Comparison of Two Preoperative Medical Management Strategies for Laparoscopic Resection of Pheochromocytoma

Basic and Translational Science Comparison of Two Preoperative Medical Management Strategies for Laparoscopic Resection of Pheochromocytoma Toby N. Weingarten, Juan P. Cata, Jerome F. O’Hara, David J. Prybilla, Tasha L. Pike, Geoffrey B. Thompson, Clive S. Grant, David O. Warner, Emmanuel Bravo, and Juraj Sprung OBJECTIVES

METHODS

RESULTS

CONCLUSIONS

To compare the intraoperative and postoperative course of patients undergoing laparoscopic pheochromocytoma resection at 2 institutions (Mayo Clinic and Cleveland Clinic) with differing approaches to preoperative preparation. Patients undergoing adrenalectomy for pheochromocytoma typically undergo a preoperative preparation to normalize their blood pressure and intravascular volume. However, no consensus has been reached regarding the best preoperative preparation regimen. A retrospective chart review was performed of 50 Mayo Clinic patients and 37 Cleveland Clinic patients who had undergone laparoscopic pheochromocytoma resection. Mayo Clinic predominantly used the long-lasting nonselective ␣1,2 antagonist phenoxybenzamine, and Cleveland Clinic predominately used selective ␣1 blockade. Data regarding the intraoperative hemodynamics and postoperative complications were collected. Almost all patients at Mayo Clinic received phenoxybenzamine (98%). At Cleveland Clinic, the predominant treatment (65%) was selective ␣1 blockade (doxazosin, terazosin, or prazosin). Intraoperatively, patients at Cleveland Clinic had a greater maximal systolic blood pressure (209 ⫾ 44 mm Hg versus 187 ⫾ 30 mm Hg, P ⫽ .011) and had received a greater amount of intravenous crystalloid (median 5000, interquartile range 3400-6400, versus median 2977, interquartile range 2000-3139; P ⬍.010) and colloid (median 1000, interquartile range 5001000, versus median 0, interquartile range 0-0; P ⬍.001). At Mayo Clinic, more patients had received phenylephrine (56.0% versus 27.0%, P ⫽ .009). No differences were found in the postoperative surgical outcomes, and the hospital stay was comparable between the 2 groups. Differences in the preoperative preparation and intraoperative management were associated with differences in intraoperative hemodynamics but not with clinically significant outcomes in patients undergoing laparoscopic adrenalectomy for pheochromocytoma at 2 large tertiary care centers. UROLOGY 76: 508.e6 –508.e11, 2010. © 2010 Elsevier Inc.

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heochromocytoma and paraganglioma are rare catecholamine-producing tumors1 that can cause hypertension, tachycardia, sweating, palpitations, headaches, and anxiety attacks.2 Hemodynamic lability is frequently present during resection of these tumors, with a positive correlation among tumor manipulation, intraoperative catecholamine release, and cardiovascular in-

This study was supported by the Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, Minnesota. From the Departments of Anesthesiology and Anesthesia Clinical Research Unit and Gastroenterologic and General Surgery, Mayo Clinic College of Medicine, Rochester, Minnesota; and Department of General Anesthesiology and Glickman Urological and Kidney Institute, Department of Nephrology and Hypertension, Cleveland Clinic Foundation, Cleveland, Ohio Reprint requests: Juraj Sprung, M.D., Ph.D., Department of Anesthesiology, Mayo Clinic College of Medicine, 200 First Street Southwest, Rochester, MN 55905. E-mail: [email protected] Submitted: February 12, 2010, received (with revisions): March 12, 2010

