Continuing Education Activity

Pheochromocytoma (PCC) is a rare catecholamine-secreting tumor of adrenal origin. When it is extra-adrenal, it is referred to as paraganglioma. PCC is the cause of hypertension in 1 in 500 adults. These tumors are usually diagnosed by the 4th to 5th decade and are found equally in both genders. Hereditary pheochromocytoma usually presents at a younger age. This activity outlines the clinical presentation of PCC, its pathophysiology, and diagnostic tests used to diagnose pheochromocytoma. This activity entails pre-operative optimization of patients for resection of PCC. This CME educates on detailed intra-operative management, including hemodynamic monitoring and management of possible intra-op complications. Post-operative management of patients has been discussed. In addition, a small section on the surgical approach has been described.

Objectives:

• Summarize the etiology of pheochromocytoma.
• Describe the clinical presentations of pheochromocytoma.
• Discuss the peri-operative risk in patients with pheochromocytoma and how to decrease the peri-operative risk and improve outcomes.
• Outline the intra-operative and post-operative complications in pheochromocytoma resection and their management.

Introduction

Pheochromocytoma (PCC) is a rare neuroendocrine catecholamine-secreting tumor originating from chromaffin tissue. The term 'pheochromocytoma' refers to the color the tumor cells get when stained with chromium salts (In Greek, phaios means dusky, chroma means color, and cytoma means tumor)[1].

Yearly, 1 to 2 per 1000 people are diagnosed with PCC. PCC is the cause of hypertension in 1 in 500 adults. These tumors are usually diagnosed by the 4th to 5th decade and are found equally in both genders[2]. Hereditary pheochromocytoma usually presents at a younger age[3][4].

Anatomy and Physiology

The cells in chromaffin tissue produce and store catecholamines i.e.norepinephrine and epinephrine. Some tumors may also produce dopamine[5]. The clinical manifestations of PCC originate from excessive catecholamine secretion by the tumor cell either continuously or intermittently[6].

The normal adrenal medulla secretes about 85% epinephrine and 15% norepinephrine, but norepinephrine is the predominant catecholamine secreted by PCC[7].

Most PCC are intra-adrenal and solitary. As per the traditional "10 percent rule" for pheochromocytoma: 10% of pheochromocytomas are familial, 10% are malignant, 10% are extra-adrenal, and 10% are in children. However, this 10 percent rule is oversimplified and incorrect as the prevalence of extra-adrenal tumors (paragangliomas) is as high as 20%, and about 20 to 30% of these tumors are hereditary[8]. 

Familial syndromes associated with pheochromocytomas include multiple endocrine neoplasia type 2A and 2B, neurofibromatosis (Von Recklinghausen disease), and Von Hippel-Lindau syndrome[9].

Indications

The classic triad of symptoms in patients with PCC consists of episodic headaches, diaphoresis, and tachycardia[10]. High blood pressure is the most common sign of pheochromocytoma, though 10 to 20 percent of patients may present with normal blood pressure[11]. High blood pressure is caused by the release of noradrenaline and adrenaline from the tumor. The release of catecholamines can be persistent or episodic; therefore, the patient may have constant hypertension or episodic hypertension. Between 10 and 20 % of patients may not have any clinical features, and the tumor is sometimes found incidentally during a workup. The prevalence of PCC in patients with hypertension is less than 0.2%[12].

Patients with PCC may also present with hyperglycemia, polyuria, polydipsia, tremor, orthostatic hypotension, visual blurring, and weight loss.[6] 

Diagnosis

Pheochromocytoma is suspected based on the clinical features and diagnosed by measuring the level of epinephrine (adrenaline), norepinephrine (noradrenaline), and their metabolites (metanephrine, normetanephrine, and vanillylmandelic acid ) either in urine or blood. Measurement of  24-hour fractionated urinary metanephrines and catecholamines levels in suspected patients is the best method to diagnose PCC[13][14][15].

