Journal of Cardiothoracic and Vascular Anesthesia 31 (2017) 1427–1439

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Review Article

Perioperative Management of Pheochromocytoma

Julian Naranjo, DO, Sarah Dodd, MD, Yvette N. Martin, MD, PhD1
Department of Anesthesiology & Perioperative Medicine, Mayo Clinic, Rochester, MN

Pheochromocytomas are rare neuroendocrine tumors that produce and store catecholamines. Without adequate preparation, the release of
excessive amounts of catecholamines, especially during anesthetic induction or during surgical removal, can produce life-threatening
cardiovascular complications. This review focuses on the perioperative management of pheochromocytoma/paragangliomas, initially
summarizing the clinical aspects of the disease and then highlighting the current evidence available for preoperative, intraoperative, and
postoperative anesthetic management.
& 2017 Elsevier Inc. All rights reserved.

Key Words: pheochromocytoma; paraganglioma; anesthesia; hypertension; perioperative management; neuroendocrine tumors

Pheochromocytomas are rare neuroendocrine tumors of the
adrenal medulla.1,2 These catecholamine-producing tumors
synthesize and store excessive amounts of norepinephrine
and epinephrine, which when released, especially during
anesthetic induction or during surgical removal, can produce
life-threatening cardiovascular complications. When a tumor
arises outside the adrenal medulla, it is known as a para-
ganglioma.3 The proportion of tumors that are extra-adrenal
are o20% and may or may not be biochemically active.2
Initially associated with high surgical mortality (3%-50%), this
number has been reduced dramatically in the current era.4
Undoubtedly, improved medical and anesthetic management
have contributed to the decreased mortality. Although resec-
tion of pheochromocytoma or paraganglioma remains a
challenging situation for the anesthesiologist, aggressive
perioperative care can significantly affect patient outcome.
Presentation
The most common symptoms reported by patients include
the classically taught triad of diaphoresis, palpitations, and
headache in addition to flushing, trembling, orthostatic hypo-
tension, pallor, and anxiety (Table 1).5 Symptoms stem from
1 occurrence is intraoperative presentation during an unrelated
Address reprint requests to Yvette N. Martin, MD, PhD, Mayo Clinic,
Department of Anesthesiology, Rochester, MN 55905.
E-mail address: martin.yvette@mayo.edu (Y.N. Martin).
intermittent or sustained release of norepinephrine, epinephr-
ine, and/or dopamine. Episodic symptoms may be triggered by
stress, position change, manipulation of the abdomen or tumor,
pain, or medication.6 Even though hypertension continues to
be an important clinical sign of pheochromocytoma, it may not
be as severe or refractory as it once was due to earlier
detection. In fact, the rate of presentation due to incidental
findings on abdominal imaging and screening in associated
familial conditions nearly equals that due to classic signs and
symptoms, although many of these patients have mild-to-
moderate symptoms revealed after a detailed history is
taken.4,7
Extra-adrenal pheochromocytomas are rare and may present
due to compression of local structures before the manifestation
of catecholamine effects. One example of this phenomenon is
cardiac pheochromocytoma, which may arise from the left
atrium, great vessels, or intraventricular septum.8
A small percentage of patients present in extremis, termed a
“pheochromocytoma multisystem crisis.” Patients in crisis may
have hypertension or hypotension, hyperthermia ( 440ºC),
altered mental status, and other end-organ dysfunction.9
Depending on the patient’s condition, emergency resection
may be required, which necessitates acute medical optimiza-
tion and careful intraoperative management. Another rare
surgery or anesthetic induction. This occurrence has been
described as having multiple possible presentations including

http://dx.doi.org/10.1053/j.jvca.2017.02.023
1053-0770/& 2017 Elsevier Inc. All rights reserved.
1428 J. Naranjo et al. / Journal of Cardiothoracic and Vascular Anesthesia 31 (2017) 1427–1439

Table 1 are high, and the management options vary based on severity
Signs and Symptoms of Pheochromocytoma of symptoms, gestational age of the fetus at diagnosis, and
Sustained or paroxysmal hypertension
response to medical management.19 Successful surgical man-
Headache agement has been reported in all 3 trimesters, with delivery of
Palpitations the fetus if adequately developed. The development of a
Diaphoresis multidisciplinary plan is critical for the safe and appropriate
Pallor care of these patients.20
Nausea
Weight loss
Fatigue Pediatrics
Psychological symptoms (anxiety, panic)
Hyperglycemia
Pheochromocytoma is rare in the pediatric population, and
the presentation and intraoperative management are similar to
severe hypertension, severe hypotension, metabolic acidosis, that of adults. The most common presentation is sustained
and multiorgan failure, and it may mimic other intraoperative hypertension, and most patients require preoperative optimiza-
catastrophes.10–12 High levels of catecholamines in these tion before surgery. Preoperatively they also may benefit from
patients may cause a takotsubo-like cardiomyopathy.13,14 genetic testing and thorough imaging because pediatric
patients are more likely to have multiple and/or extra-adrenal
Familial Presentations tumors.21,22

In about 10% of cases, pheochromocytoma occurs in patients Preoperative Management

with one of a number of hereditary conditions known to be
associated with this tumor. These include multiple endocrine
neoplasia IIA and IIB,15 neurofibromatosis type 1,16 tuberous
sclerosis, von Hippel-Lindau syndrome, Sturge-Weber syn-
drome, and simple familial pheochromocytoma. Familial pheo-
chromocytomas are more likely to be bilateral and occasionally
can be managed with partial adrenalectomy. Recommendations
for screening vary by syndrome, but pheochromocytoma should
be considered as a possible cause after the development of
