Anesthesia for the adult with pheochromocytoma

INTRODUCTION — Pheochromocytomas are neoplasms of chromaffin tissue that synthesize catecholamines. Pheochromocytoma is a rare disorder that presents challenges for the anesthesiologist. By some estimates, 25 to 50 percent of hospital deaths of patients with unmanaged or unknown pheochromocytoma occur during induction of anesthesia or during operative procedures for other conditions [1]. Since treatment of pheochromocytoma almost always includes surgical resection, most of these patients will require anesthesia.

Sympathetic paragangliomas are neuroendocrine tumors that arise from the extra-adrenal autonomic ganglia and are indistinguishable from pheochromocytomas at the histologic level [2,3]. They can secrete catecholamines and present clinically like pheochromocytomas, so the concerns for anesthesia for patients with paragangliomas are the same.

This topic will discuss the preoperative evaluation, intraoperative management, and postoperative care of patients who will undergo resection of pheochromocytoma. Diagnosis, clinical presentation, and medical optimization prior to surgery for pheochromocytoma are discussed separately. (See "Clinical presentation and diagnosis of pheochromocytoma" and "Treatment of pheochromocytoma in adults".)

PERIANESTHETIC RISKS AND OUTCOMES — Many patients who undergo pheochromocytoma resection exhibit labile blood pressure (BP), arrhythmias, and tachycardia during and after surgery, though most can be managed without lasting morbidity or mortality. Because of the rarity of pheochromocytoma, most data on the anesthetic management and perioperative outcomes have been reported in small case series that spanned many years. The following observational studies illustrate the complications seen in patients with known pheochromocytoma who present for resection:

●A single institution study of 258 patients who underwent resection of pheochromocytoma or paraganglioma between 2000 and 2015 reported substantial intraoperative hemodynamic variability, regardless of preoperative catecholamine levels [4]. Over 98 percent of patients received preoperative alpha adrenergic blockade. Most patients received intraoperative vasodilators, and approximately one-half required vasopressors. Postoperative hypotension occurred in 11 percent of patients, with approximately half requiring vasoactive therapy. Acute kidney injury and postoperative pulmonary complications occurred in 10 percent and 7 percent of patients, respectively. One patient died during the hospitalization.

●Another observational study of 143 cases reported no deaths or myocardial infarctions [5]. Twenty-five percent had sustained hypertension during surgery, and 14 percent experienced a systolic BP (SBP) >220 mmHg for a mean duration of nine minutes. Four percent required prolonged postoperative endotracheal intubation. Significant risk factors for adverse perioperative events included large tumor size, increased levels of preoperative catecholamines, and longer duration of surgery.

●A third single-institution observational study of 81 laparoscopic resections reported no deaths or myocardial infarctions [6]. Intraoperative hypertension (SBP >170 mmHg) and hypotension (SBP <90) occurred in 53 and 28 percent of patients, respectively. Tumor size over 6 cm correlated with longer surgical time, but not with increased BP lability.

Risks are much higher for patients with unrecognized pheochromocytoma who undergo anesthesia for unrelated surgery. In this setting, the patient can present with unexplained severe hypertension, tachycardia, arrhythmias, and cardiovascular collapse after induction of anesthesia [7] or at any time during surgery (eg, after administration of metoclopramide [8]). Mortality for such patients approaches 80 percent [9].

PREOPERATIVE EVALUATION — Preoperative evaluation and medical management for pheochromocytoma resection should be multidisciplinary, including the surgeon, anesthesiologist, and endocrinologist. Once the diagnosis is confirmed, the patient must be evaluated for possible end organ damage caused by excess catecholamine secretion, and preoperative medical preparation should be started. (See "Treatment of pheochromocytoma in adults", section on 'Medical preparation for surgery'.)

Timing and goals — We assess patients with pheochromocytoma at least 7 to 14 days prior to resection to allow time for modification of treatment, if necessary. Prior to this evaluation, the endocrinologist will have titrated therapy aimed at minimizing the physiologic impact of catecholamine release. This preoperative medical therapy usually takes 10 to 14 days.

The focus of our evaluation includes an assessment of the following:

●End organ damage that may affect anesthetic management. (See 'End organ damage' below.)

●The preoperative medical therapy used, which may impact intraoperative and postoperative events. (See 'Preoperative medical therapy' below.)

●Whether the preoperative medical therapy has attained its goals (ie, control of hypertension and normalization of intravascular volume). (See 'Preoperative testing' below.)

Details regarding preoperative medical therapy are discussed in more detail separately. (See "Treatment of pheochromocytoma in adults", section on 'Medical preparation for surgery'.)

Clinical assessment — The classic triad of symptoms of pheochromocytoma consists of hypertension, headache, and sweating, though most patients with pheochromocytoma do not present with all three. Other, less common signs and symptoms include orthostatic hypotension, blurred vision, papilledema, weight loss, polyuria, polydipsia, and constipation. (See "Clinical presentation and diagnosis of pheochromocytoma", section on 'Clinical presentation'.)

Some hereditary conditions are associated with pheochromocytoma (eg, von Hippel Lindau, multiple endocrine neoplasia type 2, neurofibromatosis type 1). When patients with these conditions present for other surgical procedures, signs and symptoms suggesting pheochromocytoma should be elicited. (See "Pheochromocytoma in genetic disorders", section on 'Familial pheochromocytoma'.)