Measurement of plasma fractionated metanephrines is an alternative test, but 24-hour urine tests are generally considered superior to plasma tests for diagnosis because the tumor secretes catecholamines only intermittently, and the catecholamines have a short half-life. Plasma-fractionated metanephrines may be used as a first-line test when there is a high index of suspicion for PCC. Plasma-fractionated metanephrines may also be used as a first-line test for children due to the difficulty in obtaining complete 24-hour urine.

Patients with positive results should be further evaluated with imaging to confirm and localize the tumor. Computed tomography (CT) and MRI are most commonly used due to their wide availability. MRI involves no radiation, and it can distinguish PCC from other adrenal masses though it is expensive and more time-consuming. Computed tomography with or without iodine 131–labeled meta-iodobenzylguanidine (MIBG) is very accurate in diagnosing as well as localizing the tumor[6].

A provocative test with glucagon was used to confirm or exclude PCC in the past but is not preferred due to low sensitivity (< 50%) and risk of precipitation of severe hypertension[16]. Suppression tests using clonidine or phentolamine are also sometimes used for diagnostic purposes[17][18].  Clonidine inhibits the release of catecholamines via a neurogenic mechanism. Clonidine does not affect the catecholamines released by PCC.

Preparation

Pre-op preparation and optimization are essential to decrease peri-operative morbidity and mortality in pheochromocytoma. Roizen criteria proposed by Roizen et al. in 1982 are commonly used to assess the efficacy of adequate preoperative alpha blockade[19]. These criteria include:

• No in-hospital blood pressure >160/90 mmHg for 24 h before surgery.
• No orthostatic hypotension with blood pressure <80/45 mmHg.
• No ST or T wave changes for 1-week before surgery.
• No more than five premature ventricular contractions per minute.

Catecholamines (noradrenaline is the most common) released from the tumor cause vasoconstriction, and hence patients with PCC usually have contracted intravascular volume despite being hypertensive. It is vital to optimize intravascular volume to decrease peri-operative hemodynamic fluctuation. An alpha-adrenergic blocker is administered starting 10 to 14 days preoperatively to optimize blood pressure and ensure euvolemia for volume expansion. Phenoxybenzamine is the most commonly used drug. It is an irreversible, nonspecific alpha-adrenergic blocker. It is long-acting and has a half-life of approximately 24 hours[20].

Selective alpha-1-adrenergic blocking agents, prazosin, terazosin, and doxazosin may all be used to facilitate preoperative α-blockade. Blockade of alpha-1 and alpha-2 leads to smooth muscle relaxation in arterioles and venous capacitance vessels. Orthostatic hypotension and reflex tachycardia, especially in the setting of hypovolemia, are potential side effects of the alpha blockade, particularly with long-acting phenoxybenzamine. Selective alpha-1-adrenergic blocking agents cause less reflex tachycardia than non-selective alpha-blockers because the alpha-2 inhibitory activity is left intact.

The successful alpha blockade is reflected by normalizing blood pressure with mild orthostasis. The beta blockade should never be initiated before the alpha blockade. They should be started only after an adequate length of the alpha blockade is established; if not, a hypertensive crisis can occur due to unopposed alpha-receptor stimulation[21][22]. 

Alpha-methyl-para-tyrosine (metyrosine) inhibits tyrosine hydroxylase, the rate-limiting enzyme in catecholamine synthesis[23][24]. This can be used as an appropriate adjunct in malignant or unresectable tumors. Patients with long-standing PCCs can develop severe cardiomyopathy. A detailed preoperative assessment by an experienced anesthesiologist is required to evaluate cardiovascular status, adequacy of alpha and beta blockade, volume resuscitation, and any other comorbidities.

Technique or Treatment

Surgical Approach

Minimally-invasive adrenalectomy via retroperitoneal or transperitoneal approach is the gold standard for pheochromocytoma resection. A minimally invasive approach is preferred, as it leads to lower postoperative pain scores, earlier ambulation, and faster recovery. This approach has shown a lowered incidence of postoperative thromboembolic complications, reduced hospital stays, and is cost-effective[25][26].  However, open procedures may be needed for larger masses and extra-adrenal tumors. 