hypertension in patients with these conditions. Conversely, a
patient with pheochromocytoma may benefit from genetic
testing for associated syndromes depending on patient and
family history.17 Up to 40% of pheochromocytomas are
associated with known genetic mutations.5 The most commonly
identified genes are the RET proto-oncogene, NF-1 gene, VHL
gene, and genes encoding succinate dehydrogenase subunits
(Table 2). No consensus guideline exists for the approach to
genetic testing, although the genetics of pheochromocytoma
have been described in the literature previously.18
Pregnancy
Clinical presentation during pregnancy is very rare and the
presentation can be nonspecific. Maternal and fetal mortality
Table 2
Genes Associated With Pheochromocytoma
Gene Clinical Syndrome
RET Multiple endocrine neoplasia type IIA
Multiple endocrine neoplasia type IIB
VHL Von Hippel-Lindau disease
NF-1 Neurofibromatosis type 1
SDHA
SDHB Sporadic cases of pheochromocytoma and paragangliomas
SDHC
SDHD
Adequate preoperative evaluation is crucial before surgery
for patients with pheochromocytoma (Table 3). A series
performed by Scholten et al demonstrated that surgery in
poorly prepared patients can result in serious morbidity and
mortality.23 The majority of patients present with hyperten-
sion, which can be sustained or paroxysmal. It is equally
important to know that a subset of patients can present with
normal blood pressure readings. This usually is seen with low-
circulating catecholamines.24,25 Lafont et al showed that
normotensive pheochromocytomas had comparable periopera-
tive hemodynamic instability to those with clinically signifi-
cant preoperative hypertension.26 Therefore, it is prudent to
optimally evaluate every patient with a pheochromocytoma
before anesthesia. Appropriate preoperative therapy has been
determined subjectively in one study to significantly reduce
perioperative complications.27
The goal of preoperative management includes evaluating
for cardiovascular sequelae from the high circulating levels of
catecholamines and initiating antihypertensive medications to
improve cardiac dysfunction and achieve adequate blood
pressure control to avoid intraoperative hemodynamic instabil-
ity. Initiation of antihypertensive agents is recommended even
for normotensive patients to prevent unpredictable intraopera-
tive hemodynamic instability.17 Clinical guidelines such as the
Endocrine Society Practice Guidelines and the Roizen criteria
(Table 4) are important resources for establishing adequate
preoperative management and will be discussed and referenced
throughout this section.17,28
Table 3
Preoperative Anesthetic Considerations
Evaluate overall health and functional capacity
Thoroughly assess cardiovascular system for presence of dysfunction
Assess effectiveness of antihypertensive therapy
Reduce patient anxiety with reassurance
 J. Naranjo et al. / Journal of Cardiothoracic and Vascular Anesthesia 31 (2017) 1427–1439
Table 4
Roizen Criteria to Assess for Adequate α-Adrenergic Blockade
No blood pressure reading 4160/90 mmHg should be evident for 24 hours
before surgery
Orthostatic hypotension, with readings 480/45 mmHg, should be present
Electrocardiogram should be free of ST-T changes for at least 1 week
No more than 1 premature ventricular contraction every 5 minutes
For further reading, see Roizen et al.28
Cardiac Evaluation
A thorough history and physical examination, complete
blood count, basic metabolic panel, electrocardiogram, and
echocardiogram (ECHO) should be performed on every patient
with a pheochromocytoma or paraganglioma to establish the
functional capabilities of the cardiovascular system. The
excessive catecholamine release and resultant hypertension
can contribute to clinically significant changes in the cardio-
vascular system such as increased arterial stiffness, vasocon-
striction of the coronary arteries, and tachyarrythmias.29 An
electrocardiogram may show pathologic findings such as signs
of left ventricular hypertrophy, nonspecific ST-T wave
changes, arrhythmias, and a prolonged QTc. The primary
mechanism for these abnormalities is related to the
catecholamine-induced coronary artery vasoconstriction that
restricts myocardial blood flow.30
The severe hypertension and excessive catecholamines also
can contribute to the development of cardiomyopathy that can
be chronic (hypertrophic or dilated) or acute (takotsubo).13,31
Takotsubo cardiomyopathy associated with pheochromocy-
toma typically presents with left ventricular basal or apical
hypokinesis despite normal coronary arteries.32 The pathophy-
siology is complex, but there are several hypothesized
mechanisms for the targeted effect on the left ventricle (LV).
In animal models, β-adrenoreceptor expression within the heart
is not uniform, with the largest density of β-adrenoreceptors at
the apex.33 This differential expression of receptors may help
to explain why the LV is more susceptible to the excess
circulating catecholamines. Another hypothesis is that the high
concentrations of catecholamines alter β2-adrenoreceptor sig-
naling, creating a negative inotropic effect.34 These hypotheses
are based on in vitro studies and animal models and have yet
to be validated in human models. Other mechanisms respon-
sible for the cardiomyopathy identified in those with pheo-
chromocytoma include direct effects on the myocardium by
the catecholamines13,31 or myocardial hypoxia.30
Because the degree of heart failure can increase the
perioperative risk, an ECHO is recommended to evaluate for
the presence and degree of cardiomyopathy.17,35 Abnormal
ECHO findings may include higher LV dimensions and
volumes and LV diastolic dysfunction. In a prospective study
of 35 patients by Agarwal et al, 20% of those with pheochro-
mocytoma had a left ventricular ejection fraction o45%,
although the mean left ventricular ejection fraction was
54.2%.36 In addition, it is important to obtain an ECHO to
rule out primary cardiac pheochromocytoma.8,37
1429
An ECHO study also may be useful for determining
improvement after antihypertensive therapy has been initiated.
