Pheochromocytoma: Perioperative and Intraoperative Management





Incidence, Clinical Significance, and Diagnosis


Pheochromocytoma is defined as a tumor arising from the chromaffin cells in the adrenal medulla that produces catecholamines: norepinephrine, epinephrine, and dopamine. The incidence of pheochromocytoma in the hypertensive population is 0.1% to 0.6%. It has been reported that approximately 5% of patients with an incidental finding of adrenal masses on imaging have a pheochromocytoma. Pheochromocytomas can occur sporadically or can be inherited, and at least one-third of patients have an inheritable germline mutation.


With a patient presenting with an incidental finding of adrenal nodule or with hypertension, it is prudent to confirm the presence and treat pheochromocytomas. The hypersecretion of catecholamines can lead to significant cardiovascular morbidity and mortality. Hypertensive crisis as defined by systolic blood pressure greater than 180 mm Hg and diastolic pressure of greater than 120 mm Hg, with or without end organ failure, can be elicited through tumor manipulation from surgery, exercise, various medications such as beta blockers, corticosteroids, and intravenous contrast. , Recurrent episodes of catecholamine excess can result in myocyte necrosis and inflammation leading to cardiomyopathy. In addition to the cardiovascular morbidity, at least 10% to 15% of pheochromocytomas are malignant. Malignant is defined as the presence of metastasis at sites where chromaffin histology is not usually present.


The classic symptoms of pheochromocytoma include headache, palpitations, or diaphoresis in hypertensive patients, although some patients present normotensive with the less common symptoms of fatigue, nausea, flushing, or orthostatic hypotension. Patients may also present with signs of end organ failure from hypertensive crisis including myocardial infarction, arrythmia, or stroke. As discussed earlier, up to a third of pheochromocytomas can be inheritable, so it is important to screen patients with the following diseases: multiple endocrine neoplasia type A/B, Von Hippel–Lindau disease, and neurofibromatosis type 1.


Diagnosis of pheochromocytoma can be confirmed with biochemical testing (plasma and urine) as well as anatomic imaging. The Endocrine Society Clinical Practice Guidelines on Pheochromocytoma and Paraganglioma published in 2014 recommend taking measurements of plasma free metanephrines or urinary fractioned metanephrines. This recommendation is echoed by the European Society of Endocrinology Clinical Practice Guidelines with measurements of plasma and urinary metanephrines as well as a chromogranin A.


Measurements of plasma free metanephrines or urinary fractioned metanephrines are the initial testing for patients suspected of pheochromocytoma. Plasma metanephrines have the highest sensitivity (99%) and specificity (89%) for diagnosis. Levels greater than or equal to three times the upper reference value for either metanephrine or normetanephrine should be considered highly suspicious for pheochromocytoma. Where values are not indicative of pheochromocytoma but are mildly elevated, tests should be repeated with prudence to evaluate if offending medications (i.e., levodopa, acetaminophen, certain beta blockers, or antidepressants) can be eliminated. Make sure the test is performed with the patient in a supine position for at least 30 minutes.


Modalities for initial anatomic imaging include computed tomography (CT) and magnetic resonance imaging (MRI). Recommendation 2.2 from the Endocrine Society guidelines suggests CT instead of MRI as the first choice imaging due to its spatial resolution for the abdomen, pelvis, and thorax. Sensitivity for localization on CT with contrast for pheochromocytomas is between 88% and 100%. More than 85% of pheochromocytomas elicit a mean attenuation of more than 10 Hounsfield units on unenhanced CT. On MRI scans, two-thirds of pheochromocytomas show increased signal intensity on T2-weighted images. Functional imaging such as 123 I-metaiodobenzylguanidine (MIBG) and 18 F-fluorodihydroxy-phenylalanine ( 18 F-FDG) positron-emission tomography (PET)/CT scanning have been recommended for patients with metastatic disease. The Endocrine Society guidelines suggest 18 F-FDG PET/CT as the preferred imaging modality for known metastatic disease. The sensitivity of 18 F-FDG PET was reported to be between 74% and 100% for patients with metastatic disease.