Patients with pheochromocytoma rarely present in extremis, with a condition termed pheochromocytoma crisis, or pheochromocytoma multisystem crisis. Such patients may have either hypertension or hypotension, hyperthermia (temperature >40°C), mental status changes, and other organ dysfunction [10]. Emergency pheochromocytoma resection may be required, and mortality is high [11].

End organ damage — In addition to the routine preoperative anesthesia history and physical examination, evaluation should focus on potential end organ damage resulting from excess catecholamine secretion. Excess catecholamines secreted by pheochromocytomas can cause pathophysiological changes in the cardiovascular and other systems, as shown in the table (table 1) [12,13].

Of these, damage to the cardiovascular system is the most likely to impact outcomes with anesthesia. Catecholamine excess can result in volume depletion, postural hypotension, organ or limb ischemia, aortic dissection, angina, myocardial infarction, acute or chronic cardiomyopathy, congestive heart failure, and arrhythmias [14,15]. Increased risk of cardiovascular complications may be a direct effect of catecholamine excess, rather than hypertension alone [16].

Patients with pheochromocytoma and paraganglioma are at risk for catecholamine induced cardiomyopathy (also called takotsubo cardiomyopathy), which is often reversed with preoperative optimization or after surgical treatment [17]. In a single institution retrospective review of 140 patients scheduled for surgery for pheochromocytoma or functional paraganglioma, 11 percent had acute catecholamine induce cardiomyopathy, all with normal coronary angiography; 10 of those 15 patients presented with cardiogenic shock [18]. Median left ventricular ejection fraction rose from 30 percent at diagnosis of cardiomyopathy to 71 percent at the time of surgery. There are reports of patients with refractory cardiogenic shock having been managed successfully with short-term mechanical circulatory support (ECMO) until surgery was performed [19].

Preoperative cardiac evaluation should include an electrocardiogram (ECG) to evaluate for possible ischemic changes and rhythm disturbances. ST and T wave changes suggestive of ischemia should resolve with preoperative medical preparation; if necessary, surgery should be delayed until active ischemia has resolved and arrhythmias are adequately controlled prior to elective surgery.

A preoperative echocardiogram should be performed to assess ventricular function, chamber size, and wall motion. An echocardiogram may be required to rule out primary cardiac paraganglioma, which is extremely rare [20-22]. A Holter monitor is rarely indicated as arrhythmias should resolve with preoperative medical preparation.

Preoperative medical therapy — Preoperative medical therapy aimed at minimizing the physiologic impact of catecholamine release is a key component of the care of a patient with a catecholamine-secreting neoplasm.

Goals of therapy — A goal for preoperative medical therapy is to control hypertension and reverse volume depletion. Preoperative pharmacologic preparation is indicated for all patients with catecholamine-secreting neoplasms. Preoperative alpha-adrenergic blockade may prevent or reduce hypertensive crises during surgery for pheochromocytoma, allow intravascular volume expansion, and improve cardiac function in patients with catecholamine-induced myocarditis and cardiomyopathy. While this process is usually managed by an endocrinologist, the anesthesiologist should understand the regimen used and the goals of therapy, which are twofold (see "Treatment of pheochromocytoma in adults", section on 'Medical preparation for surgery'):

●Control of hypertension, including prevention of hypertensive crisis during surgery

●Normalization of intravascular volume

There is no universally accepted regimen, and clinical practice varies. Options include combined alpha-adrenergic and beta-adrenergic blockade, calcium channel blockers, and metyrosine. A high-sodium diet is usually incorporated to aid in the expansion of intravascular volume. Details of various regimens are discussed separately. (See "Treatment of pheochromocytoma in adults", section on 'Medical preparation for surgery'.)

Preparation often takes between 10 and 14 days. Effectiveness of medical preparation is assessed by twice-daily orthostatic blood pressure (BP) measurements, typically aiming for a seated BP of 120/80 mmHg, a standing systolic blood pressure (SBP) ≥90 mmHg, and a heart rate between 60 and 70 beats/minute (bpm) seated and 70 to 80 bpm standing.

Adrenergic blockade-free preoperative preparation — Some centers avoid adrenergic blockade before surgery for pheochromocytoma. However, guidelines and many experts continue to recommend preoperative adrenergic blockade. (See "Treatment of pheochromocytoma in adults", section on 'Combined alpha and beta-adrenergic blockade'.)

The literature on alpha-blockade free management consists of retrospective studies.

●In a 2020 meta-analysis of four retrospective studies (603 patients) of patients undergoing adrenalectomy for pheochromocytoma, mortality, cardiovascular complications, mean maximal intraoperative systolic and diastolic BP, and mean maximal intraoperative heart rate were similar in patients who received preoperative alpha-blockade versus those who received no preoperative alpha blockade [23]. The quality of evidence was judged to be very low.

●In another multicenter, international retrospective study of 1860 patients with pheochromocytoma or paraganglioma, 343 of whom underwent surgery without alpha-receptor blockade, alpha-blockade was associated with increased risk of complications related to hemodynamic instability compared with no blockade (5.9 versus 0.9 percent) [24]. Mortality was similar in patients with or without alpha-blockade (0.5 versus 0.3 percent). Most operations (78.9 percent) were performed using minimally invasive techniques.

