Ir J Med Sci
DOI 10.1007/s11845-015-1383-5
REVIEW ARTICLE
Therapeutic goals in patients with pheochromocytoma: a guide
to perioperative management
N. Azadeh1 • H. Ramakrishna2 • N. L. Bhatia5 • J. C. Charles3 • F. Mookadam4
Received: 11 May 2015 / Accepted: 16 November 2015
 Royal Academy of Medicine in Ireland 2015
Abstract
Introduction Pheochromocytomas are rare neuroen-
docrine tumors of the adrenal medulla that may present
with protean manifestations. Surgical resection is the
mainstay of therapy and patients are at risk of significant
hemodynamic and circulatory complications mainly
attributable to catecholamine excess. The mainstay of
medical therapy in order to optimize patients for surgery
includes: alpha-blockers, beta-blockers, calcium channel
blocker and other agents to achieve normal blood pressure,
heart rate, as well as normal volume status. Understanding
the pathophysiology of pheochromocytoma, the pharma-
cology of medications used, and recognizing postoperative
complications will impact patient outcomes.
Conclusion A multidisciplinary team approach is best
throughout the perioperative period to prevent potential
complications that arise. The hospital physician, inten-
sivist, anesthetist and cardiovascular specialist play a piv-
otal role in the management of patients with
pheochromocytoma. In addition to the pharmacologic and
volume recommendations, a multidisciplinary discussion
allows for seamless implementation of an organized plan of
care.
& N. Azadeh
azadeh.natalya@mayo.edu
1
Department of Internal Medicine, Mayo Clinic, Scottsdale,
AZ, USA
2
Department of Anesthesia, Mayo Clinic, Phoenix, AZ, USA
3
Division of Hospital Internal Medicine, Mayo Clinic,
Phoenix, AZ, USA
4
Division of Cardiovascular Diseases, Mayo Clinic,
Scottsdale, AZ, USA
5
Cardiovascular Consultants, LTD, Glendale, AZ, USA
Keywords Pheochromocytoma
Hemodynamics

Perioperative
Neuroendocrine tumors
Illustrative case
A 67-year-old male with refractory hypertension on a
complex 6-drug medical regimen including metolazone,
irbesartan, furosemide, nifedipine, clonidine and metopro-
lol, presents to the clinic for further evaluation of resistant
hypertension. His only symptoms were that of fatigue and
dizziness with recent unintentional weight loss.
Laboratory testing revealed elevated urine and plasma
normetanephrine levels. Abdominal computerized tomo-
graphic imaging (CT) revealed an adrenal mass, confirmed
by a meta-iodobenzylguanidine scintiscan (MIBG) to be a
solitary pheochromocytoma. His home regimen of antihy-
pertensives was discontinued and phenoxybenzamine was
initiated and surgical resection was scheduled.
Within 72 h of starting alpha blockade therapy, the
patient developed debilitating orthostasis which prompted
admission for inpatient management. During the hospital
course, phenoxybenzamine was initiated at a dose of 10 mg
daily aided by gradual volume replenishment necessitated
by symptomatic orthostasis. Supine blood pressure was
210/110 mmHg, which dropped to 150/80 mmHg while
standing.
Phenoxybenzamine was aggressively increased to
60 mg every 6 h with liberal volume replenishment (a total
of 10 l infused over 36 h) until normotension was achieved
and orthostasis resolved. The remainder of the periopera-
tive course was uneventful, with successful surgical
resection, followed by gradual reduction and ultimate dis-
continuation of all antihypertensives in the postoperative
period.
123

Introduction
Pheochromocytomas are rare neuroendocrine tumors of the
adrenal medulla originating from chromaffin cells. These
cells produce either norepinephrine or epinephrine in large
amounts and the release of these substances, specifically
during surgical resection can result in potentially lethal
complications. Surgical resection is the mainstay of therapy
and patients are at risk of significant hemodynamic and cir-
culatory complications mainly attributable to catecholamine
excess. A detailed understanding of the pathophysiology and
careful management in the perioperative period is essential
to reduce the risk of morbidity and mortality in these patients.