Once biochemical diagnosis and imaging confirm pheochromocytoma, the treatment of choice is surgical excision. Minimally invasive adrenalectomy is recommended for most pheochromocytomas. Laparoscopic (lateral transabdominal/transperitoneal) or posterior retroperitoneoscopic approaches are the gold standard for pheochromocytomas, for masses less than 6 cm. Open resection is reserved for large adrenal masses greater than 6 cm or invasive tumors to ensure complete tumor resection, prevent the rupture of the tumor capsule, and to prevent local recurrence. A laparoscopic approach is associated with less blood loss, less pain, less hospital days, and less surgical morbidity than open adrenalectomy.


Preoperative Management


CATECHOLAMINES AND ADRENORECEPTORS


An excess surge of catecholamines, both epinephrine and norepinephrine, produce different effects on the adrenoreceptors on the body’s various organ systems. Both epinephrine and norepinephrine stimulate the alpha receptors that produce vasoconstriction, which leads to either paroxysmal or sustained hypertension. Beta 1 receptors located in the cardiovascular system stimulated by both epinephrine and norepinephrine result in increased heart rate and contractility, also contributing to hypertension. The epinephrine stimulation of beta 2 receptors located in the bronchioles of the lungs and the arteries of skeletal muscle cause vasodilation. In addition, epinephrine stimulates glycogenolysis and gluconeogenesis, resulting in hyperglycemia. Understanding the effects of catecholamine excess can help the clinician in the preoperative management of the pheochromocytoma patient with appropriate alpha blockade, as well as helping the clinician anticipate the possible postoperative complications following catecholamine withdrawal.


The Endocrine Society guidelines recommend that all patients with functional pheochromocytoma should have preoperative blockade to prevent perioperative complications. Perioperative complications from induction of anesthesia to tumor manipulation may lead to severe hemodynamic instability leading to reduced cardiac output resulting in end organ ischemia. Successful preoperative alpha blockade has reduced the number of perioperative complications to less than 3%. α-Adrenergic blockers are the first-line drugs of choice, followed by the add on support of calcium channel blockers and beta blockers. The length of blockade preoperatively is for 7 to 14 days to allow for control of hypertension and heart rate. In our practice, we tend to increase the length of alpha blockade to about 3 to 4 weeks to assure an adequate and stable control of blood pressure. The goal of therapy is to have blood pressure less than 130/80 mm Hg while sitting and systolic pressure greater than 90 mm Hg and heart rate of 60 to 70 beats per minute when seated and 70 to 80 beats per minute when standing. , Although this is a good goal for older patients with preexisting hypertension, for younger and healthy patients we try to reach blood pressure goals of between 110/60 mm Hg to 120/70 mm Hg. In addition to the antihypertensive medications mentioned previously, a liberal high-sodium diet of 5000 mg for at least 3 to 5 days prior to the procedure, as well as increased fluid intake to counteract the catecholamine-induced volume contraction, is started. ,


ALPHA ADRENERGIC BLOCKERS


Phenoxybenzamine is a noncompetitive, nonselective α-adrenergic blockade for both alpha 1 and 2 receptors. It blocks postganglionic synapses in exocrine glands and smooth muscle. Phenoxybenzamine onset of action is about 2 hours, its maximum effect is reached in 4 to 6 hours, and it has a half-life of 24 hours. The recommended starting dose is 10 mg by mouth twice daily, with titration by increasing to 10 to 20 mg every 2 to 3 days until the blood pressure goal is reached, to a maximum of 1 mg/kg per day. , Common adverse side effects include reflex tachycardia, orthostatic hypotension, drowsiness, fatigue, miosis, and nasal congestion. It has been reported that, due to its longer half-life, intraoperative hemodynamics are better controlled during tumor manipulation but the occurrence of postoperative hypotension is more frequent than the alpha 1 selective α-adrenergic blockers. It is of note and important to consider when prescribing to patients with limited medical insurance coverage that phenoxybenzamine is considerably more expensive than an alpha 1 selective blocker, costing over $100 per capsule compared with 0.50 cent to $1.