508.e6 © 2010 Elsevier Inc. All Rights Reserved

stability.3-5 To attenuate this instability, it is important to normalize the preoperative blood pressure (BP) and heart rate and restore the depleted intravascular volume. Pharmacologic preparation with drugs that block adrenoreceptors or decrease catecholamine synthesis has been recommended, but no consensus has been reached regarding the optimal regimen.2,6-8 A widely used treatment includes the nonselective ␣-adrenergic antagonist phenoxybenzamine, followed by ␤-adrenoceptor antagonists and/or calcium channel blockers (CCBs).7 However, the prolonged antagonism produced by phenoxybenzamine can result in hypotension immediately after tumor resection, requiring vasopressor treatment.6 An alternative approach has proposed the use of shorteracting selective postsynaptic ␣1-receptor antagonists with either a ␤-adrenergic antagonist or CCB, with the aim of less hypotension after tumor resection.2,6 How0090-4295/10/$34.00 doi:10.1016/j.urology.2010.03.032

ever, a direct comparison of these 2 approaches by a randomized trial would be problematic given the rarity of pheochromocytoma. We were able to perform a retrospective study, because the 2 different preparation regimens for patients with pheochromocytoma are favored at 2 large U.S. medical centers with considerable experience in the management of pheochromocytomas: Cleveland Clinic, Cleveland, Ohio and Mayo Clinic, Rochester, Minnesota. Mayo Clinic favored the use of phenoxybenzamine, while Cleveland Clinic favored the shorter-acting selective ␣1 antagonists. The aim of the present comparative effectiveness research study, representing observational consecutive case series at each institution, was to compare the intraoperative hemodynamic course and postoperative outcomes achieved with these 2 regimens in actual clinical practice.

MATERIAL AND METHODS Patient Population After obtaining approval from the respective institutional review boards, we reviewed the medical records of patients undergoing laparoscopic adrenalectomy for pheochromocytoma. At Mayo Clinic, we reviewed the records of 50 consecutive patients from October 2003 to November 2006. At Cleveland Clinic, we reviewed the records of 37 consecutive patients from July 2005 to May 2009. The availability of the electronic anesthesia records at both institutions allowed us to retrospectively gather accurate information on the intraoperative hemodynamics.

Preoperative Management All patients at both centers were evaluated and treated by an endocrinologist. Also, both centers encouraged liberal dietary salt intake to restore the intravascular volume, and the goal of therapy was to achieve BP within the normal limits. Mayo Clinic. Most patients first received the nonselective ␣1,2-blocker, phenoxybenzamine, 1-4 weeks before surgery, in a dose sufficient to achieve orthostatic hypotension. Typically, 2-3 days before surgery, a ␤-adrenergic antagonist (typically propranolol) was added if the heart rate was ⬎80 beats/min. If these regimens did not result in normotension, a CCB was added (typically nicardipine). If the tumor was large, a catecholamine synthesis inhibitor, metyrosine, was added 2-3 days before surgery. Patients who continued to have orthostatic hypotension (orthostatic decrease in systolic BP ⬎20 mm Hg) were hospitalized for hydration. Cleveland Clinic. Patients who were normotensive or who were only intermittently hypertensive usually received a CCB (preferably a nondihydropyridine) titrated to the desired response. A specific postsynaptic ␣1-receptor antagonist (ie, doxazosin) was then added in increments of 2 mg every third day to a maximum of 10 mg. If tachycardia developed and/or the patient had coronary artery disease, a ␤-adrenergic antagonist was added. Occasionally, asymptomatic patients received no preoperative treatment. UROLOGY 76 (2), 2010