Since the 1950s, mortality associated with pheochromo-
cytoma and paraganglioma surgery has gradually declined,
most likely as a result of meticulous attention to perioperative
control of arterial pressure and optimization of volume status.
However, there are no formal studies that have systematically
been performed to define the optimal pharmacologic treatment
regimen for patients with pheochromocytoma in the periop-
erative period. Recently published clinical practice guidelines
[3] provide a detailed discussion of pheochromocytoma and its
management. This paper aims to present a practical practice-
based discussion of the physiologic, biochemical, and hemo-
dynamic aspects of patients with pheochromocytoma based on
a review of the published literature, and to summarize best
practices for a perioperative management strategy.
Optimal medical management and preoperative as well
as intraoperative and postoperative management are
dependent upon a medical team that incorporates a multi-
disciplinary approach in a specialized center to include
contributions from: Endocrinology, Surgery, Anesthesiol-
ogy/ICU, cardiology, and clinical biochemistry.
Discussion
Symptoms and signs of pheochromocytoma occur as a result
of uncontrolled catecholamine release in the form of nore-
pinephrine, epinephrine, and dopamine (Table 1) [1]. Severe
Table 1 Effects of vasoactive
Receptor
amines
Epinephrine b2 (and some a)
Norepinephrine b1- and a1
Dopamine Dopamine
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Ir J Med Sci
hypertension and arrhythmias may be seen, especially in the
setting of adrenal manipulation during surgical excision. This
may be followed by severe hypotension following resection of
the tumor. Further complicating the hemodynamic manage-
ment of these patients is the down-regulation of adrenergic
receptors secondary to prolonged exposure to high cate-
cholamine levels. Epinephrine’s predominant effect on b2-
adrenoreceptors may result in severe vasodilation and
hypotension. Norepinephrine affects predominantly b1- and
a1-adrenoreceptors which causes vasoconstriction resulting
in hypertension. Both of these substances can increase heart
rate and may precipitate arrhythmias. Epinephrine is also is a
catabolic stimulant, which induces lipolysis, ketogenesis,
thermogenesis and glycolysis resulting in hyperglycemia and
fever, both of which may need to be addressed perioperatively
if present. The treatment of choice for pheochromocytoma is
surgical resection, but this may be fraught with risks as a result
of the catecholamine excess leading to cardiovascular and
hemodynamic consequences [2].
Data regarding the perioperative medical management is
largely based on retrospective studies. Currently, the
accepted consensus is that alpha (a) adrenoceptor blockade
should be the mainstay of management [2] with adjunctive
pharmacotherapy such as calcium channel blockers and
beta (b) blockers when needed to achieve target blood
pressure and heart rate control, and to optimize cardio-
vascular outcomes [3]. In some instances, agents such as
metyrosine (a-methyltyrosine) can be useful in patients
with highly active or widely metastatic disease, but this is
extremely uncommon.
There are no data to support the timing of adrenergic
blocker initiation when preparing a patient for surgical
resection; however, the general consensus is to aggres-
sively aim for normal blood pressure (BP) and heart rate
and rhythm (HR), endocrine society guidelines recommend
BP \130/80 [3]. The Roizen Criteria proposed in 1982 [5]
attempt to objectively gauge the efficacy of adequate pre-
operative alpha blockade and include (Table 2): (1) no in-
hospital blood pressure [160/90 mmHg for 24 h prior to
surgery; (2) no orthostatic hypotension with blood
Hemodynamic effect Biochemical effect
Vasodilation Lipolysis
Hypotension Ketogenesis
Tachycardia Thermogenesis
Arrhythmia Glycolysis resulting in hyperglycemia
Vasoconstriction Lipolysis
Hypertension Ketogenesis
Tachycardia Thermogenesis
Arrhythmia Glycolysis resulting in hyperglycemia
Hypertension
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Table 2 The Roizen Criteria

reflecting adequacy of
preoperative alpha blockade
No in-hospital blood pressure [160/90 mmHg for 24 h prior to surgery
No orthostatic hypotension with blood pressure \80/45 mmHg
No ST or T wave changes for 1 week prior to surgery
No more than five premature ventricular contractions per minute

pressure \80/45 mmHg; (3) no ST or T wave changes for
1 week prior to surgery; (4) no more than five premature
ventricular contractions per minute. These guidelines have
been in use for over 2 decades; His group also reported in
1986 that mortality from pheochromocytoma resection
decreased from 13 to 45 % before alpha blockade to 0–3 %
once blockade was instituted [6].
