Transcript Perioperative Management of Pheochromocytoma

Perioperative Management of
Pheochromocytoma
M A Y 1 ST, 2 0 1 3
CATHERINE BARRETT
PGY2 INTERNAL MEDICINE
WESTERN UNIVERSITY
Objectives
 (1) Understand the impact on catecholamine secretion
and the resulting hemodynamic changes during
surgical resection of pheochromocytoma
 (2)Review the use of alpha blockers, calcium channel
blockers and metyrosine in the preoperative
preparation of pheochromocytoma patients and their
impact on intraoperative hemodynamics
 (3) Highlight the importance of anesthetic
management and the evolution of surgical technique
from laparotomy to a laporoscopic procedure
 (3) Highlight the need for long term follow up in
patients with a history of resected
pheochromocytoma
Pheochromocytoma
 Adrenal tumor originating from the chromaffin cells
of the adrenal medulla
 Paragangliomas are closely related tumors
originating from extra-adrenal sympathetic and
parasympathetic tissue
Epidemiology
 Accounts for 0.05-0.1% of essential hypertension
 Incidence of sporadic pheochromocytoma peaks in the 4th-5th
decade
 Familial causes of pheochromocytoma include:
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
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
VHL
NF1
MEN2
Germ line mutations in succinate dehydrogenase genes (SDHB, SDHD)
 Rule of “10”
 10% bilateral
 10% extraadrenal
 10% familial

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Closer to 25% in some reports
10% malignant
Clinical Presentation
 Symptomatic
 Hypertension (paroxysmal or “essential hypertension”) most
common presenting sign
 Classic triad of headache, palpitations and sweating in 10-40%
 Hypertensive crisis may develop in some patients resulting in
cardiovascular shock with stroke, MI or multiorgan failure
 Incidental
 Increasing incidence of incidental pheochromocytoma
detected on routine imaging
 Prior to 1985 <10% of pheochromocytoma incidental, now
>25%
 Familial
Clinical Presentation
Goldstein et al. 1999
Kopetschke et al. 2009
Diagnosis
 Biochemical Diagnosis
Metanephrines (24h urine or plasma)
 Catecholamines are metabolized in the chromaffin cells
to metanephrines independent of catecholamine
release
 Blood sampling should be performed at a supine
position after about 15-20 minutes of IV catheter
insertion
 Food, caffeine, strenuous physical activity or smoking
are not permitted 8-12 hours prior to testing
 Imaging
 CT or MRI for anatomic imaging
 MIBG for functional imaging/metastases

Management
 Surgery mainstay or treatment
 First surgical resection occurred in 1926 by Dr. César
Roux in Switzerland and Dr. Charles Mayo in the United
States
 Prior to the introduction of adrenergic blocking agents
and inotropes operative mortality reported up to 25%

Mortality rate up to 50% in operations on patients with unsuspected
pheochromocytoma
 Current mortality ranges from 0 to 3.0%
 large tumor size, prolonged duration of anesthesia and
increased levels of preoperative metanephrines are
independent risk factors for adverse perioperative events
Norepinephrine <510 pg/ml and Epinephrine <170 pg/ml
T0 = before induction of anesthesia
T1 = after induction of anesthesia, laryngoscopy, orotracheal intubation
T2 = end of pneumoperitoneal insufflation
T3 = adrenal gland manipulation
T4 = after adrenal gland resected
T5 = recovery room
All times significantly different with P< 0.05
Tauzin-Fin et al. 2004
Joris et al. 1999
Investigated hemodynamics in 8
consecutive patients undergoing
laparoscopic adrenalectomy.
Significant catecholamine release
associated with
pneumoperitoneum and adrenal
gland manipulation.
Challenges
 Challenges of pheochromocytoma management
 No randomized control trials
 Few prospective studies
 Approach to blockade varies widely by institution and mainly
based on preference and availability of medications
 Unanswered Questions
 Is preoperative blockade necessary in light of advances in
anesthesia and surgical technique?
 What is the preferred method of preoperative blockade?
Choice of medication
 Duration of therapy prior to surgery

Management Goals
 Normalize blood pressure, heart rate, and function of
other organs
 Restore volume depletion
 Prevent surgery-induced catecholamine storm and
its consequences on the cardiovascular system
Current Recommendations NANETS 2010
 North America Neuroendocrine Tumor Society
Recommend that all patients with pheochromocytoma or
paraganglioma receive appropriate preoperative medical
management to block the effects of released
catecholamines
 Choice of agent may include combined α1/2 blocker,
selective α1 receptor blocker or calcium channel blocker
 Beta blockade should be reserved for arrhythmias or
angina and should not be initiated until appropriate
alpha blockade achieved
 Volume expansion recommended to decrease
postoperative hypotension after tumor removal

