Pheochromocytoma and its anaesthetic management

Pheochromocytoma and its anaesthetic management

1. Speaker: Dr.Kumar
Moderator : Dr. Prabhavati
Pheochromocytoma

3. 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

4. Catecholamine Producing Tumors
Neural Crest
Sympathoadrenal Progenitor Cell
(Neuroblasts)
Chromaffin CellSympathetic Ganglion Cell
Intra-adrenal Extra-adrenal
Pheochromocytoma
Ganglioneuroma
Neuroblastoma

5. Catecholamine Producing Tumors
Pheochromocytoma
Paraganglioma (extra-adrenal pheo)
Ganglioneuroma
Neuroblastoma
Cheodectoma
Glomus jugulare tumor

6. 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)

7. 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

8. 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

9. TyrosineL-DopaDopamine
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

10. 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

11. Adrenergic Receptors
Alpha-Adrenergic Receptors
a
1
: vasoconstriction, intestinal relaxation, uterine
contraction, pupillary dilation
a
2
: ¯ presynaptic NE (clonidine), platelet aggregation,
vasoconstriction, ¯ insulin secretion
Beta-Adrenergic Receptors
b
1
: ­ HR/contractility, ­ lipolysis, ­ renin secretion
b
2
: vasodilation, bronchodilation, ­ glycogenolysis
b
3
: ­ lipolysis, ­ brown fat thermogenesis

12. Pheochromocytoma
1.Clinical Presentation
1.Epidemiology
2.Signs & Symptoms

13. 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)

14. 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, Palpitations
Lack of all 3 virtually excluded diagnosis of pheo

15. Hypertension – commonest presenting complaint
Paroxysmal
episodic

16. 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
Drugs (opiods, unopposed b-blockade, anesthesia induction,
histamine, ACTH, glucagon, metoclopramide)
Strenuous exercise, movement that increases intra-abdo
pressure (lifting, straining)
Micturition (bladder paraganlgioma)

17. Pheo: Paroxysms, ‘Spells’
Sym depend upon the relative proportion of epi &
norepi
Excessive secretion of epi & dopamine
Due 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

18. 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)

19. 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

20. Neurologic manifestations
Hypertensive encephalopathy ( altered mental status,
focal neurological s/s, seizures )
Stroke – due to cerebral infarction/ embolus
Intracerebral bleed

21. 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)

22. 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

23. 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:
1.Tuberous sclerosis,
2. Sturge-Weber,
3. ataxia-telangectgasia,
4.Carney’s Triad (Pheo, Gastric Leiomyoma, Pulm chondroma)

24. Pheochromocytoma
Diagnosis
1.Biochemical
2.Localization

25. 24h Urine Collection
Positive results (> 2-3 fold elevation):
24h U
catechols
> 2-fold elevation
24h U
total metanephrines
> 1.2 ug/d
24h U
VMA
> 3-fold elevation
Detected by high performance liquid chromatography

26. 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

27. Plasma free metanephrines sen 99%
spec 89%
Plasma catecholaminessen 84%
spec 81%

28. 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%

29. 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.)

30. Plasma Catecholamines
Plasma total catechols > 2000 pg/mL
SEN 85% SPEC 80%
False positives: same as for 24h urine testing, also with diuretics,
smoking

31. Suppression/Stimulation Testing
Clonidine suppression
Usually they decrease catecholamines
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

32. Localization: Imaging
90% adrenal,
Extra- adrenal sites- organ of Zuckerlandl, 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%

34. 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
False negative scan:
Drugs: Labetalol, reserpine, TCAs, phenothiazines
Must hold these medications for 4-6 wk prior to scan

36. Pheochromocytoma
1.Management
1.Preoperative
2.Operative
3.Postoperative
4.Pregnancy

37. 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, a-blockade
New anesthetic techniques
oAnesthetic agents
oIntraoperative monitoring: arterial line, EKG monitor,
CVP line, Swan-Ganz
Experienced & Coordinated team:
Endocrinologist, Anesthesiologist and Surgeon

38. Preop W/up
CBP, electrolytes, creatinine, INR/PTT
CXR
ECG
Echo (dilated CMY 2º catechols)

39. Preop Preparation Regimens
Combined a + b blockade
Phenoxybenzamine
Selective a
1
-blocker (ex. Prazosin)
Propanolol
Metyrosine
Calcium Channel Blocker (CCB)
Nicardipine

40. Preop: a + b blockade
Start at least 10-14d preop
Allow sufficient time for ECF re-expansion
Phenoxybenzamine
Drug of choice
Covalently binds a-receptors (a
1
> a
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)

41. 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

42. Evaluation of a 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 a adrenergic
blockade but not < 80/45.
ECG- free of ST changes for > 2 wks
Ventricular ectopic < 1 over 5 min

43. Preop: a + b blockade
b-blockade
Used to control reflex tachycardia and prophylaxis against
arrhythmia during surgery
Start only after effective a-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 doses
oIV 1-2 mg bolus

44. 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

45. Beta adrenergic blockers
Esmolol – selective B
1
for rapid intraop BP control
Bolus IV 250-500 µ/kg/min
Infusion 25 to 250 µ/kg/min
Labetolol –mixed +
ɑ Ɓ
Dose- 50- 200 mg/d PO
IV 0.25 mg/kg
Not used as asole drug due to unpredictable control of BP

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

47. 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

48. Preop: CCB
Nicardipine
Started po 24h to few weeks preop to cntrl BP and allow ECF 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 a-blocked

49. Preop: a + b blockade
Meds given on morning of surgery
Periop HTN:
IV phentolamine (Regitine)
Short acting non-selective a-blocker
IV Nitroprusside (NTP)
Periop arrhythmia: IV esmolol
Periop Hypotension: IV crystalloid +/- colloid

50. Pheo: Rx of HTN Crisis
IV phentolamine
IV NTP
IV esmolol
IV labetalol – combined a + b blocker

51. 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 a + b blockade or other preop prep
Tyrosine L-DopaDopamine
Norepinephrine
Epinephrine
PNMT
DBH
TH

52. 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

53. Premedication
Atropine or Glyco pyrolate to be omitted- causes tachycardia
Droperidol- antiemetic, blocks a adrenoceptor and inhibit
catecholamine uptake & promotes catecholamine release

54. 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,

55. INDUCTION
Essentially imp to give induction agents slowly along with close
monitoring of HR and arterial pressure
Thiopentone / propofol widely used
Etomidate –causes pain/ involuntary movement
Ketamine – not recommended
Multimodal – benzodiazapines+ opoid+ induction agent

56. 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

57. Neuromuscular blockade
Non depolarising 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

58. 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)

59. 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!

60. Adverse perioperative effects
Large tumor size
Prolonged duration of surgery
Inc levels of preoperative urinary catecholamines and
catecholamine metabolites

61. Laparoscopic adrenalectomy.
If tumor < 8cm
Slow CO2 insufflation….. Not > 12 mm Hg

62. Postop
Post 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

63. 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 %

64. Pheo: Unresectable, Malignant
a-blockade
Selective a
1
-blockers (Prazosin, Terazosin, Doxazosin) 1
st

line as less side-effects
Phenoxybenzamine: more complete a-blockade
b-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

65. 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 + bblocker prep
Resect tumor laprascopically
3
rd
trimester:
Phenoxybenzamine + bblocker prep…..2-3 wks
When 37 weeks: cesarian section followed by tumor resection

66. 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

67. THANK YOU