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Naranjo 2017
Naranjo 2017
Naranjo 2017
Review Article
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 intermittent or sustained release of norepinephrine, epinephr-
adrenal medulla.1,2 These catecholamine-producing tumors ine, and/or dopamine. Episodic symptoms may be triggered by
synthesize and store excessive amounts of norepinephrine stress, position change, manipulation of the abdomen or tumor,
and epinephrine, which when released, especially during pain, or medication.6 Even though hypertension continues to
anesthetic induction or during surgical removal, can produce be an important clinical sign of pheochromocytoma, it may not
life-threatening cardiovascular complications. When a tumor be as severe or refractory as it once was due to earlier
arises outside the adrenal medulla, it is known as a para- detection. In fact, the rate of presentation due to incidental
ganglioma.3 The proportion of tumors that are extra-adrenal findings on abdominal imaging and screening in associated
are o20% and may or may not be biochemically active.2 familial conditions nearly equals that due to classic signs and
Initially associated with high surgical mortality (3%-50%), this symptoms, although many of these patients have mild-to-
number has been reduced dramatically in the current era.4 moderate symptoms revealed after a detailed history is
Undoubtedly, improved medical and anesthetic management taken.4,7
have contributed to the decreased mortality. Although resec- Extra-adrenal pheochromocytomas are rare and may present
tion of pheochromocytoma or paraganglioma remains a due to compression of local structures before the manifestation
challenging situation for the anesthesiologist, aggressive of catecholamine effects. One example of this phenomenon is
perioperative care can significantly affect patient outcome. 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
Presentation “pheochromocytoma multisystem crisis.” Patients in crisis may
have hypertension or hypotension, hyperthermia ( 440ºC),
The most common symptoms reported by patients include altered mental status, and other end-organ dysfunction.9
the classically taught triad of diaphoresis, palpitations, and Depending on the patient’s condition, emergency resection
headache in addition to flushing, trembling, orthostatic hypo- may be required, which necessitates acute medical optimiza-
tension, pallor, and anxiety (Table 1).5 Symptoms stem from tion and careful intraoperative management. Another rare
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. surgery or anesthetic induction. This occurrence has been
E-mail address: martin.yvette@mayo.edu (Y.N. Martin). 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
(calcium channel blockers, β-adrenergic antagonists) may be precaution that they have significantly shorter half-lives and
added and the case delayed until adequate control can be therefore require more frequent dosing and a missed dose may
achieved.17 result in inadequate blockade for the time of surgery. Urapidil
is another agent used.43,44
Selective α1-Antagonists When deciding which α-blocking agent is most useful in
Selective α1-adrenergic antagonists can be used instead of preparing for pheochromocytoma surgery, a review performed
phenoxybenzamine and often are prescribed for their shorter by van der Zee et al concluded, based on current evidence, that
duration of action and decreased likelihood to contribute to there was no superior α-blocker for the pretreatment of patients
postoperative hypotension. Additional advantages compared with pheochromocytoma.45 Between the nonselective or selec-
with phenoxybenzamine include avoidance of reflex tachycar- tive agents, there was no evidence for a superior drug and
dia by the natural negative feedback mechanism through the evidence for use of either pharmacologic class has been well
unopposed α2-adrenergic receptor.41 In contrast to the need for studied. Preoperative and intraoperative hemodynamics may
preoperative β-adrenoceptor antagonists with the use of be better controlled with phenoxybenzamine, yet significant
phenoxybenzamine, this is not necessary for α1-adrenergic postoperative hypotension can occur. Even though there are
antagonists. The side effect profile of selective α1-adrenergic fewer preoperative and postoperative side effects with the
antagonists is less pronounced than with that of competitive selective α1-adrenergic antagonists, additional
phenoxybenzamine. antihypertensive support is required intraoperatively.