Impact on intraoperative management — The medications used for preoperative management of catecholamine excess have different properties that may impact the likelihood and management of perioperative hemodynamic changes. While the regimen is usually selected and managed by an endocrinologist, the anesthesiologist must understand the potential impact on intraoperative management. Details of various regimens are discussed separately. (See "Treatment of pheochromocytoma in adults", section on 'Medical preparation for surgery'.)

Combined alpha- and beta-adrenergic blockade is the most commonly implemented strategy. Alpha blockade is initiated first, and for patients with tachycardia or arrhythmias, beta blockade is typically added cautiously several days before surgery. The beta-adrenergic blocker should never be started before the alpha blocker because blockade of vasodilatory peripheral beta-adrenergic receptors with unopposed alpha-adrenergic stimulation can lead to a further elevation in BP. Calcium channel blockers (eg, nicardipine) are sometimes used to supplement combined alpha and beta blockade or as an alternative for patients with intolerable side effects from other regimens.

●Alpha-adrenergic blockade – Several different alpha-adrenergic blocking medications may be administered preoperatively for pheochromocytoma resection, and none is clearly superior to others [25]. These medications prevent or mitigate hypertension during surgery prior to clamp of the effluent venous drainage from the tumor, but they can cause hypotension after that point, when catecholamine secretion drops precipitously. (See 'Stages of surgery' below.)

•Phenoxybenzamine – Phenoxybenzamine is a non-competitive, long-acting, nonspecific alpha-adrenergic blocking agent [26]. While phenoxybenzamine is effective for prevention of intraoperative hypertension, postoperative return of normal adrenergic function may be delayed because of its long duration of action. BP support may be required into the postoperative period after phenoxybenzamine pretreatment.

•Selective alpha₁-adrenergic blockers – In contrast to phenoxybenzamine, selective alpha₁ blockers (eg, doxazosin, prazosin, and terazosin) are competitive inhibitors and are shorter-acting.

Urapidil is a selective alpha₁-adrenergic blocker with a central sympatholytic effect, mediated by stimulation of serotonin 5HT_1A receptors, and is available in some countries outside the United States [27]. Small studies have described preoperative alpha blockade with three days of intravenous (IV) urapidil [28,29].

The choice of alpha-adrenergic blocking drugs for preoperative preparation is discussed separately. (See "Treatment of pheochromocytoma in adults".)

●Beta blockade – Beta blockade is especially important for those patients with tumors that secrete large amounts of epinephrine, with resultant tachycardia and arrhythmias. Beta blockade is started at a low dose using short-acting oral medication (eg, metoprolol). If tolerated, longer-acting and higher-dose medication is added. Complications may occur in patients with asthma or congestive heart failure. Patients with occult catecholamine-induced cardiomyopathy may develop congestive heart failure and pulmonary edema with beta blocker use. (See "Treatment of pheochromocytoma in adults", section on 'Beta-adrenergic blockade'.)

●Calcium channel blockade – As with preoperative alpha blockade, calcium channel blockers do not prevent all hemodynamic changes during these procedures. Calcium channel blockers, when combined with potent inhalation anesthetics, can cause hypotension. Treatment with calcium chloride may be indicated. (See "Treatment of pheochromocytoma in adults".)

●Metyrosine – Metyrosine is a competitive inhibitor of tyrosine hydroxylase, which is a rate-limiting enzyme in the formation of catecholamines [26]. Some institutions use a five-day (short-term) preprocedure preparation protocol using metyrosine, while others use metyrosine to supplement preoperative alpha blockade [30]. With short-term therapy, the most common side effect is hypersomnolence, while side effects of longer-term treatment may be disabling [30]. The extrapyramidal effects of haloperidol, which may be administered during anesthesia, may be potentiated by metyrosine. (See "Treatment of pheochromocytoma in adults".)

Preoperative testing — Preoperative laboratory testing should be performed as it would be for any patient having major surgery, including blood glucose, electrolytes, blood urea nitrogen, creatinine, and complete blood count.

Blood type and screen should be performed. Transfusion thresholds used for other surgical patients are appropriate for patients with catecholamine-secreting tumors. (See "Intraoperative transfusion and administration of clotting factors", section on 'Indications and risks for specific blood components'.)

Biochemical testing for excess catecholamine secretion for the diagnosis of pheochromocytoma is discussed separately. (See "Clinical presentation and diagnosis of pheochromocytoma", section on 'Approach to initial evaluation'.)

Chest radiograph should be performed to assess for cardiomegaly and pulmonary edema.

SURGICAL APPROACH — Adrenalectomy for pheochromocytoma can be performed via laparotomy, laparoscopy, or robotically [31]. Laparoscopy with either a transabdominal or retroperitoneal approach is the procedure of choice for patients with solitary intraadrenal pheochromocytomas that are less than 8 cm in diameter and that have no malignant radiologic features. If preoperative genetic testing is performed, the presence or absence of germ line mutations may also affect the choice of surgical approach and the extent of adrenal resection [32]. Most adrenalectomies for pheochromocytomas are now performed using minimally invasive surgical techniques (laparoscopically or robotically) [24,33,34]. (See "Treatment of pheochromocytoma in adults".)

Robotic adrenalectomy is associated with outcomes similar to laparoscopic adrenalectomy [35].

Open procedures can be performed using a transperitoneal approach, a subcostal or midline incision, or a retroperitoneal flank approach.