Agarwal et al studied the common cardiac abnormalities in
patients with pheochromocytomas throughout the periopera-
tive period and found that cardiac function, structure, and
conduction abnormalities generally improved after therapy and
tumor resection.36
Antihypertensive Medications
The hemodynamic instability during surgical treatment of
pheochromocytoma with inadequate or absent preoperative
antihypertensive therapy or unrecognized hypovolemia con-
tributes to high mortality. Preoperative antihypertensive ther-
apy therefore is recommended for patients with sustained or
paroxysmal hypertension17,38 and normotensive patients.26
Given the low incidence of pheochromocytomas, no rando-
mized control trials have been performed to compare the
efficacy of various preoperative blood pressure control regi-
mens to create a consensus for the most appropriate preopera-
tive management. However, the most common therapeutic
approaches include a combination of α-adrenergic receptor
antagonists, β-adrenergic receptor antagonists, and calcium
channel blockers (Fig 1).17,39 This section analyzes the current
evidence for the use of these agents in the preoperative
treatment of pheochromocytoma.
Phenoxybenzamine
Phenoxybenzamine is the most widely used agent for
perioperative blood pressure control in patients with pheo-
chromocytoma or paraganglioma resection. The Endocrine
Society consensus guidelines recommend oral phenoxybenza-
mine or other α-adrenergic antagonists as the first-line agents
for perioperative blood pressure control.17 Phenoxybenzamine
noncompetitively blocks both α1- and α2-adrenergic receptors
irreversibly, therefore blunting the physiologic effects of the
high levels of circulating catecholamines.27,40 Phenoxybenza-
mine has a long duration of action compared with the α1-
antagonists. Adequate dosing with phenoxybenzamine reduces
vasoconstriction, reduces intraoperative hypertensive crises,
and contributes to improved surgical outcomes.41,42 The
preoperative use of phenoxybenzamine commonly is asso-
ciated with orthostatic hypotension, reflex tachycardia second-
ary to inhibition of presynaptic α2-receptors, nasal congestion,
syncope, and dizziness. The degree of the reflex tachycardia
observed determines the need to initiate a preoperative β-
adrenergic receptor antagonist.
Outpatients typically are prescribed 10 mg twice daily,
which is increased daily until normalization of blood pressure
and mild orthostatic hypotension occur. This requires daily
blood pressure monitoring in the supine and standing posi-
tions, which can be managed safely and effectively on an
outpatient basis. Treatment must be initiated for at least 7-to-
14 days preoperatively or until clinical signs of adequate α-
adrenergic antagonism are present.17 Guidelines to ensure
adequate α-adrenergic blockade before surgery are included
in Table 4.28 If these criteria are not met, additional agents
1430 J. Naranjo et al. / Journal of Cardiothoracic and Vascular Anesthesia 31 (2017) 1427–1439
Fig 1. Catecholamine synthesis pathway.
(calcium channel blockers, β-adrenergic antagonists) may be
added and the case delayed until adequate control can be
achieved.17
Selective α1-Antagonists
Selective α1-adrenergic antagonists can be used instead of
phenoxybenzamine and often are prescribed for their shorter
duration of action and decreased likelihood to contribute to
postoperative hypotension. Additional advantages compared
with phenoxybenzamine include avoidance of reflex tachycar-
dia by the natural negative feedback mechanism through the
unopposed α2-adrenergic receptor.41 In contrast to the need for
preoperative β-adrenoceptor antagonists with the use of
phenoxybenzamine, this is not necessary for α1-adrenergic
antagonists. The side effect profile of selective α1-adrenergic
antagonists is less pronounced than with that of
phenoxybenzamine.
Intraoperatively, additional α-adrenergic and β-adrenergic
blockade may still be necessary because their effects can be
overcome by a large surge of catecholamines during surgical
manipulation.
Specific α1-adrenergic receptors commonly used include
prazosin, terazosin, and doxazosin. Of the 3 agents, doxazosin
has the longest duration of action, allowing for once daily
dosing. Both prazosin and terazosin can be used with the
precaution that they have significantly shorter half-lives and
therefore require more frequent dosing and a missed dose may
result in inadequate blockade for the time of surgery. Urapidil
is another agent used.43,44
When deciding which α-blocking agent is most useful in
preparing for pheochromocytoma surgery, a review performed
by van der Zee et al concluded, based on current evidence, that
there was no superior α-blocker for the pretreatment of patients
with pheochromocytoma.45 Between the nonselective or selec-
tive agents, there was no evidence for a superior drug and
evidence for use of either pharmacologic class has been well
studied. Preoperative and intraoperative hemodynamics may
be better controlled with phenoxybenzamine, yet significant
postoperative hypotension can occur. Even though there are
fewer preoperative and postoperative side effects with the
competitive selective α1-adrenergic antagonists, additional
antihypertensive support is required intraoperatively.
Careful titration should be used with α-adrenergic antago-
nists and in patients with congenital heart disease such as
tetralogy of Fallot or patients with Fontan physiology present-
ing with pheochromocytoma. In these settings, the decreased
systemic vascular resistance and venous return observed with
initiation of α-adrenergic blockade could be deleterious. Case
reports by Tang et al46 and Yuki et al47 described in detail the
perioperative management, including successful α-blockade
 J. Naranjo et al. / Journal of Cardiothoracic and Vascular Anesthesia 31 (2017) 1427–1439
with the selective antagonist doxazosin, in these rare but
complex clinical scenarios.