Data Ascertainment We collected demographic information, American Society of Anesthesiologists physical status, pre-existing medical conditions (ie, hypertension, diabetes mellitus, coronary artery disease, previous myocardial infarction, history of congestive heart failure, stroke, chronic obstructive pulmonary disease, asthma, and renal insufficiency, defined as preoperative creatinine ⱖ1.8 mg/dL), medications used to control the BP and/or heart rate, preoperative use of a high salt diet (or salt pills), hospital admission for hydration, and preoperative BP. Intraoperative hemodynamics was assessed as (a) the greatest intraoperative BP, (b) interval in minutes that the systolic BP was ⱖ30% than the preinduction baseline, (c) interval in minutes that the systolic BP was ⬎200 mm Hg, (d) lowest intraoperative BP, (e) interval in minutes that the systolic BP was ⱕ30% than the preinduction baseline, (f) greatest and lowest heart rates, and (g) duration of tachycardic (ⱖ110 beats/min) and bradycardic (ⱕ50 beats/min) episodes. The choice of these hemodynamic parameters was determined from a previous report of patients with pheochromocytoma9 and served as descriptors of hemodynamic instability. However, their potential relationship to adverse perioperative outcomes has not yet been analyzed. Fluid administration and the estimated blood losses were abstracted, as was the anesthesia duration and use of vasoactive drugs. Perioperative complications included excessive bleeding requiring reoperation, pneumothorax requiring a chest tube, tracheal intubation beyond the recovery room, stroke, myocardial infarction, acute lung injury/pulmonary edema (partial pressure of oxygen in arterial blood/fractional inspired oxygen ⬍300 mm Hg, and the presence of bilateral infiltrates), pneumonia documented by chest radiograph or clinical note, acute renal failure (increase in creatinine to 20% greater than the normal range), and pulmonary embolism (positive diagnostic procedure findings and/or therapy). Other outcomes, such as the length of hospital stay and death, were also recorded.

Statistical Analysis Statistical analysis was conducted using JMP, version 7.0.1 (SAS Institute, Cary, NC). The data are presented as the percentage, mean ⫾ standard deviation, or median and interquartile range. The clinical and demographic variables were compared using the Student t test for continuous variables with a normal distribution, the Wilcoxon rank sum test for nonparametric variables, and the chi-square test (or Fisher’s exact test) for categorical variables. In all cases, 2-tailed P ⱕ.05 was considered significant.

RESULTS All cases in the present series were confirmed as pheochromocytoma by histopathologic evaluation and biochemical testing. At Mayo Clinic, all tumors were unilateral; at Cleveland Clinic, 1 was bilateral. All procedures were done laparoscopically; however, 1 operation at Mayo Clinic was started using the laparoscopic approach but required conversion to open surgery. Table 1 lists the demographic information and preoperative comorbidities. The age and sex distribution were comparable, although a trend was seen for a greater proportion of women at Mayo Clinic. The Cleveland Clinic patients had a greater body mass index. The pre508.e7

Table 1. Preoperative demographics, comorbidities, and blood pressure Characteristic Sex Male Female Age (y) Body mass index (kg/m2) American Society of Anesthesiologists physical status II III IV Preoperative comorbidities Diabetes mellitus Cardiomyopathy (ejection fraction ⬍40%) Coronary artery disease Previous myocardial infarction Previous stroke Chronic obstructive pulmonary disease Asthma Chronic renal insufficiency* Tumor largest dimension (cm) Preoperative BP (mm Hg) Systolic BP Mean BP Diastolic BP

Mayo Clinic (n ⫽ 50)

Cleveland Clinic (n ⫽ 37)

19 (38.0) 31 (62.0) 53 ⫾ 16 26.5 ⫾ 4.6

22 (59.5%) 15 (40.5%) 52 ⫾ 13 29.8 ⫾ 7.1

P Value .054

21 (42.0) 28 (56.0) 1 (2.0)

.884 .009 .602

13 (35.1) 22 (59.5) 2 (5.4)

5 (10.0) 0 (0.0) 6 (12.0) 3 (6.0) 4 (8.0) 1 (2.0) 3 (6.0) 0 (0.0) 4.0 ⫾ 1.8

9 (24.3) 2 (5.4) 4 (11) 2 (5.4) 3 (8.1) 2 (5.4) 1 (2.7) 3 (8.1) 4.4 ⫾ 2.2

.085 .178 1.000 1.000 1.000 .572 .634 .073

139 ⫾ 22 99 ⫾ 18 83 ⫾ 12

139 ⫾ 22 93 ⫾ 19 73 ⫾ 17

.950 .402 .058

Data presented as numbers, with percentages in parentheses, or mean ⫾ standard deviation. * Defined as preoperative creatinine ⱖ1.8 mg/dL.