STAGES OF SURGERY — Surgical resection of pheochromocytoma can be divided into two phases based on ligation of the blood supply to the tumor. Close communication between the surgeon and the anesthesiologist allows anticipation of hemodynamic changes during the course of surgery.

Phase I — Phase I includes the portion of surgery during which the tumor is dissected and the vascular supply is isolated, before clamping of the effluent vein. This phase is often characterized by periods of severe episodic hypertension and arrhythmias as adrenal manipulation releases catecholamines. Phase I also includes endotracheal intubation and insufflation of the abdomen with carbon dioxide (CO₂) for laparoscopy, both of which can also result in marked hypertension and arrhythmias [36-39].

●Endotracheal intubation – Catecholamine levels can rise during surgery in patients without pheochromocytoma (200 to 2000 pg/mL) but can rise much higher in patients with these tumors (2000 to 20,000 pg/mL), with potential for severe hypertension and arrhythmias [39,40]. The elevation in catecholamines associated with intubation can be prevented or minimized with deep anesthesia, even in patients with pheochromocytoma [41].

●Peritoneal insufflation – Peritoneal insufflation during laparoscopic resection of pheochromocytoma can lead to hypertension and increased catecholamine levels [6,38,39]. Several mechanisms may be responsible for this response, including compression of the tumor, a change in tumor blood flow, and the sympathetic response to the hypercapnia related to CO₂ absorption [39,42].

●Tumor manipulation – Tumor manipulation during either laparoscopic or open adrenalectomy for pheochromocytoma causes the greatest release of catecholamines and the highest blood pressure (BP) recordings [6,38,39]. Catecholamines can remain high even after ligation of the adrenal vein, a phenomenon possibly related to the hypervascularity of some tumors (figure 1).

Phase II — Phase II is the portion of surgery after the effluent vein is clamped. Precipitous hypotension can occur because of the sudden drop in endogenous catecholamine levels, the chronic downregulation of alpha-adrenergic receptors, the presence of alpha-blocking medication, and intravascular volume depletion [6,38,39,43]. Vasopressor support is often necessary. (See 'Intraoperative hemodynamic changes' below.)

ANESTHESIA MANAGEMENT

Choice of anesthetic technique — General anesthesia, with or without epidural anesthesia, is used for pheochromocytoma resection. If epidural anesthesia is used during surgery, the resulting sympathectomy and vasodilation may exaggerate hypotension during stage II of the surgery, especially for patients who have received phenoxybenzamine for alpha-adrenergic blockade. (See 'Impact on intraoperative management' above.)

An epidural catheter may be placed before open or laparoscopic adrenalectomy for postoperative pain control. We place the epidural prior to induction of anesthesia and administer a test dose with or without epinephrine for patients with pheochromocytoma. We do not activate the epidural during surgery in order to avoid the sympathectomy that results. Dilute solutions of opioids combined with local anesthetic are infused while titrating vasopressors to blood pressure (BP), starting during closure of the abdomen. In retrospective study of 97 patients who underwent open resection of pheochromocytoma epidural analgesia was associated with early postoperative hypotension, especially in patients who were on preoperative beta-blocker therapy [44]. (See "Continuous epidural analgesia for postoperative pain: Technique and management", section on 'Hypotension'.)

Monitoring and venous access — As for any general anesthetic, standard American Society of Anesthesiologists (ASA) monitors (eg, blood pressure, electrocardiography, oxygen saturation, capnography, and temperature) are applied. Large-bore venous access should be obtained. For pheochromocytoma, additional monitoring and venous access may be added as follows:

●Arterial pressure monitoring – Continuous intraarterial BP monitoring is used for all patients with pheochromocytoma. For patients who remain hypertensive preoperatively, we place the arterial catheter prior to induction. For patients with well-controlled preoperative BP, when personnel are available to assist, we place the arterial line during induction but prior to endotracheal intubation.

●Central venous catheterization – Practice varies with respect to the use of central venous catheters (CVCs) during pheochromocytoma resection. The author places a central venous catheter for most patients with pheochromocytoma, primarily for secure and effective administration of vasoactive drugs. Others avoid placement of CVCs in otherwise healthy patients with adequate large bore peripheral venous access.

●Pulmonary artery (PA) catheterization and transesophageal echocardiography (TEE) – PA catheterization and TEE may be indicated for patients with known depressed cardiac function, though these modalities are rarely required. In one large series of patients undergoing pheochromocytoma, very few patients required a PA catheter [43].

●Depth of anesthesia – Anesthetic requirements may change during tumor manipulation due to changes in cardiac output, which can alter blood levels of both inhaled and intravenous anesthetics [45]. Changing requirements may be reflected in processed electroencephalography monitors (eg, bispectral analysis monitor [BIS]).

Premedication — Patients should be premedicated (eg, midazolam 1 to 2 mg intravenously [IV], titrated to effect) as they would be for other surgeries in order to allay anxiety and to facilitate smooth and atraumatic placement of arterial, central, and additional peripheral venous catheters.

Induction and maintenance of anesthesia — A wide variety of medications can be used for the induction and maintenance of anesthesia for patients with pheochromocytoma. Ketamine should be avoided in most cases because of its sympathomimetic properties, and halothane should not be administered because of its potential to cause arrhythmias. (See "General anesthesia: Intravenous induction agents", section on 'Ketamine' and "Inhalation anesthetic agents: Clinical effects and uses", section on 'Halothane'.)