Anesthesia Management

Patients should be pre-medicated with anti-anxiety medication like midazolam. An arterial line is preferred before induction as induction may result in hemodynamic lability. General anesthesia alone or with an epidural is used for PCC resection. Epidural may be considered if open surgery is planned to provide adequate pain management in the postoperative period. Good IV access with two peripheral lines is necessary. Intra-operative transesophageal echocardiogram (TEE)/Pulmonary artery catheter may be considered in patients with severe cardiomyopathy to guide fluid management/inotrope administration or to assess ventricular function.

Central venous access for vasopressor/inotrope administration may be placed in patients with poor LV function. Propofol is the most commonly used agent for the induction of anesthesia if the patient has good LV function. Patients with cardiomyopathy would need cardio-stable slow induction with divided doses of propofol or etomidate or narcotic-based induction. Ketamine should be avoided because of its sympathomimetic properties. Smooth induction of anesthesia with an optimal depth of anesthesia is the main goal to avoid hypertensive response during laryngoscopy and endotracheal intubation.

Laryngoscopy and endotracheal intubation often cause hypertension and tachycardia, which could be exaggerated in patients with PCC due to the release of catecholamines. Severe hypertension and tachycardia may result in arrhythmias and myocardial ischemia. The elevation in blood pressure and heart rate associated with laryngoscopy and intubation can be prevented or minimized by ensuring adequate depth of anesthesia.

Sevoflurane is the most commonly used inhalational agent for the maintenance of anesthesia for PCC resection as it lacks the arrhythmogenic potential and has a favorable hemodynamic profile compared with other inhalational agents. Desflurane can result in tachycardia and hypertension, especially when concentration is increased rapidly. Sympathomimetic drugs (ketamine, ephedrine) and drugs causing histamine release (atracurium, morphine) should be avoided. Metoclopramide is contra-indicated as it can induce hypertensive crisis and can also cause adrenergic myocarditis with cardiogenic shock in patients with PCC.[27] 

It may be mediated by metoclopramide inhibiting dopaminergic suppression of presynaptic norepinephrine release. It has also been found to directly stimulate the release of catecholamines in PCC.[28] Glucagon can release catecholamines in PCC, resulting in a hypertensive crisis[29].

Intra-operative Hemodynamic Management

Peritoneal insufflation during laparoscopic resection and tumor manipulation during surgery can cause an abrupt release of catecholamine, resulting in severe hypertension and tachycardia. This hypertensive crisis may result in myocardial ischemia or stroke[30][31][32]. 

Short and rapidly acting vasodilators like nitroprusside, nitroglycerine, or calcium channel blockers like nifedipine and clevidipine are commonly used to control hypertension. Catecholamine excess can also result in life-threatening coronary artery vasospasm. Calcium channel blockers are beneficial in controlling vasospasm. Clevidipine is a newer dihydropyridine calcium channel antagonist used intravenously to reduce blood pressure. Intravenous clevidipine has a rapid onset and short duration of action and can be easily titrated for predictable blood pressure control. Phentolamine can be used to rapidly control hypertensive episodes. It is a short-acting non-selective alpha-1 and alpha-2 antagonist with a duration of action of 10 to 15 minutes.

In a patient with PCC, beta-blocker should only be considered after α-blocker administration. Or else, unopposed catecholamine-induced α-agonism can trigger an acute hypertensive crisis and significantly raise afterload and myocardial oxygen demand. Labetalol is not preferred due to its β-adrenergic antagonism, which can provoke unpredictable, unopposed α-receptor agonism from circulating catecholamines resulting in hypertensive crisis. 

Intravenous labetalol has an α:β receptor antagonism ratio of 1:7. Thus, it has a preference for β-receptor and the potential for worsening hypertension. Labetalol may result in persistent hypotension and bradycardia following the removal of the tumor. If pre-operative α-antagonism has been instituted, beta-blocker like esmolol or metoprolol may be titrated to control heart rate.