Intraoperatively, additional α-adrenergic and β-adrenergic Careful titration should be used with α-adrenergic antago-
blockade may still be necessary because their effects can be nists and in patients with congenital heart disease such as
overcome by a large surge of catecholamines during surgical tetralogy of Fallot or patients with Fontan physiology present-
manipulation. ing with pheochromocytoma. In these settings, the decreased
Specific α1-adrenergic receptors commonly used include systemic vascular resistance and venous return observed with
prazosin, terazosin, and doxazosin. Of the 3 agents, doxazosin initiation of α-adrenergic blockade could be deleterious. Case
has the longest duration of action, allowing for once daily reports by Tang et al46 and Yuki et al47 described in detail the
dosing. Both prazosin and terazosin can be used with the perioperative management, including successful α-blockade
J. Naranjo et al. / Journal of Cardiothoracic and Vascular Anesthesia 31 (2017) 1427–1439 1431
with the selective antagonist doxazosin, in these rare but 250 mg 4 times a day with gradual daily increases until a
complex clinical scenarios. maximum total dose of 4 g/day is reached.27 Unfortunately,
the commonly associated somnolence, anxiety, diarrhea, and
Calcium Channel Antagonists extrapyramidal side effects make this agent less tolerable at the
Calcium channel antagonists, such as oral diltiazem or higher doses.
nicardipine, are another class of agents that have been used There are varying reports on the effectiveness of α-
in the perioperative preparation of patients with pheochromo- metyrosine as a monotherapy. Wachtel et al showed that
cytomas to control blood pressure.48,49 These agents are preoperative α-metyrosine treatment improved intraoperative
especially useful for normotensive patients or those with very hemodynamic stability in patients undergoing pheochromocy-
mild hypertension because these short-acting agents are devoid toma or paraganglioma resection.57 However, there are case
of the constraints of α-adrenergic antagonists. In addition to reports in which it was not as useful as a monotherapy.58 Most
the lack of drug-induced orthostatic hypotension and tachy- would advocate the use of metyrosine in conjunction with an
cardia, other proposed benefits of calcium channel antagonists α-adrenergic antagonist, and it is most useful for patients with
include cardioprotection and renal protection.50 Mechanisms metastatic or inoperable tumors.54
for this protection include prevention of catecholamine-
induced coronary vasospasm and myocarditis. Calcium chan-
nel antagonists reduce arterial pressure by inhibiting Surgical Approach
norepinephrine-mediated transmembrane calcium influx in
vascular smooth muscle. Calcium channel blockers can be Because the surgical approach influences the complexity of
used safely as monotherapy in a subset of patients or even in anesthetic management, close cooperation between the sur-
combination with α-adrenergic antagonists when blood pres- geon and anesthesiologist is paramount for successful out-
sure is not well controlled.40 A recent retrospective study by comes. Remarkable advances have been made in the surgical
Siddiq et al found no differences in intraoperative hemody- approach to adrenalectomy for pheochromocytomas, with a
namic stability or 30-day outcomes in patients prepared for majority being performed laparoscopically and only select
pheochromocytoma resection using nicardipine compared with cases undergoing open surgery.59–61
phenoxybenzamine.51 A similar result was found in a study by
Brunaud et al comparing preoperative α-antagonists and Laparoscopic Adrenalectomy
calcium channel blockers.52 Oral diltiazem has been studied Laparoscopic adrenalectomy is considered the standard for
but is not used commonly due to the reported poor intrao- surgical treatment of pheochromocytoma tumors up to 15
perative outcomes.53 cm.17,62–64
Open surgery is limited to only specific indications such as
β-adrenergic Antagonists large tumors or extra-adrenal tumors with limited access or
The addition of a β-adrenergic antagonist to the preoperative after failed laparoscopic approach. The reported advantages of
regimen is determined by the extent of catecholamine-induced the laparoscopic approach demonstrated in retrospective stu-
tachycardia. Treatment with a β-adrenergic antagonist should dies include milder hemodynamic changes,65 reduced catecho-
never be initiated as a sole agent in a patient with pheochro- lamine release,66 better intraoperative hemodynamic
mocytoma or before adequate α-blockade. Doing so might stability,67 and faster recovery.68,69 The first prospective study
precipitate a catastrophic hypertensive crisis because unop- comparing laparoscopic versus open adrenalectomy for pheo-
posed α-receptor stimulation can result in significant increases chromocytoma confirmed these advantages even for large
in arterial pressure.27,54 Caution also should be used in patients tumors.64 Although there are well-documented advantages
with catecholamine-induced cardiomyopathy; β-adrenergic for the laparoscopic approach, it is important to be vigilant
blockade in this subset of patients can lead to intractable for the establishment of pneumoperitoneum because this can
hypotension, bradycardia, and cardiac arrest.55 The β1- lead to massive catecholamine release with resultant hyperten-
adrenorecptor antagonists atenolol or metoprolol and the sion and tachycardia.