Calcium Channel Antagonists
Calcium channel antagonists, such as oral diltiazem or
nicardipine, are another class of agents that have been used
in the perioperative preparation of patients with pheochromo-
cytomas to control blood pressure.48,49 These agents are
especially useful for normotensive patients or those with very
mild hypertension because these short-acting agents are devoid
of the constraints of α-adrenergic antagonists. In addition to
the lack of drug-induced orthostatic hypotension and tachy-
cardia, other proposed benefits of calcium channel antagonists
include cardioprotection and renal protection.50 Mechanisms
for this protection include prevention of catecholamine-
induced coronary vasospasm and myocarditis. Calcium chan-
nel antagonists reduce arterial pressure by inhibiting
norepinephrine-mediated transmembrane calcium influx in
vascular smooth muscle. Calcium channel blockers can be
used safely as monotherapy in a subset of patients or even in
combination with α-adrenergic antagonists when blood pres-
sure is not well controlled.40 A recent retrospective study by
Siddiq et al found no differences in intraoperative hemody-
namic stability or 30-day outcomes in patients prepared for
pheochromocytoma resection using nicardipine compared with
phenoxybenzamine.51 A similar result was found in a study by
Brunaud et al comparing preoperative α-antagonists and
calcium channel blockers.52 Oral diltiazem has been studied
but is not used commonly due to the reported poor intrao-
perative outcomes.53
β-adrenergic Antagonists
The addition of a β-adrenergic antagonist to the preoperative
regimen is determined by the extent of catecholamine-induced
tachycardia. Treatment with a β-adrenergic antagonist should
never be initiated as a sole agent in a patient with pheochro-
mocytoma or before adequate α-blockade. Doing so might
precipitate a catastrophic hypertensive crisis because unop-
posed α-receptor stimulation can result in significant increases
in arterial pressure.27,54 Caution also should be used in patients
with catecholamine-induced cardiomyopathy; β-adrenergic
blockade in this subset of patients can lead to intractable
hypotension, bradycardia, and cardiac arrest.55 The β1-
adrenorecptor antagonists atenolol or metoprolol and the
nonselective β-adrenoreceptor antagonist propranolol can be
administered 1-to-3 times a day. Doses are titrated to a goal
heart rate of 60 to 80.
α Methyl-para-tyrosine
α-Methyl-para-tyrosine (α-metyrosine) also is an option for
preoperative management of pheochromocytoma. This agent
decreases the biosynthesis of catecholamines through compe-
titive inhibition of the enzyme tyrosine hydroxylase.56 The
significant depletion of catecholamine stores reduces hemody-
namic fluctuations during tumor manipulation. For maximal
effect, α-metyrosine must be administered a minimum of 2-to-
3 days before surgery. A typical dosing regimen begins with
1431
250 mg 4 times a day with gradual daily increases until a
maximum total dose of 4 g/day is reached.27 Unfortunately,
the commonly associated somnolence, anxiety, diarrhea, and
extrapyramidal side effects make this agent less tolerable at the
higher doses.
There are varying reports on the effectiveness of α-
metyrosine as a monotherapy. Wachtel et al showed that
preoperative α-metyrosine treatment improved intraoperative
hemodynamic stability in patients undergoing pheochromocy-
toma or paraganglioma resection.57 However, there are case
reports in which it was not as useful as a monotherapy.58 Most
would advocate the use of metyrosine in conjunction with an
α-adrenergic antagonist, and it is most useful for patients with
metastatic or inoperable tumors.54
Surgical Approach
Because the surgical approach influences the complexity of
anesthetic management, close cooperation between the sur-
geon and anesthesiologist is paramount for successful out-
comes. Remarkable advances have been made in the surgical
approach to adrenalectomy for pheochromocytomas, with a
majority being performed laparoscopically and only select
cases undergoing open surgery.59–61
Laparoscopic Adrenalectomy
Laparoscopic adrenalectomy is considered the standard for
surgical treatment of pheochromocytoma tumors up to 15
cm.17,62–64
Open surgery is limited to only specific indications such as
large tumors or extra-adrenal tumors with limited access or
after failed laparoscopic approach. The reported advantages of
the laparoscopic approach demonstrated in retrospective stu-
dies include milder hemodynamic changes,65 reduced catecho-
lamine release,66 better intraoperative hemodynamic
stability,67 and faster recovery.68,69 The first prospective study
comparing laparoscopic versus open adrenalectomy for pheo-
chromocytoma confirmed these advantages even for large
tumors.64 Although there are well-documented advantages
for the laparoscopic approach, it is important to be vigilant
for the establishment of pneumoperitoneum because this can
lead to massive catecholamine release with resultant hyperten-
sion and tachycardia.
Transperitoneal or Retroperitoneal Approach. There are
2 common approaches for the laparoscopic adrenalectomy—
the more commonly used transperitoneal approach and the
retroperitoneal approach. The transperitoneal approach may be
considered for larger masses or bilateral tumors or in obese
patients. The retroperitoneal approach is a newer approach.70 It
is performed with the patient in the lateral or prone position.
The prone position is preferred for bilateral tumors because
repositioning is unnecessary. Both are considered safe,62 but
the decision of which approach depends on surgeon preference
and expertise.71
1432 J. Naranjo et al. / Journal of Cardiothoracic and Vascular Anesthesia 31 (2017) 1427–1439
Robotic Surgery
Robotic surgery also has been introduced into the surgical
practice and is considered a feasible technique for adrenalect-
omy.72 Early reports suggested better outcomes for the robotic
approach compared with the laparoscopic approach,73
although more comparative studies will be necessary to
establish this as a superior approach for pheochromocytoma.
Intraoperative Management
Providing an anesthetic that maintains hemodynamic stabi-
lity during catecholamine surges and tumor ligation requires
careful planning and meticulous technique. This begins in the
immediate preoperative period by providing adequate preme-
dication to minimize any anxiety experienced by patients with
a pheochromocytoma. Furthermore, intraoperative manipula-
tion and resection of a pheochromocytoma have been found to
result in measurable catecholamine release and have been
associated with significant hemodynamic perturbations, espe-
cially if performed via a conventional transabdominal
approach compared with laparoscopic resection.74,75 Antici-
pated problems and collaboration among all team members
should be discussed preoperatively to alleviate intraoperative
problems and concerns (Table 5).