General principles for the induction and maintenance of anesthesia for these patients include the following:

●Aim for a smooth induction, with adequate depth of anesthesia to prevent a hypertensive response to endotracheal intubation.

●Open communication with the surgeon to anticipate events likely to cause hemodynamic instability (ie, insufflation of the abdomen, tumor manipulation, ligation of tumor blood supply).

Choice of anesthetic agents — Sevoflurane is often used for maintenance of anesthesia in patients undergoing pheochromocytoma resection due to its lack of arrhythmogenic potential and relatively favorable hemodynamic profile compared with nitrous oxide, desflurane, and isoflurane. Nevertheless, isoflurane, nitrous oxide, enflurane, and total intravenous anesthesia (TIVA) with propofol have been used safely for pheochromocytoma resection [46]. Desflurane is usually avoided because it may cause tachycardia and hypertension, particularly with high or abruptly increased concentrations.

A single center retrospective study of 197 patients who underwent pheochromocytoma resection compared intraoperative hemodynamic events in patients who had TIVA with propofol and remifentanil, versus desflurane with remifentanil, targeting a similar anesthetic depth by processed EEG (BIS of 40 to 60) [47]. TIVA was associated with increased incidence of intraoperative hypertension (72.7 versus 27.3 percent, odds ratio 2.57, 95% CI 1.23-5.38) [47]. More data is required before a particular general anesthetic technique can be recommended.

Medications to avoid — A number of medications commonly used in anesthesia should be avoided or used cautiously in patients with pheochromocytoma. When patients having anesthesia for other procedures exhibit severe hypertension, arrhythmias, or other unexplained adverse reactions to these medications, occult pheochromocytoma should be suspected.

●Dopamine-blocking drugs – Metoclopramide is contraindicated for patients with pheochromocytoma. Metoclopramide has been reported to induce hypertensive crisis and, in some cases, adrenergic myocarditis with cardiogenic shock in patients with pheochromocytoma [8,48-50]. The mechanism is likely multifactorial; metoclopramide inhibits dopaminergic suppression of presynaptic norepinephrine release and has also been shown to directly stimulate release of catecholamines from pheochromocytoma cells [51].

There are case reports of hypertensive crisis when large doses of droperidol were administered to patients with pheochromocytoma without alpha blockade. Small doses (0.625 mg IV) of droperidol, as well as droperidol used as part of neuroleptic anesthesia, have been used safely in patients with preoperative alpha blockade [52]. Haloperidol, which is often used in small doses (eg, 1 mg IV) for prevention and treatment of postoperative nausea and vomiting, shares structural similarities with droperidol and should similarly be used with caution in patients with pheochromocytoma. Chlorpromazine and prochlorperazine should also be avoided in patients with pheochromocytoma.

Patients with pheochromocytomas may be unusually susceptible to the hypotensive effects of phenothiazine derivatives, via an unknown mechanism. Chlorpromazine and prochlorperazine should also be avoided in patients with pheochromocytoma [53].

●Glucagon – Glucagon is contraindicated in patients with pheochromocytoma. It has been shown to release catecholamines from these tumors and has been associated with hypertensive crisis [54]. In the past, glucagon stimulation was used as part of a diagnostic test for pheochromocytoma.

●Sympathomimetic drugs – Ketamine and cocaine should be avoided for these patients because of their sympathomimetic properties and the potential to exacerbate hypertension and arrhythmias. Halothane sensitizes the myocardium to catecholamines, is associated with arrhythmias, and should be avoided for these patients. Ephedrine is an indirect-acting alpha and beta agonist used to treat hypotension. It should be avoided until the tumor is excised in order to prevent an exaggerated response via release of catecholamines from the tumor.

●Histamine-releasing medications – Drugs that release histamine when given in large doses (eg, morphine, atracurium) should theoretically be avoided for patients with pheochromocytoma. However, when given slowly, histamine release can be minimized, and both morphine and atracurium have been used safely in these patients [43]

INTRAOPERATIVE HEMODYNAMIC CHANGES

Incidence and risk factors — Patients undergoing pheochromocytoma resection have substantial intraoperative hemodynamic instability regardless of their preoperative catecholamine levels, and despite preoperative alpha adrenergic blockade. (See 'Stages of surgery' above.)

Retrospective studies have identified a number of risk factors associated with intraoperative hemodynamic instability, including large tumor size, history of diabetes, duration and dose of preoperative alpha-blocker intake, type of surgical approach, preoperative catecholamine levels, and intraoperative hemodynamic management [4,47,55,56]. Examples include the following:

●In a single-center retrospective review of 258 patients who underwent resection of pheochromocytoma or paraganglioma with preoperative pharmacologic preparation, intraoperative changes in blood pressure and heart rate were greater in patients with increased preoperative catecholamine levels, but substantial variability occurred even in patients with normal hormone levels [4]. Patients with normal preoperative catecholamine levels had a median interquartile range (IQR) change in systolic blood pressure of 75 (63 to 83) mmHg, and median IQR change in heart rate of 34 (26 to 43) beats per minute.