Concurrently, volume expansion is needed to avoid
prolonged/severe hypotension as a result of catecholamine
surges and/or alpha blockade [3, 4]. Central venous pres-
sure monitoring, intra-arterial blood pressure monitoring
and continuous ECG in an intensive care setting allows for
more reliable monitoring of hemodynamics. However,
patients who are hemodynamically stable pre-operatively
may be safely cared for on a non-ICU monitored room. All
patients with a diagnosis of pheochromocytoma should
have echocardiography to identify potential catecholamine-
induced cardiomyopathy. Baseline laboratory testing can
assist in identifying renal dysfunction.
Pharmacotherapy
Alpha (a) blockade has been the mainstay of preoperative
preparation for pheochromocytoma patients for decades [7]
and historically is reputable with a track record of safety.
To date, there are no randomized trials comparing the
efficacy of various strategies for preoperative blood pres-
sure control [8, 9] (Table 3). Retrospective studies support
the use of alpha blockers as the first choice drug, starting
7–14 days prior to surgery. In most centers, a combination
of alpha-adrenergic and beta-adrenergic blockade and
calcium channel blockers are routinely used.
Alpha (a) receptor blockade
Alpha-adrenergic blockade is typically administered starting
10–14 days preoperatively which, in addition to normalizing
blood pressure, also aids in expanding the highly contracted
intravascular volume, an often underappreciated issue. The
risk of intravascular volume depletion is especially signifi-
cant in patients with catecholamine-induced cardiomyopa-
thy and myocardial infarction and those with refractory
hypertension. Successful alpha blockade is reflected by
normalizing blood pressure with mild orthostasis.
Phenoxybenzamine (a long lasting blocker) is the drug
most commonly used at doses ranging from 10 mg twice a
day titrated to a total daily dose of 1 mg/kg. The general
dose considered to be effective is 1 mg/kg; however, doses
should be adjusted to achieve normotension in each patient
on a case by case basis. Other more specific, short-acting
and competitive a-1 antagonists include prazosin, tera-
zosin, and doxazosin. The main adverse effect of this class
of medications is hypotension, and thus it is prudent to start
at lower doses and titrate until target cardiovascular
parameters are reached (a target blood pressure of less than
130/80 mmHg while seated and greater than 90 mm Hg
systolic while standing seems reasonable, with a target
heart rate of 60–70 bpm seated and 70–80 bpm standing)
[3]. Additionally, given the longer half-life of Phenoxy-
benzamine, patients can remain hypotensive for hours after
surgery [1]. Volume expansion is beneficial in preventing
severe hypotension and hypoperfusion in the setting of
preoperative aggressive alpha blockade. The recommen-
dation is that patients are started on a high sodium and fluid
diet when initiating alpha blockade, as this can correct
previous volume contraction and prevent dangerous acute
drops in blood pressure during the pre-operative period. In
the post-operative setting patients can be at risk of dan-
gerous hemodynamic swings if not appropriately resusci-
tated with fluids. Care should be taken in patients with
congestive heart failure or renal failure who are prone to
adverse effects of intravenous fluid resuscitation.