Monitoring Systems and Intravascular Access
Invasive blood pressure monitoring via arterial cannulation
before induction is an absolute indication and is considered the
gold standard for beat-to-beat monitoring of arterial blood
pressure in all patients with pheochromocytoma.76,77 An intra-
arterial catheter allows for real-time monitoring of hemody-
namic fluctuations and frequent blood draws, and it facilitates
faster pharmacologic intervention. Urine output monitoring via
urinary bladder catheterization is used routinely for pheochro-
mocytoma resection.78,79
A central venous catheter should be strongly considered in
the management of pheochromocytoma intraoperatively in
order to administer vasoactive agents and provide fluid
management; it has been a standard of care for decades.77 In
a comparison of 2 institutions, the rate of central venous
catheter placement for pheochromocytoma resection was
between 30% and 60%.39
Prolonged peripheral vasoconstriction secondary to high
catecholamine levels results in volume depletion in patients
with pheochromocytoma.80 In addition, right-sided and left-
Table 5
Intraoperative Anesthetic Considerations
Strongly consider anxiolytic therapy
Monitor intra-arterial catheter
Establish large-bore intravenous access, strongly consider central access
Achieve depth of anesthesia to attenuate dramatic hemodynamic fluctuations
Anticipate and treat hemodynamic fluctuations based on surgical approach and
progress
Be prepared to treat hyperglycemia and hypoglycemia
sided filling pressures may be discordant, particularly during
tumor manipulation, tumor ligation, or rapid infusion of fluid.
This discrepancy results in central venous pressure (CVP)
readings that may not accurately reflect left-sided pressures,
which typically are measured via pulmonary artery occlusion
pressure (PAOP) readings. Hypovolemia and discrepancy
between right- and left-sided cardiac filling pressures have
been observed in patients undergoing pheochromocytoma
resection regardless of the presence or absence of cardiac
dysfunction before surgery. Furthermore, severe hypertension
and tachycardia may decrease left ventricular compliance,
which may not be evident during CVP monitoring intraopera-
tively. Due to these hemodynamic factors and the relationship
between vascular capacity and circulating blood volume
during tumor removal, measurement of PAOP and cardiac
output (CO) have been suggested to have an advantage over
CVP monitoring, especially in the presence of cardiac dis-
ease.81,82 However, in a large multicenter, randomized clinical
trial of high-risk patients undergoing major surgery, no benefit
was found in therapy directed by a pulmonary artery catheter
compared with standard care with or without CVP monitor-
ing.83 In a comparison of 2 large academic institutions, the
pulmonary artery catheter placement rate for pheochromocy-
toma resection was 8% to 24%.39
Fluid status, ventricular filling (preload), contractility, and
valvular competence can be monitored via intraoperative
transesophageal echocardiography (TEE). Echocardiography
affords real-time monitoring of intravascular volume status and
early detection of myocardial wall motion abnormalities,
which would aid in the diagnosis of myocardial ischemia
intraoperatively.76,84 As it compares to invasive pulmonary
artery monitoring, pulmonary artery catheter data interpreta-
tion can be misleading in some cases due to the assumptions
required to interpret hemodynamic data. Measured pressures in
a system that may be poorly compliant due to positive end-
expiratory pressure, vasopressors, and poor myocardial con-
tractility may not reliably correlate with intravascular volumes.
In a study by Burns et al, TEE findings yielded immediate,
real-time data regarding inadequate preload in just under half
the patients who, despite large resuscitation volume, had
“acceptable” PAOP measurements.84 However, TEE has the
disadvantage of not being a feasible monitor postoperatively
due to sedation requirements to maintain patient comfort, risk
of aspiration, and significant operator reliance to obtain and
interpret data.85,86
A potential alternative to invasive pulmonary artery mon-
itoring is a new device for indirectly monitoring hemodynamic
parameters such as CO, cardiac index, stroke volume, and total
systemic vascular resistance using whole-body bioimpedance
cardiography via electrodes placed on an upper extremity and
on the contralateral lower extremity. It reportedly can measure
CO repeatedly and noninvasively to monitor hemodynamic
status in patients with pheochromocytoma.80 Good correlation
of cardiac output measurements has been found in a compar-
ison among bioimpedance, thermodilution, and Fick measure-
ments, suggesting that the bioimpedance method may be an
accurate and potentially useful monitor.87,88
 J. Naranjo et al. / Journal of Cardiothoracic and Vascular Anesthesia 31 (2017) 1427–1439
General Anesthesia
Pheochromocytoma resections typically are performed with
the patient under general anesthesia and have been performed
with several anesthetic agents successfully. The choice of
anesthetic agent generally is less important than the depth of
anesthesia achieved to optimally inhibit adrenergic and cardi-
ovascular responses.65,77,89
Inhalation Agents
At the Mayo Clinic, sevoflurane typically is used for
maintenance of anesthesia in patients undergoing pheochro-
mocytoma resection due to its lack of arrhythmogenic potential
and relatively favorable hemodynamic profile compared with
nitrous oxide, desflurane, and isoflurane.90–92 Nevertheless,
isoflurane, nitrous oxide, and enflurane have been known to be
safe in pheochromocytoma resection.91
Desflurane is known to cause hypertension, tachycardia, and
airway irritation, which may exacerbate hemodynamic
derangements in pheochromocytoma patients and as such
may not be the best volatile agent for pheochromocytoma
resection.92
Intravenous Anesthetic Agents
Induction with propofol is common and is considered safe
in these patients. Etomidate induction may be considered in
patients in whom a concern for hypovolemia-induced hypo-
tension exists due to its superior hemodynamic profile during
induction. Dexmedetomidine and remifentanil also have been
used with success.93 Total intravenous anesthesia via propofol
target-controlled infusion also has been described as a
recognized technique for maintaining surgical anesthesia.94
Analgesia typically is achieved via use of opioids such as
fentanyl, hydromorphone, remifentanil, and sufentanil, which
are dosed based on patient tolerance, surgical approach, and
the hemodynamic derangements encountered.77,90,93,95 Mor-
phine typically is avoided due to its propensity to elicit
histamine release.96
Agents that cause an indirect increase in catecholamines
levels or sympathetic stimulation (ketamine, ephedrine, and
meperidine); elicit histamine release (morphine); or trigger
hypertension (droperidol) should be avoided.96,97
Neuromuscular Blockers
Satisfactory neuromuscular blockade can be achieved with
many of the multiple agents available, and specific agent
selection likely is not crucial to the conduction of the overall
anesthetic. However, when managing pheochromocytoma,
agents that increase sympathetic tone, stimulate catecholamine
release, or stimulate histamine release should be avoided.