Selective α1-adrenergic blockers include prazosin, doxazosin, and terazosin. They competitively inhibit postsynaptic α1-adrenergic receptors, which in return vasodilate veins and arterioles to decrease total peripheral resistance and blood pressure. Due to their shorter half-life than phenoxybenzamine, α1-selective blockers are associated with less postoperative hypotension. The longest half-life of the selective α1-adrenergic blockers is doxazosin, which accounts for its once/day dosing, starting at 1 to 2 mg/day with dose titration to desired effects up to 16 mg/day. , , Time to peak effect is approximately 2 to 3 hours, which may lead to a side effect of orthostatic hypotension; patients are urged to take it at night prior to going to bed. , Prazosin is administered in doses of 1 mg 2 to 3 times per day up to 15 mg/day in two to three divided doses, and terazosin is given in doses of 1 to 5 mg/day to a maximum of 20 mg/day. , , Common adverse reactions of selective alpha 1 blockers include orthostatic hypotension, central nervous system depression, drowsiness, dizziness, fatigue, and weakness. Selective alpha blockers are associated with less reflex tachycardia than phenoxybenzamine. This is due to the preferential alpha 1 blockade causing vasodilation to the lesser extent of binding to alpha 2 unlike phenoxybenzamine that causes the reflex tachycardia. They are also less expensive, making them a more attractive choice for pheochromocytoma patients.


Calcium channel blockers are added as an adjunct to alpha blockage for patients when blood pressure goals are not achieved, or patients are intolerable to the side effects of alpha blockade, or for patients with intermittent hypertension. , , Calcium channel blockers function through the inhibition of the norepinephrine-mediated calcium transit into vascular smooth muscle cells, which controls hypertension and tachyarrhythmias and is less likely to cause orthostatic hypotension. , , This class of drug also prevents catecholamine induced vasospasm, which is useful in the subset of pheochromocytoma patients who present with coronary vasospasm or myocarditis. , Calcium channel blockers that are frequently used as add on therapy include: nifedipine, amlodipine, nicardipine, and verapamil. Common side effects are headache, peripheral edema, nausea, constipation, fatigue, flushing, and tachycardia. The starting dose for amlodipine is 2.5 to 5 mg/day, titrating weekly to the desired effect to a maximum dose of 10 mg/day. The starting dose for nicardipine is 20 mg orally three times daily, titrated every 3 days to the desired effect to a maximum dose of 120 mg/day. , The extended-release form of nifedipine has a starting dose of 30 mg/day, with titration every 7 days to the desired effect to a maximum dose of 90 mg/day. , Verapamil, the extended release starts at 180 mg/day with a maximum dose of 540 mg/day. 12


β-Adrenergic receptor blockers are also an adjunct to alpha blockade for the preoperative management of pheochromocytoma patients. Beta blockers should only be added after the patient is on alpha blockade. The Endocrine Society guidelines published in 2014 stated that the addition of β-adrenergic blockers should only be added after at least 3 to 4 days of alpha blockade. Adding prior to alpha blockade may lead to a hypertensive crisis due to the unopposed stimulation of α-adrenergic receptors by exacerbating the epinephrine-induced vasoconstriction through losing the vasodilator properties of beta receptors. , The preference for β1-selective adrenergic blockers over nonselective β-adrenergic blockers has not been validated. Beta blockers help control the reflex tachycardia that is commonly seen with α-adrenergic receptor blockers, as well as assisting in achieving target blood pressure. The side effects of β-adrenergic blockers include bradycardia, fatigue, dizziness, confusion, and exacerbation of asthma. Beta blockers used as adjunct treatment in pheochromocytoma patients include atenolol, metoprolol, and propranolol. The starting dose of atenolol is 25 mg/day, with titration weekly to a maximum dose of 100 mg/day. , Propranolol has a starting dose of 20 mg orally three times daily, adjusted up to goal heart rate to a maximum of 120 mg/daily in three divided doses. , Metoprolol has a starting dose of 50 mg orally twice day, with titration weekly to a maximum dose of 400 mg/day in two divided doses. β-Adrenergic receptor blockers not recommended in the treatment of pheochromocytoma include labetalol and carvedilol. Labetalol has both alpha and beta antagonistic activity; however, its fixed ratio of alpha to beta (1:7) can lead to paradoxical hypertension or crisis. , It is recommended to achieve a desired antihypertensive effect that the ratio of alpha to beta should be at least 4:1. Carvedilol has effects similar to labetalol.