Beta blockers
After successful alpha blockade, beta-adrenoceptor block-
ing agents can be used to achieve target heart rates in the
control of tachyarrhythmias. Beta blockade should never be
used in isolation and added only after an adequate length of
alpha blockade owing to the catastrophic hypertensive
crisis that may ensue with unopposed alpha receptor
stimulation [10, 11]. Agents such as propranolol can be
used starting at a dose of 10 mg every 6 h and titrating to
achieve hemodynamic targets. Beta blockers should be
used cautiously in patients with cardiomyopathy or evi-
dence of congestive heart failure. There is no evidence to
support the preference of beta1-selective adrenergic
receptor blockers over nonselective beta-adrenergic
receptor blockers. Labetalol, a more potent inhibitor of beta
than alpha activities (alpha:beta of 1:5) should not be used
as the initial therapy because it can result in paradoxical
hypertension or even hypertensive crisis [3].

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Table 3 Agents to be used for achievement of hemodynamic parameters pre and postoperatively
Drug class Example/dose Mechanism Target Benefit Adverse effects

Alpha blocker Phenoxybenzamine— Alpha 1-adrenergic Starting Mainstay of therapy Postural hypotension
start 10 mg bid— blockade leading 10–14 days Normalizes BP
Usual dose 1 mg/ to vasodilation before surgery
Aids expand intravascular
kg/day Titrate till volume
Prazosin 2–5 mg achieve normal
Terazosin 2–8 mg BP w/mild
orthostasis
Doxazosin 2–8 mg
Beta blocker Propranolol 10 mg Beta-adrenergic Start at low dose Helps target BP and HR Only to be used after patient
Q6 h blockade e.g., control is on maximal dose of
Atenolol propranolol alpha blocker
25–50 mg/day 10 mg Q6 and Use cautiously in patients
increase as with cardiomyopathy
tolerated to
target HR
60–80
Start after at least
3–4 days of
alpha blocker
Calcium Nicardipine SR Reduction of Normotension Can be used as Augments BP control when
channel 30 mg bid starting catecholamine- monotherapy if intolerant other agents inadequate or
blocker dose mediated to other agents. Beneficial intolerant side effects of
Nifedipine calcium influx in in cardiomyopathy or alpha blockers
30 mg/day starting vascular smooth coronary vasospasm.
dose, titrate to muscle Common first adjust to
60 mg/day alpha blocker therapy
Amlodipine
5–10 mg/day
Catecholamine Metyrosine 250 mg Competitively Normotension Used in metastatic disease Significant side effects:
synthesis q6 h ? titrate over inhibits tyrosine adjunctive to other sedation, depression,
inhibitors days to 1000 mg hydroxylase, the medications or for diarrhea, anxiety,
q6 h rate-limiting step intolerance to other nightmares, crystalluria
in catecholamine medical regimens and urolithiasis,
biosynthesis galactorrhea, and
extrapyramidal signs

Calcium channel blockers
Calcium channel blockers can be used as an adjunct to help
control BP and HR. One of the life threatening manifes-
tations of catecholamine excess can be coronary artery
vasospasm. In this situation calcium channel blockers can
be used as an adjunct to help control vasospasm as well as
tachyarrhythmias. The dihydropyridine calcium channel
blockers remain useful in the perioperative period largely
because they are relatively easy to titrate and less likely to
cause orthostatic hypotension [10]. Functioning through
the inhibition of catecholamine-mediated calcium influx in
vascular smooth muscle (they do not cause reflex tachy-
cardia), nicardipine has been well studied and most widely
used in the perioperative setting [12, 13]. Nicardipine at a
starting dose of 30 mg twice daily of the sustained release
preparation is given orally to control blood pressure pre-
operatively and is given as an intravenous infusion intra-
operatively. Although there is less collective experience
with calcium channel blockers than with alpha- and beta-
adrenergic blockade, when used as the primary mode of
antihypertensive therapy, they may be as effective [14].