●In another retrospective single-center study involving 123 patients who underwent laparoscopic resection of pheochromocytoma with preoperative pharmacologic preparation, prolonged hypotension (ie, requiring continuous catecholamine support for >30 minutes to maintain mean arterial pressure ≥60 mmHg) occurred following tumor removal in 44 percent of patients [55]. Patients with higher levels of preoperative epinephrine and dopamine were more likely to become hypotensive.

●A single institution study of 82 patients who underwent laparoscopic adrenalectomy found that 37 percent of patients developed hemodynamic instability (systolic blood pressure ≥200 or <80 mmHg) [56]. Diabetes was associated with increased risk of hemodynamic instability (odds ratio 3.84, 95% CI 1.06-13.8). Conclusions are limited by the small number of events and associated wide confidence intervals which approach one.

●In a single institution retrospective study of 172 patients who underwent minimally invasive adrenalectomy for pheochromocytoma, risk factors that were associated with hemodynamic instability included large tumor size, preoperative selective versus nonselective alpha-blocker, use of preoperative beta blockers, and TIVA rather than balanced anesthesia with desflurane [47].

Vasopressors, vasodilators, and antiarrhythmic medications should be prepared in advance and ready for immediate administration. A number of intravenous (IV) medications have been used to treat hemodynamic perturbations during pheochromocytoma resection. In this setting, drugs are chosen for ease of titration, with rapid effect and quick offset, to respond to changing hemodynamic conditions.

Treatment of hypertension and arrhythmias — Most patients with pheochromocytoma become hypertensive at some point during surgery. When severe hypertension occurs, the surgeon should be alerted, and treatment should begin immediately. Surgery may need to be paused to allow for blood pressure (BP) control.

Antihypertensive medications — Drugs used to control hypertension during pheochromocytoma resection include the following:

●Nitroprusside – Nitroprusside, an ultrashort-acting vasodilator, is our drug of choice for intraoperative hypertensive crisis. It is typically administered as an infusion at 0.5 to 5 mcg/kg/minute and adjusted every few minutes for target BP response. To prevent thiocyanate toxicity, prolonged nitroprusside infusion should not exceed 3 mcg/kg/minute. Reflex tachycardia is often treated with infusion of a short-acting beta blocker (esmolol).

●Phentolamine – Phentolamine is a nonselective alpha blocker that can be administered intravenously. An initial test dose of 1 mg is administered, followed by a 5-mg bolus and/or continuous infusion (0.5 to 1 mg/minute IV) [26].

●Nicardipine – Nicardipine, a calcium channel blocker, can be started at 5 mg/hour and increased by 2.5 mg every 15 minutes to desired effect, not exceeding 15 mg/hour [26].

●Clevidipine – Clevidipine is an ultrashort-acting third-generation dihydropyridine calcium channel blocker that has been used to manage hypertension during and after pheochromocytoma surgery [57,58] . It decreases peripheral vascular resistance via direct arteriolar dilatation. Clevidipine starting dose is 1 to 2 mg/hour intravenously and doubled every 90 seconds with a maximal dose up to 32 mg/hour, for a maximum duration of 72 hours. The infusion is titrated based on therapeutic response and is usually maintained at a rate of 4 to 6 mg/hour.

●Labetalol – Labetalol is a combined alpha and beta blocker that can be administered intravenously (5 to 20 mg IV).

●Esmolol – Esmolol is an ultrashort-acting selective beta₁-adrenergic blocker. It can be administered by bolus (10 to 50 mg IV) or by infusion (25 to 250 mcg/kg/minute).

●Magnesium – Magnesium is a vasodilator that inhibits catecholamine release from the adrenal medulla, antagonizes alpha-adrenergic receptors, and is a calcium antagonist [59-61]. In addition, it is an antiarrhythmic with cardiac membrane-stabilizing effects. Theoretically, magnesium may be useful for patients with arrhythmias associated with pheochromocytoma who are intolerant of beta blockers.

We do not routinely administer magnesium for pheochromocytoma resection; we reserve magnesium for patients whose BP is particularly difficult to control. However, given its safety profile, magnesium is considered a first line antihypertensive agent in the intraoperative management of pregnant patients undergoing pheochromocytoma resection [57,62].

Magnesium has been used in bolus form and as an infusion for BP stabilization during pheochromocytoma resection. The literature on the effects of magnesium in this setting is inconsistent. A number of case reports and small series have reported that magnesium has a beneficial hemodynamic effect during these procedures [63,64]. However, a retrospective review of 64 patients who underwent alpha blockade prior to surgery for pheochromocytoma found no improvement in hemodynamic stability with magnesium administration [65].

Magnesium sulphate is usually administered with a bolus of 2 to 4 g IV over 20 minutes after induction and endotracheal intubation, followed by infusion at 1 to 2 g/hour IV, with the infusion adjusted based on blood levels. The infusion is discontinued once the venous drainage from the tumor is ligated or the tumor is removed.

Because magnesium potentiates the effects of neuromuscular blocking agents (NMBAs), dosing and reversal of NMBAs should be guided by a peripheral nerve stimulator.

Antiarrhythmics — Supraventricular tachycardia is common during these procedures, though any arrhythmia is possible, including ventricular ectopy. IV lidocaine, beta blockade with esmolol as above, or treatment with amiodarone (especially for patients with impaired cardiac pump function) may be necessary. Treatment of arrhythmias is discussed more fully separately. (See "Overview of the acute management of tachyarrhythmias".)