Table 2. Distribution of treatment regimen combinations at Mayo Clinic and Cleveland Clinic Calcium Mayo Cleveland Channel Clinic* Clinic ␣-Blockade ␤-Blockade Blockade (n ⫽ 50) (n ⫽ 37)

␣1,2 ␣1,2 ␣1,2 ␣1,2 ␣1 ␣1 ␣1 ␣1 None None None None

Yes Yes No No Yes Yes No No Yes Yes No No

Yes No Yes No Yes No Yes No Yes No Yes No

9 30 1 9 0 0 1 0 0 0 0 0

1 2 2 1 2 11 5 6 0 1 1 5†

* At Mayo Clinic, 3 patients received metyrosine; no patient received metyrosine at Cleveland Clinic. † At Cleveland Clinic, 1 patient had slight renal insufficiency (creatinine 1.5 mg/dL), was considered to have secondary hypertension, and was preoperatively treated with losartan only; 4 additional patients received no preoperative antihypertensive treatment.

operative comorbidities were comparable between the 2 groups. The preoperative preparation differed between Mayo Clinic and Cleveland Clinic (Table 2). Almost all patients at Mayo Clinic received phenoxybenzamine (98%), 78% (n ⫽ 39) received ␤-adrenergic antagonists, and 22% (n ⫽ 11) received a CCB (amlodipine or diltiazem). Only 1 patient at Mayo Clinic received a selective ␣1-adrenergic antagonist, and 3 patients received metyrosine. At Mayo Clinic, 1 patient with a biopsy-confirmed pheochromocytoma who was asymp508.e8

tomatic and had normal plasma and urine catecholamine levels was still pretreated with phenoxybenzamine. Also, 30 patients (60%) received supplemental oral sodium chloride, and 4 were admitted for hydration. At Cleveland Clinic, most patients (65%) received selective ␣1-adrenergic antagonists (ie, doxazosin, terazosin, or prazosin), and 16% received phenoxybenzamine. At Cleveland Clinic, 46% of patients received ␤-adrenergic antagonists and 30% received a CCB (5 Cleveland Clinic patients did not receive any preoperative treatment, and no Cleveland Clinic patient received metyrosine). At Cleveland Clinic, 33 patients (89%) received supplemental oral sodium chloride and oral hydration. Both groups achieved satisfactory preoperative BP control (Table 1). Central venous access was used more prevalently at Cleveland Clinic (Table 3). For treatment of hypertension, the Mayo Clinic anesthesiologists predominantly used nitroprusside and esmolol. In contrast, the Cleveland Clinic anesthesiologists used nitroprusside, nitroglycerin, and labetalol. Before adrenal vein ligation, the maximal intraoperative systolic and mean BP levels were significantly lower in the Mayo Clinic patients (Table 4). The duration of severe hypertension tended to be less at Mayo Clinic, but not significantly. The lowest intraoperative BP levels were not different between the 2 centers (Table 4). Patients at Mayo Clinic showed a trend toward more BP episodes of ⱕ30% of baseline (28 versus 13 minutes). However, when these periods were normalized to the duration of anesthesia, the Mayo Clinic patients had relatively more time “hypotensive” than the Cleveland Clinic patients (15.7% versus 5.1%, P ⫽ .026; Table 4). The use of phenylephUROLOGY 76 (2), 2010

Table 3. Intraoperative characteristics; anesthesia duration, invasive monitoring, and intraoperative use of vasoactive drugs Characteristic Anesthetic duration (min) Monitors Arterial line Central line Pulmonary artery catheter Vasoactive drugs Nitroprusside Nitroglycerin ␤-Blocker ␣/␤-Blocker (labetalol) Calcium channel blocker Phenylephrine Dopamine Epinephrine Norepinephrine