Clearly, the exclusive use of calcium channel blockers
for the perioperative management of patients with cate-
cholamine-secreting tumors does not prevent all of the
hemodynamic changes seen in this patient group; however,
its use has been associated with low morbidity and mor-
tality [15]. The main role for the calcium channel blocker
class of drugs may be either to supplement the combined
alpha- and beta-adrenergic blockade protocol when blood
pressure control is inadequate or to replace the adrenergic
blockade protocol in patients with intolerable side effects.
Other agents
Catecholamine synthesis inhibitors have also been used, a -
Methyl-L-tyrosine or metyrosine (Demser, Aton Pharma,
Lawrenceville, NJ) competitively inhibits tyrosine

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hydroxylase, the rate-limiting step in catecholamine
biosynthesis. It significantly, but not completely, depletes
catecholamine stores with maximum effect after about
3 days [16, 17]. Again, it is most useful as an adjunct to
full alpha blockade, perhaps most useful in those with
widely metastatic disease or those whose tumor is highly
active. The limited availability of this drug and the effec-
tiveness of alpha blockade make its use rare.
Substances to avoid perioperatively
There are various drugs/substances that can stimulate cat-
echolamine release and should be avoided [3].
• Glucagon
• Corticosteroids
• Histamine
• Angiotensin II
• Vasopressin
• Sympathomimetic drugs: for example, metham-
phetamine and pseudoephedrine
• Medications which decrease catecholamine reuptake,
such as tricyclic antidepressants (TCAs), and mono-
amine oxidase inhibitors (MAOIs)
• Serotonin reuptake inhibitors
• Dopaminergic agents such as antipsychotics, antiemet-
ics (e.g., metoclopramide, prochlorperazine)
• Beta-adrenergic receptor blockers (before adequate
alpha blockade)
• Opioid analgesics
• Neuromuscular blocking agents: Succinylcholine,
tubocurarine, atracurium.
Preoperatively patients should be counselled on diet.
Certain foods which contain sympathomimetic amines
(e.g., tyramine) such as in cheese, wine, and avocados, may
provoke catecholamine release. Dietary advice should also
include consumption of a high salt diet with liberal fluid
intake to aid volume expansion and avoid hypotension
perioperatively. Additional perioperative measures include
anxiolytics and strict glucose control, the latter to avoid
worsening volume depletion that may occur during obli-
gatory glycemic diuresis.
Lifestyle advice should include avoidance of strenuous
physical activity, tobacco and alcohol consumption.
Preoperative cardiovascular evaluation
A thorough preoperative cardiovascular evaluation is rec-
ommended prior to surgical resection. The 12- lead ECG is
mandatory to assess the presence and severity of LV
hypertrophy, arrhythmia, bundle branch block and ische-
mia. Preoperative echocardiography in addition is indicated
to assess global bi ventricular systolic and diastolic
function, including strain-rate assessment. Dilated car-
diomyopathy should be ruled out in patients with severe
and long-standing pheochromocytomas.
Anesthesia evaluation and intensive care evaluation
and management
Pheochromocytomas may represent significant manage-
ment difficulties to the anesthesiologist, from a hemody-
namic perspective [18]. The induction of anesthesia,
especially in a patient with an undiagnosed and untreated
pheochromocytoma may precipitate a hypertensive crisis
which can be life threatening with a published 80 %
mortality [5].
Anesthesiologists (ASA) monitors plus intra-arterial
monitoring is the gold standard in pheochromocytoma
resection for beat to beat blood pressure monitoring in the
United States. In addition, central venous pressure (CVP)
monitoring is essential and widely considered the standard
of care, allowing for rapid delivery of vasoactive agents
into the central circulation. Patients with poor left ven-
tricular function as a result of catecholamine cardiomy-
opathy, pulmonary hypertension or significant myocardial
disease may benefit from pulmonary artery catheter and
intraoperative TEE placement/monitoring [19]. In hemo-
dynamically unstable patients, the use of pulmonary
artery catheters may be of greater utility following tumor
resection, for more accurate fluid management in the
intensive care unit [20]. Intraoperative TEE is another
useful monitor for volume status and ventricular function
assessment. Intraoperative management should always
include close communication with the surgeon allowing
for large volume fluid bolus administration just prior to
tumor ligation. Data suggest that massive fluid resuscita-
tion is more effective than vasopressor administration in
these situations [21]: It is not uncommon for the anes-
thesiologist to administer 2–3 l of fluid (crystalloid and
colloid) prior to tumor ligation, in addition to rapidly
discontinuing all vasodilators. In terms of vasoactive
agents, dopamine, norepinephrine and vasopressin have
been used; however, in refractory circulatory shock, acute
vasopressin therapy has been used with success [22].