Treatment of hypotension — Hypotension should be treated with aggressive administration of IV fluid, discontinuation of vasodilator infusions, and administration of rapidly acting vasopressors. Drugs commonly used to support BP in this setting include the following:

●Phenylephrine – Phenylephrine is our drug of choice for the management of hypotension during these procedures. It is a pure alpha agonist with a short half-life that can be given by bolus (40 to 160 mcg IV) or infusion (wide range of dosing; 10 to 200 mcg/minute IV), titrated to effect.

●Ephedrine – Ephedrine is an indirect-acting alpha and beta agonist. It should be avoided before tumor removal. When hypotension occurs after tumor resection, ephedrine can be given by bolus (5 to 25 mg IV, repeated as needed). Ephedrine should not be administered during paraganglioma resection or during incomplete pheochromocytoma resection to avoid release of catecholamines and severe hypertension.

●Norepinephrine – Norepinephrine is a combined alpha and beta agonist that is given by infusion (wide range of dosing; 2 to 20 mcg/minute IV), titrated to effect.

●Vasopressin – Vasopressin infusion (initial dose 0.01 to 0.03 units/minute; maintenance dose 0.03 to 0.04 units/minute) has been used in cases of refractory hypotension after tumor removal, commonly after significant blood loss or in patients with extremely high preoperative levels of catecholamines, to supplement other vasopressors [15,66-68].

ALTERATIONS IN BLOOD GLUCOSE — Blood glucose should be monitored intraoperatively for these patients, and if necessary blood glucose should be controlled with an insulin infusion. Diabetes occurs in approximately 36 percent of patients with pheochromocytoma [69], and is due to catecholamine induced insulin resistance or insulin suppression. (See "Clinical presentation and diagnosis of pheochromocytoma", section on 'Less common symptoms and signs'.)

These changes resolve after tumor resection, as soon as the immediate postoperative period [70,71]. (See 'Postoperative care' below.)

OUR ANESTHETIC STRATEGY — A variety of anesthetic techniques and medications can be used for resection of pheochromocytoma. Our usual strategy is as follows, unless medical comorbidities require modification:

●Premedication – We administer midazolam up to 2 mg intravenously (IV) in divided doses, with small doses of fentanyl (25 mcg IV) titrated to enhance analgesia prior to arterial line and/or epidural placement. (See 'Premedication' above.)

●Line placement – We insert an arterial catheter under local anesthesia or, if assistance is available, after induction of anesthesia but prior to intubation. We typically place a central venous catheter after induction and intubation but prior to positioning and incision. (See 'Monitoring and venous access' above.)

●Epidural placement – For open procedures, we place a low thoracic epidural for postoperative pain control. For laparoscopic surgeries, we do not typically place epidural catheters for postoperative pain management. Epidural catheter placement is tested with local anesthetic (typically 3 mL of 1.5% lidocaine). (See 'Choice of anesthetic technique' above.)

●Induction of anesthesia – We induce anesthesia as follows:

•Fentanyl 1 to 3 mcg/kg IV

•Lidocaine 1 mg/kg IV

•Propofol 1 to 2 mg/kg IV

•Nondepolarizing neuromuscular blocking agent (NMBA) (eg, rocuronium 0.5 mg/kg IV) (see 'Induction and maintenance of anesthesia' above)

●Maintenance of anesthesia – We maintain inhalation anesthesia at 1 minimum alveolar concentration (MAC), adjusted for age. Opioids are administered as required.

●Treatment of hemodynamic changes – We treat hemodynamic changes as follows (see 'Intraoperative hemodynamic changes' above):

•During phase I of surgery, we typically aim to keep systolic blood pressure (SBP) between 100 and 160 mmHg. Blood pressure (BP) during phase I is often very labile; vasodilator infusion may require frequent adjustment or pause.

-We treat BP elevations with nitroprusside, administered by an infusion of 0.5 to 4 mcg/kg/minute or a bolus of 20 mcg, supplemented as needed by boluses of phentolamine 1 to 5 mg IV.

-We treat hypotension with phenylephrine, administered by a bolus of 50 to 150 mcg IV or an infusion of 20 to 200 mcg/minute IV.

•During phase II of surgery, we treat hypotension with the following sequence of medication, as necessary:

-IV fluid bolus.

-Phenylephrine bolus of 50 to 150 mcg or infusion of 20 to 200 mcg/minute.

-Ephedrine 5 to 25 mg bolus IV; however, ephedrine should not be used in paraganglioma resection or if incomplete pheochromocytoma resection is suspected.

-Norepinephrine 2 to 20 mcg/minute IV, if necessary.

-Vasopressin 0.03 to 0.04 units/minute.

●Postoperative disposition – Most patients can be extubated at the end of surgery and can be transferred to the post-anesthesia care unit (PACU) for further monitoring. Patients who require vasoactive medications (eg, phenylephrine, norepinephrine, or vasopressin infusion) to maintain adequate BP are subsequently transferred to the intensive care unit (ICU). In addition, we transfer patients to the ICU for closer monitoring if the intraoperative course was eventful (ie, significant blood loss and fluid administration).