No Preoperative Treatment
 Goldstein et al. 1999
 Retrospective review of 104 patients from 1950 to 1998
 Sixteen patients in the early years of the series
underwent surgical resection without preoperative
blockade
 Subjectively, the surgical course was classified as
relatively smooth in 5 patients and complicated in 11
(69%)
 Nevertheless, there was no perioperative complications
attributable to hemodynamic instability.
Case series of 30
pheochromocytoma
resections.
First 13 patients received no
preoperative preparation.
Phentolamine used during
surgery to control blood
pressure variations.
This patient illustrates the
wide variation in blood
pressure that can be seen in a
patient who has not
undergone pretreatment
prior to surgery.
Ross et al. 1967
113 patients,
retrospective study
from the Cleveland
Clinic (1977 to 1994)
This paper argues that
preoperative
preparation is not
necessary as they found
no difference in
intraoperative
hemodynamics with
pretreatment.
However, this paper
only accounts for
medications in the 24
hours prior to surgery
and does not document
the doses of
medications.
Ulchaker et al. 1999
Phenoxybenzamine
Dibenzyline
In use since the 1950s
Irreversible, noncompetitive alpha 1/2 adrenoreceptor blocker
Long-lasting effect that diminishes only after de novo receptor
synthesis
 Oral and IV titration protocols
 The initial dose of phenoxybenzamine is usually 10 mg twice a
day and is increased up to a total daily dose of 1 mg/kg
 Side effects
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Postural hypotension
Reflex tachycardia
Nasal congestion
Somnolence
Postoperative hypotension
Prys-Roberts 2002
 62 patients with pheochromocytoma from 1956-1982
 51 patients received preoperative pheonoxybenzamine
Median dose was 160mg/day
 42 patients received IV infusion of phenoxybenzamine the evening
before or morning of surgery
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11 patients from 1956-1963 received no preoperative treatment
Operative and six month mortality was zero
Stenstrom et al. 1985
Day
PXB
(10mg)
PP
(40mg)
Supine
BP
Standing
BP
Supine
HR
Standing
HR
1
0-0-1
0-0
AM: PM:
AM: PM:
AM: PM:
AM: PM:
2
1-0-1
0-0
3
1-1-1
0-0
4
1-1-2
0-0
5
2-1-2
1-1
6
2-2-2
1-1-1
7
2-2-3
1-1-1
8
3-2-3
1-1-1-1
9
3-3-3
1-1-1-1
10
3-3-3
1-1-1-1
11
3-3-3
1-1-1-1
12
3-3-3
1-1-1-1
13
3-3-3
1-1-1-1
14
3(-3)
1(-1)
PXB = Phenoxybenzamine; PP = Propranolol
Weight
(kg)
Selective Competitive α1 Receptor Blockers
 Specific, competitive alpha 1 adrenergic antagonist
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Doxazosin (Cardura)
 In use since 1988
 Half life 16-30 hours
 Dose range: 1-16mg per day
Prazosin (Minipress)
 Half life 2-3 hours
 Dose range: 2-5mg BID-TID
Terazosin (Hytrin)
 Half life 12 hours
 Dose range: 2-5mg per day
Urapidil
 Continuous infusion 10-15mg/hour 3 days prior to OR
 Half life 2-4.8hours
Selective Competitive α1 Receptor Blockers
 Side effects
 Postural hypotension
 Advantages:
 No reflex tachycardia
 Absence

of alpha 2 blockade on presynaptic receptors
Decreased risk of hypotension postoperatively
Prys-Roberts 2002
Phenoxybenzamine vs Doxazosin
 73 patients from 1995-2007
From 1995 to 2003:
 31 patients blocked with phenoxybenzamine
 25 also received propranolol
 55% achieved adequate pretreatment with target MAP < 100
 From 2003 to 2007:
 42 patients blocked with doxazosin
 37 also received propranolol
 53% achieved adequate pretreatment with target MAP < 100
 All patients received saline preoperatively (2L/day) x 2 days