Because vasopressin does not rely on peripheral adren-
ergic receptors for its pressor effect, it is particularly
effective for refractory hypotension following tumor
resection. In addition, once all agents have been used to
little or no effect, the use of intravenous methylene blue
can be considered. Success with this agent has been
shown recently for hemodynamic rescue following
pheochromocytoma resection [23]. Steroid replacement is
recommended in all patients who are undergoing bilateral
adrenalectomy, or if there is a clinical or subclinical
concurrent Cushing’s syndrome: In rare occasions when
123

there is concurrent secretion of cortisol, thought should be
given to cortisol replacement post- operatively.
Postoperative management
In the majority of patients who undergo laparoscopic tumor
resection, postoperative issues are minimal; however,
postoperatively all pheochromocytoma patients need
intensive monitoring in the intensive care unit because
complications, if present, can be severe. The major
potential postoperative complications are hypertension,
hypotension, and rebound hypoglycemia. Our recommen-
dation that blood pressure, heart rate and plasma glucose
levels should be closely monitored for 24–48 h is mainly
based on retrospective studies and institutional experience.
Electrolyte and endocrine abnormalities must be investi-
gated as putative causes in drowsy and unresponsive
patients. Meticulous fluid management is necessary.
Patients who exhibit persistent hemodynamic instability
may need postoperative ventilator support. Sudden
hypotension may occur following ligation of the tumor.
This, in conjunction with a contracted plasma volume,
surgical bleeding and anesthetic-induced vasodilation may
cause profound, persistent hypotension. In patients who are
persistently hypertensive postoperatively, fluid overload,
return of autonomic reflexes, inadvertent ligation of the
renal artery or presence of residual tumor should be con-
sidered in the differential diagnosis [24].
To document successful tumor removal, biochemical
testing should be performed upon recovery of the patient
from surgery (e.g., 2–4 weeks after surgery). Additionally
measuring plasma or urine levels of metanephrines on
follow-up can help diagnose persistent/recurrent disease.
Long-term follow-up should include annual biochemical
testing to assess for recurrent or metastatic disease [3].
Conclusion
Pheochromocytoma presents a challenge from the outpa-
tient to the inpatient management for a successful outcome.
After a decision is made to surgically resect the tumor, a
strong multidisciplinary team approach is necessary
throughout the perioperative period to prevent expectant
complications and to optimally manage unexpected com-
plications that arise. This team-based, seamless multidis-
ciplinary medical care has shown high success and
improved outcomes for patients undergoing resection of a
pheochromocytoma. Understanding the pathophysiology of
pheochromocytoma, the pharmacology of medications
used, and recognizing postoperative complications will
dramatically impact patient outcomes. The hospital physi-
cian, intensivist, anesthetist and cardiovascular specialist
123
Ir J Med Sci
play a pivotal role in the management of patients with
pheochromocytoma. In addition to the pharmacologic and
volume recommendations, a multidisciplinary discussion
allows for seamless implementation of an organized plan of
care.
Compliance with ethical standards
Funding This study received no funding, all work was done on a
volunteer basis.
Conflict of interest Authors (Azadeh, Ramakrishna, Charles,
Bhatia and Mookadam) Declare that he/she has no conflict of interest.
Ethical approval This article does not contain any studies with
human participants or animals performed by any of the authors. This
study was approved by the Mayo Clinic IRB.
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