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. Transperitoneal or Retroperitoneal Approach. There are
2 common approaches for the laparoscopic adrenalectomy—
α Methyl-para-tyrosine the more commonly used transperitoneal approach and the
α-Methyl-para-tyrosine (α-metyrosine) also is an option for retroperitoneal approach. The transperitoneal approach may be
preoperative management of pheochromocytoma. This agent considered for larger masses or bilateral tumors or in obese
decreases the biosynthesis of catecholamines through compe- patients. The retroperitoneal approach is a newer approach.70 It
titive inhibition of the enzyme tyrosine hydroxylase.56 The is performed with the patient in the lateral or prone position.
significant depletion of catecholamine stores reduces hemody- The prone position is preferred for bilateral tumors because
namic fluctuations during tumor manipulation. For maximal repositioning is unnecessary. Both are considered safe,62 but
effect, α-metyrosine must be administered a minimum of 2-to- the decision of which approach depends on surgeon preference
3 days before surgery. A typical dosing regimen begins with and expertise.71
1432 J. Naranjo et al. / Journal of Cardiothoracic and Vascular Anesthesia 31 (2017) 1427–1439
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 anesthesiologist must be prepared for these abnormalities with
Practice Guidelines.17 any surgery for any adrenal mass. Genetics and advances in
In a review of 258 pheochromocytoma and paraganglioma imaging have helped to diagnose tumors early and this may
resections, Weingarten et al reported other potential complica- contribute to the improved outcomes because the smaller the
tions such as acute kidney injury, major pulmonary event, fluid tumor, the better the surgical outcome. Pharmacologic agents
overload, and thromboembolic events.74 For fluid overload, can suppress the clinical symptoms of pheochromocytomas,
diuretic administration may be necessary. Adrenal insuffi- but surgical resection remains the only curative option.
ciency also is a potential complication if the patient underwent Perioperative morbidity and mortality have decreased in the
a bilateral adrenalectomy or removal of a solitary past few decades, which is the result of meticulous manage-
adrenal gland. ment throughout the perioperative period and improved
With the widespread adoption of the laparoscopic surgical surgical technique.42 Although a rare disease, which limits
approach, improvements in anesthetic technique, and aggres- the ability for large randomized control trials to determine the
sive preoperative medical preparation, the incidence of post- most appropriate management strategies, high-caliber guide-
operative complications has decreased.142 As a result of these lines for the perioperative management of patients with
improvements, hemodynamically stable patients are managed pheochromocytoma or paraganglioma have been developed.
more frequently postoperatively in a non-intensive care unit This management includes extensive preoperative cardiac
monitored room.143 However, any patient who exhibits evaluation and aggressive preoperative blood pressure control.
persistent hemodynamic instability including severe hyperten- There still remains variability in the selection of antihyperten-
sive and hypotensive episodes in the immediate postoperative sive agents, and newer agents are being considered. General
setting needs intensive postoperative monitoring.142 anesthesia is the primary anesthetic choice, with special
attention to agents available to treat wide swings in blood
Follow-Up Examination and Long-Term Medical pressure. In contrast to decades ago, more patients are being
Management recovered in non-intensive care unit settings. Postoperative
monitoring for hypotension, persistent hypertension, and
The primary concerns after surgical resection are persistent electrolyte abnormalities still is necessary to prevent unex-
tumors from incomplete tumor resection or tumor spillage pected complications and optimally manage any complications
during surgery and recurrence, which has been reported to be that can arise in the recovery period.
between 14% to 30%, and is more likely with larger tumors Undoubtedly, patients with pheochromocytoma present a
and those with familial disease.144–147 At present there are no challenge for the anesthesiologist. Diagnosis and perioperative
clinical, biochemical, genetic, or pathologic markers to indi- management of pheochromocytomas will continue to be
cate which tumors may become metastatic; therefore, close evolving processes, hopefully continuing on the trajectory of
follow-up is imperative. The European Society of Endocrinol- the improved outcomes observed over the last few decades.
ogy has published current recommendations for long-term
follow-up of postsurgical pheochromocytoma or paragan-
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