POSTOPERATIVE CARE — The majority of patients who undergo laparoscopic pheochromocytoma resection can be observed in the post-anesthesia care unit (PACU) and then sent to a hospital floor, though some patients require intensive care postoperatively [6]. Postoperative concerns specific to pheochromocytoma resection include the following:

●Hemodynamic instability – In most cases, extended recovery room or intensive care stays are for hemodynamic monitoring. Transient postoperative hypotension is common due to downregulation of alpha-adrenergic receptors, residual effects of long-acting antihypertensive medications, or hypovolemia. Fifty percent of patients remain hypertensive for one to three days after excision of pheochromocytoma; 75 percent of patients become normotensive after 10 days of surgery [72].

●Hypoglycemia – Hypoglycemia can occur intraoperatively or postoperatively because of a rebound increase in insulin secretion, as the catecholamine inhibition of insulin secretion is eliminated with tumor removal [70,71]. Hypoglycemia should be suspected when patients are slow to emerge from anesthesia or are lethargic postoperatively. Blood glucose should be measured every six hours postoperatively, and more frequently if hypoglycemia develops.

●Adrenal insufficiency – Patients who undergo bilateral adrenalectomy are at risk for acute postoperative adrenal insufficiency and therefore require glucocorticoid replacement. Regimens for replacement vary among institutions. Our typical regimen is as follows:

•Hydrocortisone 100 mg IV with induction of anesthesia

•Hydrocortisone 100 mg IV every eight hours for 24 hours

•Hydrocortisone taper over three days to maintenance dose (eg, hydrocortisone 25 mg IV or by mouth [PO] twice daily, or prednisone 10 mg PO daily)

Patients who undergo bilateral adrenalectomy require lifelong steroid supplementation. (See "Treatment of adrenal insufficiency in adults".)

●Renal Failure – Acute renal failure is an unusual complication after pheochromocytoma resection. The mechanism of renal failure is thought to be due to massive catecholamine release causing increased renin activity and hypertensive crisis, causing renal hypoperfusion and ischemia. Renal failure due to rhabdomyolysis as a result of skeletal muscle ischemia has also been reported [73,74]. Hypotension can also lead to acute kidney injury.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pheochromocytoma and paraganglioma".)

SUMMARY AND RECOMMENDATIONS

●Perioperative risk – Many patients who undergo pheochromocytoma resection exhibit labile blood pressure (BP), arrhythmias, and tachycardia during and after surgery, though most can be managed without lasting morbidity or mortality. Risks are much greater for patients who are found incidentally to have pheochromocytoma during unrelated surgery. (See 'Perianesthetic risks and outcomes' above and 'Incidence and risk factors' above.)

●Preoperative evaluation – Preoperative evaluation should include assessment for end organ damage from elevated catecholamines and confirmation of effective medical preparation for surgery. Medical preparation should include alpha-adrenergic blockade, beta blockade if necessary, and normalization of intravascular volume. (See 'Preoperative evaluation' above and 'Preoperative medical therapy' above.)

●Phases of surgery – Pheochromocytoma resection can be divided into two phases of surgery based on ligation of the tumor blood supply (see 'Stages of surgery' above):

•Phase I (prior to ligation of the effluent vein) is often characterized by periods of hypertension, tachycardia, and arrhythmias, particularly during endotracheal intubation, insufflation of the abdomen during laparoscopic procedures, and tumor manipulation.

•Phase II (after ligation of the effluent vein) is often complicated by hypotension.

●Goals for anesthetic management – General anesthesia is used for pheochromocytoma resection. A variety of techniques and medications can be used for induction and maintenance of anesthesia. Goals for anesthesia management should include:

•Smooth induction with adequate depth of anesthesia to prevent a hypertensive response to endotracheal intubation.

•Close communication with the surgeon to allow anticipation of events likely to cause hemodynamic instability. (See 'Induction and maintenance of anesthesia' above.)

●Monitoring – We place an intraarterial catheter for continuous BP monitoring and a central venous catheter for drug administration. (See 'Monitoring and venous access' above.)

●Hemodynamic management – A variety of vasoactive medications with rapid onset of effect and short duration of action should be available and ready for administration to respond quickly to hemodynamic changes. (See 'Intraoperative hemodynamic changes' above.)

Our typical regimen for the treatment of hemodynamic changes is as follows (see 'Our anesthetic strategy' above):

•During phase I of surgery, we typically aim to keep systolic BP (SBP) between 100 and 160 mmHg.

-We treat BP elevations with nitroprusside administered by an infusion of 0.5 to 4 mcg/kg/minute or a bolus of 20 mcg, supplemented as needed by boluses of phentolamine 1 to 5 mg intravenously (IV).

-We treat hypotension with phenylephrine, administered by a bolus of 40 to 160 mcg IV or an infusion of 20 to 200 mcg/minute IV.

•During phase II of surgery, we treat hypotension with the following sequence of medication, as necessary:

-IV fluid bolus

-Phenylephrine bolus of 50 to 150 mcg or infusion of 20 to 200 mcg/minute

-Norepinephrine 2 to 20 mcg/minute IV, if necessary

-Vasopressin 0.03 to 0.04 units/minute

●Postoperative care

•We place an epidural catheter for postoperative pain control for open adrenalectomy but usually not for laparoscopic procedures. (See 'Our anesthetic strategy' above.)

•Postoperative concerns for patients after pheochromocytoma resection include recovery of normal adrenergic function with stable BP, potential for rebound hypoglycemia, and possible adrenal insufficiency. (See 'Postoperative care' above.)