Less commonly used as an adjunct to alpha blockade for patients with refractory hypertension is metyrosine. It may be beneficial for patients with significantly excessive amounts of catecholamines. , Predictors of intraoperative hemodynamic instability include larger mass size and higher preoperative metanephrine/catecholamine levels. Metyrosine controls catecholamine production by inhibiting the enzyme tyrosine hydroxylase, which is involved in catecholamine synthesis, thus depleting adrenal catecholamine stores. The maximum effect of significantly depleted stores occurs after 3 days of treatment. Its depletion of stores is not entirely complete, thus alpha blockade is still recommended with the use of metyrosine. It is recommended to initiate treatment approximately 1 to 3 weeks prior to surgery, with starting doses of 250 mg orally every 8 to 12 hours and titration of dose every 3 days by 250 to 500 mg/day to a total dose of 1.5 to 2 g/day. , Limitations to metyrosine use is due to its limited availability, cost, and side effects. Metyrosine crosses the blood–brain barrier leading to both peripheral and central decreased catecholamine synthesis, which in turn causes side effects of sedation, depression, anxiety, diarrhea, tremors, and extrapyramidal signs. , ,


Treatment with α-adrenergic blocker alone will only restore the blood volume in 60% of patients. Patients with pheochromocytoma have significant volume contraction and require preoperative intravascular fluid resuscitation. This will help minimize refractory postoperative hypotension after tumor resection. The patient is instructed to start a high-sodium diet (greater than 5000 mg/day) about 3 days prior to surgery with adequate fluid intake to promote volume expansion. Patients with multiple comorbidities may require admission to hospital 1 day prior to surgery to have an intravenous administration of isotonic fluids , to aid with volume expansion. Aggressive volume expansion may be contraindicated in patients with renal insufficiency or heart failure.


Anesthetic Preoperative Assessment and Optimization


The process to achieve patient optimization as described earlier can take from 5 to 15 days or longer in patients with cardiomyopathy or refractory hypertension. , Prior to undergoing anesthesia, the following objectives should be met to assure proper patient optimization 13 :



  • ■

    arterial pressure control


  • ■

    reversal of chronic circulating volume depletion


  • ■

    heart and arrhythmia control


  • ■

    assessment and optimization of myocardial function


  • ■

    reversal of electrolyte and glucose disturbances.



ARTERIAL PRESSURE CONTROL


Severe preoperative and intraoperative hypertension can lead to stroke, arrhythmias, myocardial ischemia, left ventricular failure, and subsequent refractory hypotension following tumor resection. Preoperative alpha blockade is standard practice to provide preoperative blood pressure control. Successful alpha blockade is reflected by normalizing blood pressure with only mild orthostasis. Adequacy of blockade is assessed using Roizen’s criteria 14 :



  • 1.

    Blood pressure less than 160/80 mm Hg


  • 2.

    Orthostatic hypotension not less than 80/60 mm Hg


  • 3.

    No more than one premature ventricular contraction (PVC) in 5 minutes


  • 4.

    No new ST-T changes on the electrocardiogram (ECG) within the previous week.



Although these criteria were established in 1982, they have remained consistently reliable.


VOLUME DEPLETION


A patient in a chronic hypertensive state is volume-depleted secondary to the intense vasoconstriction through the α-1 receptors. This vasoconstriction is ameliorated by initiation of alpha blockade as mentioned previously; however, this can result in severe orthostatic hypotension in the preoperative phase and during tumor removal. In the patient with pheochromocytoma, the Endocrine Society guidelines recommend the patient increase fluid and salt intake. This can be achieved with 2 to 3 L of fluid orally, with 5 to 10 g of salt in the days prior to surgery. This volume expansion can be monitored and titrated with serial hematocrits. Hematocrit levels can fall 5 % to 10% in a patient who has been well hydrated.


HEART RATE AND ARRHYTHMIA CONTROL


Tachyarrhythmias can be the result of the epinephrine/dopamine secreting tumor or secondary to the alpha blockade treating the tumor. Selective β1-antagonists are the preferred treatment modality but must be started after complete alpha blockade. In doing so, unopposed alpha-mediated vasoconstriction that could occur after antagonism of β2-mediated dilation will be avoided. Should a selective β1-antagonist be started prior to proper and complete alpha blockade, a hypertensive crisis could occur, and the negative inotropic effect of the beta blockade will further compromise myocardial function.