Vecuronium, rocuronium, and cisatracurium are widely
used during anesthetic management of pheochromocytoma
because they have few or no autonomic effects and are not
associated with histamine release.91,98–100 At the Mayo Clinic,
vecuronium primarily is used as the neuromuscular blocker of
choice.
1433
Although succinylcholine has been used safely in the
anesthetic management of patients with pheochromocytoma,91
the fasciculations and stimulation of autonomic ganglia
associated with its administration may result in mechanical
stimulation of the tumor, increase in concentration of circulat-
ing catecholamines, and subsequent hypertension, tachycardia,
and cardiac arrhythmias.101
Even though atracurium has been used without incident in
some case reports,102,103 it has been noted to stimulate release
of histamine and has been associated with severe arterial
hypertension, ventricular arrhythmias, and elevation of plasma
catecholamine levels.104 Similar effects have been seen with
other benzylisoquinolinium compounds such as mivacurium.99
Pancuronium typically is avoided in the management of
pheochromocytoma. Pancuronium administration has been
associated with a vagolytic effect, resultant tachycardia, and
a profound hypertensive reaction. This hemodynamic response
likely is secondary to stimulation of catecholamine release and
inhibition of catecholamine reuptake.105,106
Regional Anesthesia
Spinal and epidural anesthesia have been used in the past
with satisfactory results.55,107–109 Despite the mostly favorable
results, caution must be practiced when performing neuraxial
techniques in order to provide a safe and hemodynamically
stable anesthetic. Spinal anesthesia may cause profound
hypotension in a patient with pheochromocytoma who likely
is hypovolemic from prolonged peripheral vasoconstriction.
Nizamoglu et al observed that hemodynamics and hormone
levels were more stable in patients receiving epidural anesthe-
sia in addition to general anesthesia for laparoscopic adrena-
lectomy.108 However, hypertension secondary to
catecholamine release from tumor manipulation may not be
alleviated by performance of a neuraxial technique and the
subsequent sympatholysis.110
Hypertension and Arrhythmias
Two separate etiologies have been hypothesized to explain
hypertensive responses to stimuli during surgical resection of
pheochromocytoma.
First, noxious stimuli such as laryngoscopy, tracheal intuba-
tion, skin incision, insufflation, and abdominal exploration
likely result in profound hypertension in these patients due to
catecholamine release from adrenergic nerve endings with
excessive stores of catecholamines. Adequately deep levels of
anesthesia may attenuate or eliminate this response to noxious
stimuli.39,42,111
Second, a more severe hypertensive response can be elicited
from catecholamine release secondary to tumor manipulation.
This likely is due to the high concentrations of catecholamines
within the tumor and is associated with significant increases in
plasma norepinephrine and epinephrine concentrations. Cau-
tious and meticulous surgical resection of the tumor can
prevent this type of hypertensive response.39,42,111
1434 J. Naranjo et al. / Journal of Cardiothoracic and Vascular Anesthesia 31 (2017) 1427–1439
Intraoperatively, hypertension during pheochromocytoma
resection is best treated with vasodilators. The combined use
and titration of multiple short-acting agents (sodium nitroprus-
side, remifentanil, and esmolol) in the perioperative manage-
ment of hypertension may be useful.93 Magnesium,
nicardipine, and clevidipine also have been noted to be
effective agents in the management of hypertension in tumor
resection.111,112 Magnesium has emerged as an efficacious
antiarrhythmic.113–116
Nitric Oxide Modulators: Nitroprusside and Nitroglycerin
Due to their favorable pharmacodynamic profiles (short
duration, easily titratable), sodium nitroprusside and nitrogly-
cerin are considered mainstays of hypertensive crisis manage-
ment during pheochromocytoma resection to obtain a gradual
reduction of arterial blood pressure.117,118
After administering sodium nitroprusside, both preload and
afterload are decreased, onset is immediate, and its clinical
effect recedes in approximately 1-to-3 minutes.119 Cyanide
and thiocyanate toxicity can cause serious complications at
higher doses of nitroprusside.120 From the authors’ experience
and as demonstrated in previous studies, intravenous nitrogly-
cerin had a similar pharmacokinetic profile, with an immediate
onset and duration of approximately 3-to-5 minutes.121 Nitro-
glycerin acts mostly on capacitance vessels, thus affecting
preload more than afterload.122,123
β-adrenergic Antagonists
β-adrenergic antagonists are used widely in the management
of tachycardia or tachyarrhythmias caused by a variety of
conditions,124,125 and pheochromocytoma resection is no
exception. Esmolol is a commonly used β-adrenergic antago-
nist in pheochromocytoma resection due to its favorable
pharmacokinetic profile. Esmolol is a selective β1-antagonist
with a fast onset (approximately 1-2 minutes) and short
duration of action (approximately 9 minutes), which make it
useful both as an infusion and as an intermittent bolus
medication.126 Esmolol has hemodynamic effects that are
uniquely suited for the intraoperative management of pheo-
chromocytoma, in particular its reduction of systolic blood
pressure without affecting diastolic blood pressure.126 The
typical practice at the Mayo Clinic is to treat tachycardia and
hypertension with an infusion of 50 mg/kg/min titrated in 50
mg/kg/min increments up to a maximum infusion rate of 300
mg/kg/min to achieve desired heart rate and blood pressure.
For faster blood pressure control, an initial bolus of 0.5 mg/kg
over 30 seconds may be used before starting the aforemen-
tioned infusion rate.