Mayo Clinic (n ⫽ 50)

Cleveland Clinic (n ⫽ 37)

P Value

201 ⫾ 43

306 ⫾ 185

⬍.001

50 (100.0) 15 (30.0) 4 (8.0)

37 (100.0) 22 (59.5) 9 (24.3)

.425 .008 .065

31 (62.0) 1 (2.0) 26 (52.0) 12 (24.0) 0 (0.0) 28 (56.0) 1 (2.0) 2 (4.0) 1 (2.0)

25 (67.6) 17 (46.0) 10 (27.0) 15 (40.5) 3 (8.1) 10 (27.0) 0 (0.0) 1 (2.7) 1 (2.7)

.592 ⬍.001 .027 .109 .073 .009 1.00 1.00 1.00

Data presented as mean ⫾ standard deviation or numbers, with percentages in parentheses.

Table 4. Intraoperative hemodynamics and administered fluids Intraoperative Hemodynamics Greatest intraoperative BP (mm Hg) Systolic BP Mean BP Diastolic BP Systolic BP ⱖ30% baseline (min) Systolic BP ⱖ200 mm Hg (min) Lowest intraoperative BP (mm Hg) Systolic BP Mean BP Diastolic BP Systolic BP ⱕ 30% baseline, min Systolic BP ⱕ30% baseline (% anesthesia time) Greatest heart rate (beats/min) Interval heart rate ⱖ110 beats/min (min) Lowest heart rate (beats/min) Interval heart rate ⱕ50 beats/min (min) Estimated blood loss (mL) Intraoperative crystalloid (L) Intraoperative colloid (L)

Mayo Clinic (n ⫽ 50)

Cleveland Clinic (n ⫽ 37)

187 ⫾ 30 136 ⫾ 20 109 ⫾ 18 2 (0–11) 0 (0–2)

209 ⫾ 44 151 ⫾ 30 114 ⫾ 26 5 (0–22) 0 (0–7)

73 ⫾ 14 55 ⫾ 11 46 ⫾ 9 28 (6–62) 15.7 (3.3–24.9) 104 ⫾ 28 0 (0–1) 47 ⫾ 10 2 (0–11) 75 (25–150) 3.0 (2.0–3.1) 0 (0–0)

78 ⫾ 15 56 ⫾ 10 43 ⫾ 9 13 (3–49) 5.1 (0.9–16.0) 105 ⫾ 18 0 (0–1) 51 ⫾ 10 0 (0–7) 100 (82–250) 5.0 (3.4–6.4) 1.00 (0.5–1.0)

P Value .011 .004 .294 .119 .071 .159 .870 .191 .114 .026 .765 .719 .120 .379 .010 ⬍.001 ⬍.001

BP ⫽ blood pressure. Data presented as mean ⫾ standard deviation or median, with interquartile ranges in parentheses.

rine was more common at Mayo Clinic, and intraoperative fluid use was greater at Cleveland Clinic (Tables 3 and 4). The estimated blood loss was low at both centers, albeit significantly greater at Cleveland Clinic (P ⫽ .01). Only 1 patient at Mayo Clinic and 2 patients at Cleveland Clinic received a blood transfusion. The duration of surgery was longer at Cleveland Clinic (P ⬍ .001). The postoperative course was similar in the proportion admitted to the intensive care unit (20.0% versus 18.9%, P ⫽ .900) and the length of hospital stay (median 2, interquartile range 2-3, and median 3, interquartile range 2-4; P ⫽ .223). Three patients at Cleveland Clinic, but no patient at Mayo Clinic, required postoperative ventilatory support (P ⫽ .073). Of these 3 patients, 2 had not received any preoperative treatment. The complication rates were low and consisted of 1 case of pneumothorax at Mayo Clinic, 1 case of surgical re-exploration for bleeding at Cleveland Clinic, 1 case of pulmonary edema UROLOGY 76 (2), 2010

at Cleveland Clinic, and 1 case of pneumonia at Cleveland Clinic. Death, myocardial or cerebral ischemia, and infarction were not observed at either institution.