No statistical difference between the intraoperative hemodynamics in the patients
treated with phenoxybenzamine vs doxazosin. Higher doses of esmolol were required
in the phenoxybenzamine group (P<0.05) but dosages of other drugs did not differ.
Bruynzeel et al. 2010
Phenoxybenzamine vs Doxazosin
 Retrospective review from March 2003 to June 2008
 31 patients treated with phenoxybenzamine
 Initial dose 5-10mg BID and increased by 10-20mg every 2-3
days to maximum dose of 60mg/day
 36 patients treated with doxazosin
 Initial dose was 4mg daily and increased by 4mg increments
every 3-5 days to maximum dose of 16mg/day
 If the blood pressure was not <160/100 then
additional antihypertensive agent added (CCB or
ACE)
 Beta blockers were used to control tachycardia
Zhu et al. 2010
Zhu et al. 2010
Fourteen patients (38.9%) pretreated with DOX required supplementary
antihypertensive therapy vs five patients (16.1%) in the PXB group (P<0.05).
Fewer patients required beta blocker treatment in the DOX group vs PXB
group (11.1 vs 77.4%, P<0.05)
Zhu et al. 2010
Mayo Clinic vs Cleveland Clinic
 Mayo clinic (October 2003 to November 2006)
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Phenoxybenzamine 1-4 weeks prior to surgery titrated to achieve
orthostatic hypotension
2-3 days prior to surgery, beta blocker added if heart rate > 80
If BP still elevated, a CCB was added (nicardipine)
If the tumor was large, metyrosine was added 2-3 days prior to
surgery
 Cleveland clinic (July 2005 to May 2009)
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Normotensive or intermittent hypertensive patients received CCB
Alpha1 receptor antagonist was added in increments of 2mg every
third day to a maximum of 10mg
If tachycardia developed and/or the patient had a history of CAD
then a beta blocker was used
Mayo Clinic vs Cleveland Clinic
 Anesthesia records were electronic
 Intraoperative hemodynamics
 Greatest intraoperative BP
 Interval in minutes SBP > 30% of preinduction baseline
 Interval in minutes that the SBP was 200mmHg
 Lowest intraoperative BP
 Interval in minutes that the systolic BP was 30% than the
preinduction baseline
 Greatest and lowest heart rates
 Duration of tachycardia (>100 beats/min) and bradycardia (50
beats/min)
Weingarten TN et al. 2010
Mayo Clinic:
- 49 patients treated
with PXB
- 1 patient treated with
alpha 1 antagonist
Cleveland Clinic:
- 5 patients treated
with PXB
- 24 patients treated
with alpha 1
antagonist (prazosin,
doxazosin, terazosin)
- 1 patient with
losaratan
- 4 patients received no
treatment
Weingarten TN et al. 2010
Weingarten TN et al. 2010
Postoperative course similar between both sites. The complication rates were low:
- 1 pneumothorax at MC
- 1 case of surgical re-exploration for bleeding at the CC
- 1 case of pulmonary edema at the CC
- 1 case of pneumonia at CC
Weingarten TN et al. 2010
Adequate Alpha Blockade
 No blood pressure reading >160/90 for 24 hours
prior to surgery
 Orthostatic hypotension with readings > 80/45
should be present
 ECG should be free of ST changes for at least one
week
 No more than one PVC q5 minutes
Patients with a MAP above 100 (n=25) experienced more and longer
intraoperative episodes of SBP above 160 (true after adjustment for
tumor size, pathology, procedure type).
Bruynzeel et al. 2010
Calcium Channel Blockers
 Block NE-mediated calcium influx into vascular smooth
muscle, controlling hypertension and tachyarrhythmias
 Generally felt to be less effective than alpha blockade
 Indications:
 Supplement adrenoceptor blockers in patients with
inadequate blood pressure control
 Replace
adrenoceptor blockers in patients with
intolerable side effects
 Advantages
 Decreased orthostatic hypotension and postoperative
hypotension
Nicardipine
 105 patients from 1991 to 2002
 Nicardipine 20-60mg/day divided TID x 3-10 days
 All patients received nicardipine 20mg one hour prior to surgery and
a continuous infusion at 0.5-2.0mg/kg/min
 Hypertensive crises were treated by increasing the infusion rate
from 2-10mg/kg/min or by IV boluses of 1-2mg
 Tachycardia (HR > 120) were treated with esmolol boluses
(0.5mg/kg)
 Once the main vein of the tumor was clamped infusions were
stopped
 If hypotension occurred, an infusion of colloid + IV ephedrine (39mg) was administered
 Persistent hypotension treated with continuous EPI/NE
All hypertensive episodes were
controlled with nicardipine.
Persistent hypotension in 13
patients requiring volume
expansion and ephedrine. Two
patients required NE infusion.
Three deaths occurred in this
series. One patient died secondary
to massive hemorrhage. The
second patient died from
cardiovascular collapse in the OR