Esmolol is a short-acting, competitive antagonist of beta-1-adrenergic receptors[33]. It is rapidly inactivated by red cell esterases and has a half-life of 9 minutes. Due to the short half-life, esmolol is only administered intravenously. For intra-operative hypertensive crisis and tachycardia, a loading dose of 500 to 1000 mcg/kg over 1 minute, followed by an infusion of 50 mcg/kg per minute until the max dose of 200 mcg/kg per minute, can be used to control blood pressure.

The depth of anesthesia can also be changed to optimize hemodynamic response. After the ligation of the blood vessel of the tumor, a precipitous drop in blood pressure may occur. This is usually due to the sudden drop in endogenous catecholamine levels in the setting of chronic downregulation of alpha-adrenergic receptors in patients with PCC. Fluid bolus with vasoconstrictors like phenylephrine and noradrenaline are used to maintain blood pressure. In refractory hypotension, vasopressin infusion ( 0.01 to 0.03 units/minute) has been used to maintain blood pressure[34][35][36]. 

Vasopressin is particularly effective in managing hypotension in pheochromocytoma as vasopressin has no action on peripheral adrenergic receptors for its effect. When all these vasoactive agents are not adequately effective, methylene blue may be tried. Methylene blue inhibits nitric oxide synthase and guanylate cyclase and has been found effective in managing refractory vasoplegic patients[37]. Hemodynamically stable patients are extubated at the end of surgery and transferred to the post-anesthesia care unit. However, patients requiring vasopressors to maintain adequate blood pressure are transferred to the intensive care unit.

Complications

Following the excision of the tumor, hypotension may ensue. This hypotension is multifactorial. It may be due to the downregulation of alpha-adrenergic receptors, hypovolemia, or residual effects of long-acting antihypertensive medications like phenoxybenzamine. Up to half of the patients may be hypertensive for a few days after the tumor resection.

Plasma catecholamine levels (norepinephrine) may not decrease to normal for a few days after the tumor resection. Persistent hypertension may also signify a residual tumor. Hypoglycemia is another significant concern; blood sugar should be checked regularly every 4 to 6 hours. As catecholamine inhibits insulin secretion, hence sudden decrease in catecholamine level after the resection of a tumor can result in a rebound increase in insulin secretion[38].

Clinical Significance

Surgical resection of the tumor is the treatment of choice for PCC and has a success rate of more than 90%. However, due to end organ damage resulting from excessive catecholamine and labile hemodynamics from fluctuating catecholamine levels, it is one of the most complex and challenging tasks for anesthesiologists.

Adequate pre-op optimization is mandatory to decrease perioperative morbidity and mortality. Perioperative management for PCC should be done by a multidisciplinary team, including an anesthesiologist, surgeon, and endocrinologist. Pre-operative evaluation should focus on assessing end-organ damage due to elevated catecholamine levels. These patients are at risk for catecholamine-induced cardiomyopathy and may present with arrhythmias, myocardial ischemia, and reduced ventricular ejection fraction.

Pre-op preparation with alpha-adrenergic and beta blockade is recommended to control blood pressure and restore intravascular volume. Despite optimization, the patient may have labile hemodynamics in the perioperative period. General anesthesia is required for laparoscopic resection of PCC. Smooth induction with adequate depth of anesthesia is the goal of anesthesia. Invasive blood monitoring is mandatory during surgery. An arterial line should be placed before induction of anesthesia, which facilitates the early recognition and management of hemodynamic changes.

Hemodynamic instability is the most common complication during surgery. Hypertension and tachycardia are common during intubation and before the ligation of the tumor. Hypotension may be commonly seen after ligation/removal of the tumor—close communication with the surgeon help in anticipation of events that might cause hemodynamic fluctuation.

Enhancing Healthcare Team Outcomes

Pheochromocytoma resection is a high-risk surgical procedure. An interprofessional team consisting of an experienced surgeon, anesthesiologist, and endocrinologist is required. Pre-operative optimization with alpha-blocking agents and close hemodynamic monitoring in the peri-operative period is essential for the best outcome.