COMMENT The present study presents the largest reported case series of laparoscopic pheochromocytoma resection. The major finding was that 2 different approaches to preoperative medical preparation for these patients were associated with differences in intraoperative hemodynamics but no differences in clinically significant outcomes. The preoperative preparation of patients with pheochromocytoma is believed to be important to improve intraoperative hemodynamic stability and reduce morbidity during resection.10-13 Several therapeutic regimens have been recommended, but direct comparisons have been few. Mayo Clinic endocrinologists have favored the 508.e9

traditional approach of using phenoxybenzamine,7,14 which covalently binds to ␣-adrenoreceptors and produces long-lasting noncompetitive antagonism. In contrast, the Cleveland Clinic practice has preferred competitive, selective, ␣1-adrenergic antagonists, which have a shorter duration of action. The rationale for using selective ␣1-adrenergic antagonists was that these medications do not affect the presynaptic ␣2-receptors; therefore, norepinephrine release will not be enhanced, and reflex tachycardia will be avoided.2 Although some studies have suggested that selective ␣1-adrenergic antagonists are useful in preparing for adrenalectomy for pheochromocytoma,15 other studies have not supported such conclusions.16-18 In contrast to the prolonged receptor inactivation mediated by phenoxybenzamine, agents such as prazosin are competitive antagonists, and their effects can be overcome by a large surge of catecholamines. At both centers, ␣-adrenergic receptor blockade was preoperatively initiated to secure adequate time for normalization of the BP and heart rate and expansion of the blood volume, often aided by fluid and salt supplementation. The goal was to attain the preoperative BP within the normal range for age with minimal orthostatic hypotension. These BP targets have been supported by observational studies and personal experience rather than prospective clinical studies. Orchard et al10 reported no difference in intraoperative BP control in patients who were medicated for ⬍1 week compared with those who were medicated for ⬎1 week. The other elements of the preoperative preparations were similar between the 2 institutions, including the addition of ␤-adrenoceptor antagonists (used less frequently at Cleveland Clinic) and the addition of a CCB when the BP or heart rate could not be well controlled.7,14 A ␤-adrenergic antagonist could be required to treat catecholamine-induced tachycardia or tachydysrhythmia, but it was not used as the initial or sole therapy because, in the absence of ␤2-mediated vasodilation, profound vasoconstriction can lead to a hypertensive crisis.19,20 The more profound ␣-blockade achieved with phenoxybenzamine might have resulted in more reflex tachycardia among patients treated with it, which might explain the increased use of ␤-blockers at Mayo Clinic. Some investigators have suggested that the use of a CCB alone represents an effective preoperative treatment in patients with pheochromocytoma.12,13 The rationale has been that a CCB does not produce hypotension after tumor removal and is cardioprotective and renoprotective.21 In addition, the CCB can inhibit the vasoconstrictive response to neuropeptide Y, which is often increased in patients with adrenal pheochromocytoma. Metyrosine (␣-methyl-L-tyrosine), a drug that competitively inhibits tyrosine hydroxylase, the rate-limiting step in catecholamine biosynthesis,22 was used infrequently at both institutions. 508.e10