followed by multiorgan failure in
the ICU. The final patient died
from a postop pulmonary
embolism.
Lebuffe G et al. 2005
Metyrosine
 Used since the late
1970s
 Alpha methyl
tyrosine 0r
metyrosine (Demser)
 Inhibits tyrosine
hydroxylase
 It significantly but
does not completely
depletes
catecholamine stores
Metyrosine
 Maximum effect seen after about 3 days of treatment
 Typically used in combination with an alpha blocker
 Start at 250mg BID-TID, increasing by 250-500mg
q2-3 days to max 1.5 to 2.0g per day
 Readily crosses the blood-brain barrier
 Side effects (more common if age > 65)
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Sedation
Depression
Anxiety
Extrapyramidal signs (rare)
Diarrhea
Metyrosine
 25 patients from 1982-1989
 Phenoxybenzamine started at 10mg BID and titrated
to 0.5mg/kg/day in divided doses
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
Mean dose: 28mg/day (10-60mg/day)
Mean duration: 15 days (1-35 days)
 Propranolol or atenolol added in 5 patients with
persistent tachycardia
 19 patients were also treated with metyrosine, initial
dosage of 250mg every 6 hours increased up to max
4g/day
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Mean dose: 833mg/day (500-1500mg/day)
Mean duration: 10 days (4-21 days)
Perry et al. 1990
Meytrosine
 Adequate preparation:
 Absence of symptoms
 Normalization of BP and HR
 Presence of mild (<20mmHg) orthostatic hypotension
 The total dose of phenoxybenzamine was reduced
after the addition of metyrosine in some patients
 On the day of surgery patients received 1mg/kg
phenoxybenzamine and 1g metyrosine
 1 patient received prazosin
Perry et al. 1990
Perry et al. 1990
There was no statistically significant difference in the intraoperative
hemodynamic measurements between the two groups. The authors
felt the OR was smoother in the metyrosine treated group with less
need for intraoperative medications but this was not significant.
Patients treated with metyrosine required less crystalloid during the
OR but not in the postoperative period.
Perry et al. 1990
Beta Blocker
 Atenolol, propranolol
 Loss of beta receptor mediated vasodilation in a patient
with unopposed alpha induced vasoconstriction can lead
to dangerous increases in blood pressure
 Useful for preoperative control of tachyarrhythmias or
angina
 Particularly useful in combination with phenoxybenzamine as
tachycardia is a common side effect of alpha blockade
 Labetalol (PO) has a fixed ratio of α to β antagonist
activity that is about 1:7 and therefore should not be used
for preoperative blockade unless another alpha blocker
used
Pacak 2007
Volume Expansion
 Patients are volume constricted b/c of alpha 1
stimulation
 Normalization of blood volume minimizes the
possibility of protracted hypotension at the time of
tumor removal
 Historically patients received blood transfusions
preoperatively
 Standard now is a high salt diet +/- preoperative
saline infusion
Pacak 2007
Anesthesia
 Increasing depth of anesthesia and muscle relaxation
common practice to reduce blood pressure variations
 Nicardipine
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Arterial vasodilation
Reduced afterload
Improvement left ventricular function
Preservation venous return
Response in 1-3 min
Half life is 3-7 min
 Phentolamine
 Competitive alpha 1 and weak alpha 2 adrenergic receptor antagonist
with short duration action
 Sodium nitroprusside
 Decreases preload and afterload
 Onset immediate, recovery in 1-2 min
Anesthesia
 Nitroglycerin
 Rapid venodilator
 Reduces preload
 Increases coronary blood flow by dilating the collateral vessels
and suppressing coronary vasospasm
 High doses produce arteriolar vasodilation
 Esmolol
 Ultra short acting cardiac selective beta blocker
 Onset in 60sec
 Duration 10-20min
 Phenylephrine
 Norepinephrine
Advances in Surgical Approach
 Laparotomy
 Prior to advances in imaging technique, manual exploration
was required to exclude accessory tumor deposits
 Still useful in large tumors or metastatic disease
 Laparoscopic surgery
 Since 1992
 Initial concern of increased cardiovascular risks with CO2
insufflation, increased abdominal pressure and manipulation
of adrenal gland
 Up to 10cm tumors can be removed
 Less pain, reduced hospital stay and more rapid return to
normal activity
Postoperative Care
 May need monitored setting such as the ICU
 Blood glucose monitoring as increased risk of
developing hypoglycemia
Long Term Follow Up
 Recurrence rate of 17%
 More common in the setting of:
 Extraadrenal disease (33%) vs adrenal disease (14%)
 Familial (33%) vs nonfamilial (13%)
 Pathology does not determine malignant potential of
pheochromocytoma

