineCOMT

MAO

Metaneprine
MAO

Vanillymandelic Acid
(VMA)

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
3rd to 10th 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 Ps:

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

complaint
Paroxysmal
episodic

commonest presenting

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)
Caf-au-lait spots, neurofibroma, optic glioma
Familial paraganglioma
Familial pheo & islet cell tumor
Other: Tuberous sclerosis, Sturge-Weber, ataxiatelangectgasia, Carneys 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 Utotal metanephrines > 1.2 ug/d (6.5 umol/d)

24h UVMA > 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 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

Plasma catecholamines

sen 99%
spec 89%
sen 84%
spec 81%

Biochemical Tests: Summary

SEN

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 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 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

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

I 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
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
123

Localization: Nuclear medicine

MIBG
111Indium-pentreotide

Some pheo have somatostatin receptors

PET
F-fluorodeoxyglucose (FDG)
6-[18F]-fluorodopamine
18

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 2 catechols)

Preop Preparation Regimens

Combined + blockade
Phenoxybenzamine
Selective -blocker (ex. Prazosin)
1
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

(contd)

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 1st pass

metabolism)
Atenolol-

selective B1

Dose 50- 100 mg/d PO

Max 300 mg/d
IV 2.5 to 10 mg/d

Beta adrenergic blockers

Esmolol

selective B1 for rapid intraop BP control

Bolus IV 500 /kg/min

Infusion 50 to200 /kg/min

Labetolol

mixed +

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 1st line agents as preop po med
Selective -blockers (Prazosin, Terazosin,
1
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)

Tyrosine

TH

L-Dopa

Dopamine
DBH

Synthetic inhibitor of Tyrosine

Norepinephrine
Hydroxylase (TH)
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
+ blockade or other preop prep

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 g/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 -blockers (Prazosin, Terazosin,
1
Doxazosin) 1st line as less side-effects
Phenoxybenzamine: more complete -blockade
-blocker
CCB, 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 & 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
1st & 2nd trimester (< 24 weeks):
Phenoxybenzamine + blocker prep
Resect tumor laprascopically
3rd 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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