ASSESSMENT OF MYOCARDIAL FUNCTION


Patients with a pheochromocytoma need to be assessed for the effect of catecholamine excess on end organs. The end organ most commonly effected is the heart and it can present as dilated and/or catecholamine cardiomyopathy with varying degrees of heart failure. , All patients undergoing removal of pheochromocytoma need a complete cardiovascular evaluation. This will involve a 12-lead echocardiogram, which will show the presence and severity of left ventricular strain, hypertrophy, bundle branch blocks, and ischemia. Preoperative echocardiography is helpful to assess systolic and valve function as well as delineate the degree of diastolic dysfunction. Left ventricular hypertrophy can correlate with the severity, duration, and degree of blood pressure control. Catecholamine induced cardiomyopathy can cause both cardiogenic and noncardiogenic pulmonary edema. The impaired cardiac function associated with pheochromocytoma may improve once catecholamine levels return to normal.


REVERSAL OF ELECTROLYTE AND GLUCOSE DISTURBANCES


Assessment of electrolytes can identify catecholamine-induced renal impairment. Hypercalcemia can occur secondary to a pheochromocytoma and is often associated with a parathyroid adenoma. Hyperglycemia can result from increased glycogenolysis, impaired insulin release, lipolysis, and increased glucagon release. This, coupled with peripheral insulin resistance, requires standard therapies of oral hyperglycemics and/or insulin.


Anesthetic Preparation and Goals for the Operating Room


Preparation of hypotensive and vasoactive drugs should be prepared prior to the patient entering the operative suite. Commonly used hypotensive drugs are sodium nitroprusside (SNP), nitroglycerine (NTG), esmolol, vasopressin, phenylephrine, and norepinephrine. Vasoactive drugs commonly used include magnesium sulfate, labetalol, and nicardipine. In patients with catecholamine cardiomyopathy, inotropes inclusive of epinephrine and dopamine may be necessary. Fluids in the form of colloids, crystalloids, blood, and blood products should also be readily available. Preparing all infusions in a programed intravenous pump with tubing to a manifold allows for quick and ready administration. Traditional general anesthesia set up is warranted with an endotracheal tube (ETT) and basic standards of monitoring as recommended by the American Society of Anesthesiologists. Invasive blood pressure monitoring with an arterial line is imperative in patients with pheochromocytoma.


Positioning of the patient can vary dependent on the surgical approach. Overall, the primary goal is to deliver an anesthetic that provides stable hemodynamics despite catecholamine surges during anesthetic induction, peritoneal insufflation, surgical stimulation, and tumor handling followed by the opposite with tumor ligation. Careful planning and open communication with the surgical team is pivotal.


Anesthetic Induction and Monitoring


Preinduction relief from anxiety with a benzodiazepine will assist in keeping the patient calm. Apprehension and anxiety can predispose to catecholamine surges. The benzodiazepine of choice in the hospital setting and prior to entering the operative suite is intravenous midazolam. However, some patients may need lorazepam or diazepam the night before to assist in anxiety relief. ,


One of the most critical portions of anesthetic delivery is the direct visual laryngoscopy (DVL) and endotracheal intubation, which is why a preinduction arterial line insertion is recommended. The allowance for continuous beat-to-beat monitoring and rapid pharmacologic intervention as needed during this critical time is necessary. The anesthetic induction goal is to limit the hemodynamic stresses of DVL and ETT insertion. , Anesthetic induction agents often include propofol and etomidate. Propofol is preferred because it produces vasodilation and blunts the response to laryngoscopy and intubation, whereas etomidate is recommended for its cardiovascular stability. Ketamine is avoided due to its sympathomimetic effects. All agents that cause histamine release should be avoided. Neuromuscular blockade is generally achieved with a nondepolarizing blocker such as rocuronium, vecuronium, or cisatracurium. The depolarizing neuromuscular blocker succinylcholine is avoided as research has shown the potential for catecholamine surges from the muscle fasciculations that it produces with administration. It is said that the muscle fasciculations in the abdominal compartment can mechanically compress the tumor, which can result in catecholamine surge. Succinylcholine can also stimulate the autonomic ganglia, which can result in cardiac arrhythmia. ,


Central venous access is a consideration for guiding fluid therapy as well as providing access to the central venous compartment for administration of vasodilators and vasoconstrictors. Central venous access is not mandatory and surgical resection can be achieved without insertion but should be considered in particularly compromised patients. If a central venous catheter is not utilized, two large-bore peripheral intravenous catheters should be initiated.