Requires presence of tumor deposit outside of chromaffin
tissue
Algorithm for genetic testing for
genes associated with
pheochromocytoma. The algorithm
should be applied if there is a family
hx of pheochromocytoma, the
patient is < 50 years old or there are
multiple, malignant or bilateral
tumors. The biochemical phenotype
of the tumor should also be
considered in selection of the most
appropriate genes to test.
Pacak et al. 2006
Malignant Pheochromocytoma
 Incidence ranges 3-36% depending on genetic
background and tumor localization
 Overall five year survival 34-60%
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Longer survival in metastatic bone disease
Shorter survival with liver or lung lesions
 External beam radiation for bony metastases
 Combination chemotherapy with cyclophosphamide,
vincristine and dacarbazine
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Tumor regression and symptom relief in up to 50% of patients
Response short lived
 MIBG therapy

Dosing regimen still unclear
Conclusions
 Surgery is the mainstay of treatment for
pheochromocytoma but is associated with secretion
of catecholamines which can lead to hemodynamic
compromise
 Preoperative blockade does not completely eliminate
blood pressure variation during surgery but ensures
a relatively smoother course than without treatment
 Further advances in the care of pheochromocytoma
patients will be based on preoperative preparation,
anesthetic management and surgical technique as all
are important components of its management
Conclusions
 All patients with pheochromocytoma will require
long term follow up as there remains a life long risk
of recurrence
 Special considerations to genetic testing should be
made in the appropriate clinical circumstance
References
 Goldstein RW et al. Clinical Experience Over 48 Years
with Pheochromocytoma. Annals of Surgery. 1999.
229(6):755-766
 Guerrero et al. Clinical Spectrum of Pheochromocytoma.
J Am Coll Surg. 2009 209:727-732
 Chen H et al. The NANETS Consensus Guideline for the
Diagnosis and Management of Neuroendocrine Tumors:
Pheochromocytoma, Paraganglioma and Medullary
Thyroid Cancer. Pancreas. 2010. 39(6):775-783
 Pacak K. Preoperative Management of the
Pheochromocytoma Patient. The Journal of Clinical
Endocrinology and Metabolism. 2007. 92(11):4069-4079
References
 Tauzin-Fin P et al. Effects of perioperative alpha 1 block
on haemodynamic control during laparoscopic surgery
for pheochromocytoma. British Journal of Anesthesia.
2004. 92 (4):512-517
 Kopetschke R et al. Frequent incidental discovery of
pheaochromocytoma: data from a german cohort of 201
pheochromocytoma. European Journal of
Endocrinology. 2009. 161:355-361
 Joris JL et al. Hemodynamic Changes and
Catecholamine Release During Laparoscopic
Adrenalectomy for Pheochromocytoma. Anesth Anal
1999. 88:16-21
References
 Stenstrom G et al. Influence of Pre-operative Treatment
with Phenoxybenzamine on the Incidence of Adverse
Cardiovascular Reactions during Anesthesia and Surgery
for Pheochromocytom. Acta Anaesthesiol Scand. 1985.
29: 797-803
 Pacak K et al. Pheochromocytoma: recommendations for
clinical practice from the first international symposium.
2006. www.nature.com/clinicalpractice/endmet
 Kinney MAO et al. Perioperative Management of
Pheochromocytoma. Journal of Cardiothoracic and
Vascular Anesthesia. 2002. 359-369
References
 Lenders JWM et al Pheochromocytoma. Lancet. 2005.
366:665-675
 Bruynzeel H et al. Risk factors for hemodynamic
instability during surgery for pheochromocytoma. J Clin
Endocrinol Metab. 2010. 95(2) 678-685
 Ulchaker JC et al. Succesful outcomes in
pheochromoctoma surgery in the modern era. The
Journal of Urology. 1999. 161:764-767
 Zhu Y et al. Selective a1-adrenoceptor antagonist
(controlled release tablets) in preoperative management
of pheochromocytoma. Endocr. 2010, 38:254–259
References
 Weingarten TN et al. Comparison of Two Preoperative Medical
Management Strategies for Laparoscopic Resection of
Pheochromocytoma. 2010. 76: 508.e6 –508.e11
 Prys-Roberts C et al. Efficacy and Safety of Doxazosin for
Perioperative Management of Patients with
Pheochromocytoma. World J. Surg. 2002. 26, 1037–1042.
 Perry RR et al. Surgical Management of Pheochromocytoma
with the use of Metyrosine. Annal Surgery. 1990. 212(5): 621–
628
 Lebuffe G. et al. The effect of calcium channel blockers on
outcome following the surgical treatment of
phaeochromocytomas and paragangliomas. 2005. (60):439–
444