Calcium Channel Blockers
Calcium channel blockers have some advantages over the
nitric oxide modulators (nitroprusside and nitroglycerin) and
can be used as an alternative, if necessary. Calcium channel
blockers demonstrated less reduction in preload, fewer
instances of hypotension during initial titration, absence of
rebound hypertension from discontinuation, less tachycardia,
and elimination of the risk for cyanide toxicity.111
Nicardipine is a potent dihydropyridine calcium channel
blocker and has a strong arterial vasodilatory effect.111 Its
disadvantage compared with the nitric oxide modulators is its
pharmacokinetic profile, as exemplified by its relatively long
duration of action. Intravenous nicardipine has an onset of 1-
to-5 minutes and has a duration of action of 3-to-6 hours
compared with 3-to-10 minutes with nitric oxide modulators.
Clevidipine is an ultrashort-acting, third-generation dihy-
dropyridine arterial vasodilator. The initial half-life of clevi-
dipine is approximately 1 minute, and it is metabolized by
plasma esterases. In some studies it has been shown to be
effective at achieving tight hemodynamic control due to its
quick onset of action and fast metabolism.112 Due to its
pharmacokinetics, it has been nicknamed the “esmolol” of
calcium channel blockers and is ideal for intravenous
infusion.111
Magnesium
Magnesium acts as a vasodilator by inhibiting catechola-
mine release, acting directly on catecholamine receptors in an
antagonist fashion, and functioning as an endogenous calcium
antagonist. Magnesium, in particular, recently has been
garnering more attention and has seen increased use during
pheochromocytoma resection due to its established antiar-
rhythmic properties, calcium-blocking properties, and effec-
tiveness as a vasodilator. Magnesium already has established
efficacy in the management of cardiac arrhythmias in patients
with pheochromocytoma and paraganglioma even in the
presence of acute myocardial failure, tumor resection in the
pediatric and obstetric populations, and catecholamine release
during laryngoscopy and endotracheal intubation. Additional
advantages include its wide availability, low cost, high
therapeutic index, and well-established reversibility of toxi-
city.113–116 However, due to the low incidence of pheochro-
mocytoma and the scarcity of large prospective clinical trials,
conclusions about the use and dosing of magnesium have to be
drawn from small studies and case reports. In a series of 16
patients, magnesium was found to be highly effective in
providing hemodynamic stability when administered as a
loading dose of 40-to-60 mg/kg followed by an infusion of
2 g/h.127
α-Adrenergic Antagonist
Phentolamine is a competitive α1-adrenergic and weak α2-
adrenergic receptor antagonist that can be administered as an
intravenous infusion or in incremental doses.128,129 Reflex
tachycardia is a known side effect that typically is not seen in
patients concurrently receiving β-blockers.123,130,131
Hypotension
Inadequate intravascular volume secondary to prolonged
peripheral vasoconstriction and residual effects of preoperative
preparation with α-adrenergic blockade, β-adrenergic blockade
and calcium channel blockade are likely causes of hypoten-
sion. Intraoperatively, sudden increases in venous capacitance
from tumor removal and hypovolemia from hemorrhage may
 J. Naranjo et al. / Journal of Cardiothoracic and Vascular Anesthesia 31 (2017) 1427–1439 1435

contribute to hypotension. Postoperatively, down-regulation of Table 6

α- and β-adrenergic receptors caused by prolonged elevation in
circulating catecholamines likely is associated with postopera-
tive hypotension.132
Intravenous fluid administration is likely of benefit to these
patients early on in their surgical procedure before tumor
resection due to the aforementioned reasons and is believed to
reduce surgical mortality compared with the use of catecho-
lamines for hypotension. Pressor agents have an attenuated
effect during persistent hypovolemia and are likely to be
ineffective without fluid resuscitation. If vasopressors are used,
norepinephrine, phenylephrine, vasopressin, and dopamine all
have been recommended.111 Vasopressin, in particular, has a
unique role in the management of persistent hypovolemic
shock after tumor resection because vasopressin acts on V1
receptors on smooth muscle and, therefore, does not rely on
the availability of adrenergic receptors for its pressor effect,
which may be down-regulated in patients with pheochromo-
cytoma.133 Methylene blue also has been used for a hemody-
namic rescue after tumor resection with positive results,
although the data were anecdotal.111
Hyperglycemia
Catecholamine excess is known to cause hyperglycemia due
to inhibition of insulin release and action via α2-adrenergic
blockade. Hyperglycemia may be encountered at any point in
the preoperative and intraoperative management of pheochro-
mocytoma resection and should be treated with insulin
infusion as clinically indicated. In most instances, it resolves
after resection of the tumor.111
Hypoglycemia
The sudden reduction in circulating catecholamines after
tumor resection can result in hyperinsulinemia and subsequent
hypoglycemia because the inhibitory effect on insulin release
and action is removed. These metabolic derangements may
manifest during emergence and the immediate postoperative
period as slow emergence from anesthesia, lethargy, somno-
lence, weakness, diaphoresis, pallor, combativeness, and
seizure activity, among other signs and symptoms.134 β-
adrenergic antagonists may exacerbate complications from
hypoglycemia by masking clinical symptoms and hindering
correction toward normoglycemia.
Adrenal Steroid Replacement Therapy After Bilateral Adrenalectomy
POD 0 Methylprednisolone 40 mg IV every 8 h
POD 1 Methylprednisolone 20 mg IV every 8 h
POD 2 Methylprednisolone 10 mg IV every 8 h
Maintenance Prednisone and fludrocortisone Prednisone
5 mg orally every morning
2.5 mg orally every
evening
Fludrocortisone
0.1 mg orally every
morning
Abbreviation: POD, postoperative day.