Anesthetic Maintenance


Maintenance of anesthesia can be maintained with inhalational agents or total intravenous anesthetics. Sevoflurane is preferred for its cardio stability and lack of arrhythmogenic potential. Isoflurane lowers peripheral vascular resistance and blood pressure, and therefore can also be used. Halothane and desflurane should be avoided secondary to their arrhythmia potential and sympathetic stimulation, respectively. Total intravenous anesthesia is often maintained with propofol and remifentanil or dexmedetomidine. Propofol is a short-acting drug that acts by increasing inhibitory γ-aminobutyric (GABA) synapses and inhibiting glutamate. This, coupled with the short-acting opioid remifentanil, acts by binding μ-receptors in the brain, spinal cord, and peripheral nerves. Synergistically the drugs can decrease the hemodynamic response during pheochromocytoma resection.


Intraoperative transesophageal echo can be utilized for real-time monitoring of intravascular volume status, as well as early detection of myocardial wall motion abnormalities, suggesting myocardial ischemia. Noninvasive methods for cardiac output estimation and stroke volume variation to diagnose fluid deficit can also be utilized. Fluid management and balance are critical, as underhydration can lead to severe hypotension following tumor resection, whereas overhydration can lead to pulmonary edema and congestive heart failure in a heart that is already compromised.


Hyperglycemia is a common result of catecholamine excess, and insulin infusion therapy should be routine management in this patient population.


Anesthetic Management of Intraoperative Hypertension and Hypotension


The main complication anticipated during surgery on a pheochromocytoma is the hemodynamic instability with hypertension prior to the tumor removal and hypotension after tumor isolation. However, hypertension can also result from a multitude of sources prior to tumor manipulation, such as patient positioning, anesthetic induction, pneumoperitoneum, and surgical incision. In these situations, the catecholamine release is from excessive stores in nerve endings and is generally more transient and responsive to therapy. Communication with the surgeon is critical prior to and during tumor manipulation. Risk factors for hemodynamic instability include large tumor, baseline mean arterial pressure more than 100 mm Hg, and a high plasma norepinephrine concentration.


Tumor manipulation can cause a significant increase in plasma levels of norepinephrine and epinephrine. Management of hypertension should be with short-acting and potent vasodilators ( Table 13.1 ). The secretion of norepinephrine will result in intense hypertension with either bradycardia or tachycardia, with bradycardia being more common. Epinephrine secretion will result in severe tachycardia (paroxysmal supraventricular tachycardia and ventricular arrhythmias) and hypertension, but with less severity. Immediate response to the hemodynamic change should occur with deepening of the anesthetic and rapidly administering SNP and/or nitroglycerin. SNP will have rapid onset of arterial dilation with the infusion started at 0.5 to 1.5 μg/kg per minute. Both drugs have a rapid onset of action and can be easily titrated to achieve hemodynamic stability and preload reduction. Esmolol (0.5 to 1 mg/kg intravenous bolus or infusion) is a short-acting beta-receptor antagonist and can be an adjunct for vasodilatation to combat intraoperative hypertension and tachycardia. Labetalol (5 to 10 mg intravenously) can also be used to control these crises. In resistant cases, nicardipine and/or fenoldopam can be used. Nicardipine, a dihydropyridine calcium channel antagonist, is a potent arterial vasodilator and can be used as a bolus or infusion. The half-life of 40 to 60 minutes for nicardipine can result in persistent hypotension. Fenoldopam (dose of 0.2 mg/kg per minute) causes peripheral vasodilation while increasing renal blood flow. Magnesium sulfate can be used as a potent arterial vasodilator inhibiting catecholamine release by directly inhibiting their receptors. It is generally used as an intravenous bolus in 1 to 3 g and is a strong calcium antagonist. Catecholamine excess will often result in hyperglycemia, and insulin infusion therapy, as indicated, should be considered.


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Nov 10, 2024 | Posted by in ENDOCRINOLOGY | Comments Off on Pheochromocytoma: Perioperative and Intraoperative Management

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