Postoperative Management
The main postoperative complications include profound
hypotension, severe hypertension, and rebound hypoglycemia
(Table 7). Catecholamine withdrawal after surgery, along with
the residual preoperative α blockade and loss of peripheral
vasoconstriction, can lead to profound hypotension and even
shock.132 This catecholamine-resistant vasoplegia136,137 may
require vasopressin infusion for management.138 Reports of
extracorporeal membrane oxygenation being used for this
refractory shock have been reported.139 Surgical bleeding
and hypovolemia also should be considered for causes of
profound hypotension and must be treated appropriately with
fluids, blood products, or redo surgery. Presently, there are no
indices available to determine which patients will experience
postoperative hypotension; however, several have demon-
strated a correlation between higher preoperative adrenergic
activity and postoperative hypotension.74,140
Persistent hypertension is not uncommon and is observed in
up to 50% of patients.141 If the duration is 41 week, an
underlying cause such as residual tumor, volume overload,
return of autonomic reflexes, or iatrogenic causes such as
accidental ligation of the renal artery should be determined.40
The other major postoperative complication is hypoglyce-
mia. Hypoglycemia occurs in about 4% of patients and
presents in the early postoperative period.134 The proposed
mechanism is rebound hyperinsulinemia and increased periph-
eral glucose uptake. The major risk factors for this complica-
tion include epinephrine-secreting tumors and longer surgical
times.134 Plasma glucose levels should be monitored closely
Table 7
Common Postoperative Complications and Management

Complication Management
Perioperative Steroid Replacement in Bilateral Adrenalectomy
Hypotension Fluids
Blood transfusion
In consultation with the surgical team and an endocrinolo- Vasopressors (vasopressin)
gist, steroid supplementation should be initiated postopera- Consider redo surgery if signs of surgical bleeding
tively in patients who have undergone bilateral adrenalectomy ECMO if refractory shock
(Table 6). Unilateral adrenalectomy patients typically do not Hypertension Diuresis if fluid overload
require steroid supplementation unless they are experiencing Consider residual tumor
Hyperglycemia Monitor glucose for 24-48 h
Cushing syndrome or currently are receiving steroids for other
medical conditions.135 Abbreviation: ECMO, extracorporeal membrane oxygenation.
1436 J. Naranjo et al. / Journal of Cardiothoracic and Vascular Anesthesia 31 (2017) 1427–1439
for the first 48 hours according to the Endocrine Society
Practice Guidelines.17
In a review of 258 pheochromocytoma and paraganglioma
resections, Weingarten et al reported other potential complica-
tions such as acute kidney injury, major pulmonary event, fluid
overload, and thromboembolic events.74 For fluid overload,
diuretic administration may be necessary. Adrenal insuffi-
ciency also is a potential complication if the patient underwent
a bilateral adrenalectomy or removal of a solitary
adrenal gland.
With the widespread adoption of the laparoscopic surgical
approach, improvements in anesthetic technique, and aggres-
sive preoperative medical preparation, the incidence of post-
operative complications has decreased.142 As a result of these
improvements, hemodynamically stable patients are managed
more frequently postoperatively in a non-intensive care unit
monitored room.143 However, any patient who exhibits
persistent hemodynamic instability including severe hyperten-
sive and hypotensive episodes in the immediate postoperative
setting needs intensive postoperative monitoring.142
Follow-Up Examination and Long-Term Medical
Management
The primary concerns after surgical resection are persistent
tumors from incomplete tumor resection or tumor spillage
during surgery and recurrence, which has been reported to be
between 14% to 30%, and is more likely with larger tumors
and those with familial disease.144–147 At present there are no
clinical, biochemical, genetic, or pathologic markers to indi-
cate which tumors may become metastatic; therefore, close
follow-up is imperative. The European Society of Endocrinol-
ogy has published current recommendations for long-term
follow-up of postsurgical pheochromocytoma or paragan-
glioma patients.148 Follow-up for evaluation of plasma meta-
nephrine levels should be performed within 2-to-6 weeks after
surgery to confirm adequate resection.17 If metanephrine levels
are elevated at any point in the postoperative period, it is
recommended that imaging be performed at 3 months post-
resection. Long-term management includes annual follow-up
after surgery that includes biochemical testing and imaging
with each visit.17,148 For the majority of patients the recom-
mended length of follow-up is 10 years, but life-long annual
visits are recommended for those considered high risk (young
age at presentation, those with genetic disease, large tumor).
More frequent visits may be necessary for patients with extra-
adrenal disease, familial pheochromocytoma, or metastatic
pheochromocytoma.2
Summary
Pheochromocytomas are biochemically active
catecholamine-secreting tumors. The clinical presentation can
vary but typically includes the triad of hypertension, headache,
and palpitations. More often, pheochromocytomas are discov-
ered incidentally during imaging unrelated to the adrenal gland
and thus may not demonstrate the typical presentation, but the
anesthesiologist must be prepared for these abnormalities with
any surgery for any adrenal mass. Genetics and advances in
imaging have helped to diagnose tumors early and this may
contribute to the improved outcomes because the smaller the
tumor, the better the surgical outcome. Pharmacologic agents
can suppress the clinical symptoms of pheochromocytomas,
but surgical resection remains the only curative option.
Perioperative morbidity and mortality have decreased in the
past few decades, which is the result of meticulous manage-
ment throughout the perioperative period and improved
surgical technique.42 Although a rare disease, which limits
the ability for large randomized control trials to determine the
most appropriate management strategies, high-caliber guide-
lines for the perioperative management of patients with
pheochromocytoma or paraganglioma have been developed.
This management includes extensive preoperative cardiac
evaluation and aggressive preoperative blood pressure control.
There still remains variability in the selection of antihyperten-
sive agents, and newer agents are being considered. General
anesthesia is the primary anesthetic choice, with special
attention to agents available to treat wide swings in blood
pressure. In contrast to decades ago, more patients are being
recovered in non-intensive care unit settings. Postoperative
monitoring for hypotension, persistent hypertension, and
electrolyte abnormalities still is necessary to prevent unex-
pected complications and optimally manage any complications
that can arise in the recovery period.
Undoubtedly, patients with pheochromocytoma present a
challenge for the anesthesiologist. Diagnosis and perioperative
management of pheochromocytomas will continue to be
evolving processes, hopefully continuing on the trajectory of
the improved outcomes observed over the last few decades.
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