Overall, the intraoperative systolic and mean BP levels were lower, and the duration of substantial hypertension showed a trend toward being shorter at Mayo Clinic. This suggested that preoperative preparation with a selective ␣1-adrenergic antagonist might be associated with a lesser ability to control hypertensive responses during tumor manipulation. In contrast, after tumor excision, the Mayo Clinic patients showed a trend toward a relatively longer time at a systolic BP at ⬍30% of baseline, despite a greater use of intraoperative phenylephrine. The possible factors responsible for this difference included more aggressive preoperative treatment using phenoxybenzamine at the Mayo Clinic, more aggressive use of intraoperative fluids at Cleveland Clinic, or other unidentified factors. These findings suggested a tradeoff between attenuation of increased intraoperative systolic BP and the development of intraoperative hypotension. However, the greater administration of intraoperative fluids at Cleveland Clinic might have reflected differences in the preoperative preparation. Perhaps the more profound vasodilatory effects of phenoxybenzamine allowed Mayo Clinic patients to restore their depleted intravascular volume more completely, and, thus, these patients required less intraoperative fluid. Nonetheless, these differences in hemodynamics were not associated with substantial differences in the postoperative course, as measured by intensive care unit admissions, hospital stay, or the occurrence of major adverse events, which occurred infrequently at both centers. Three patients at Cleveland Clinic but no patients at Mayo Clinic required continued postoperative ventilatory support, including 2 of the 5 patients at Cleveland Clinic who had not received preoperative treatment. At Cleveland Clinic, 5 asymptomatic patients did not receive any preoperative treatment (for 1 of these patients, the correct diagnosis was established after surgery from the pathology report). Intraoperatively, these 5 patients had hypertensive episodes, but the extent was similar to that of the rest of the Cleveland Clinic group (data not shown). However, 2 of these patients required postoperative ventilatory support. Additional study would be needed to comment on the advisability of routinely not preparing asymptomatic patients; however, our results have shown that preoperatively normotensive patients consistently become hypertensive during surgery and deciding, a priori, who would be stable during surgery might be unpredictable.23-25 The present study had several limitations. First, any retrospective study has the inherent limitation of the potentially inconsistent nature of information in the medical record. Second, we could not distinguish whether the recorded hemodynamic effects and administered fluids primarily resulted from the differences in the preoperative medical preparations or from different practices among the respective institution anesthesiologists. For example, differences were present in the use of intraoperative vasoactive drugs, and the Cleveland Clinic anesthesioloUROLOGY 76 (2), 2010

gists were more likely to use fluid administration and central venous access. Third, although differences were found in the broad approaches used by each institution, considerable variations were present within each institution among the individual patients, which introduced variability that could obscure differences that depend on individual elements of the preparation regimen or intraoperative management. Fourth, medical records from slightly different periods were reviewed. Finally, because of the low number of cases, the ability to detect severe, but relative low-frequency, events, such as stroke, was limited. Also, given the rarity of this disorder, randomized controlled trials would not be feasible. Our series represents the largest series of laparoscopic pheochromocytoma reported to date.

CONCLUSION Differences in the preoperative preparation and intraoperative management between 2 large medical centers were associated with differences in intraoperative hemodynamics but not clinically significant outcomes in patients undergoing pheochromocytoma resection. The use of noncompetitive ␣-adrenergic antagonist phenoxybenzamine appeared to produce better attenuation of intraoperative hypertension, but at the cost of longer lasting intraoperative hypotension that required a greater use of vasopressors. References 1. Beard CM, Sheps SG, Kurland LT, et al. Occurrence of pheochromocytoma in Rochester, Minnesota, 1950 through 1979. Mayo Clin Proc. 1983;58:802-804. 2. Bravo EL, Tagle R. Pheochromocytoma: state-of-the-art and future prospects. Endocr Rev. 2003;24:539-553. 3. Russell WJ, Metcalfe IR, Tonkin AL, et al. The preoperative management of phaeochromocytoma. Anaesth Intensive Care. 1998; 26:196-200. 4. Fernandez-Cruz L, Saenz A, Benarroch G, et al. Does hormonal function of the tumor influence the outcome of laparoscopic adrenalectomy? Surg Endosc. 1996;10:1088-1091. 5. Miccoli P, Bendinelli C, Materazzi G, et al. Traditional versus laparoscopic surgery in the treatment of pheochromocytoma: a preliminary study. J Laparoendosc Adv Surg Tech A. 1997;7: 167-171. 6. Bravo EL. Pheochromocytoma: an approach to antihypertensive management. Ann NY Acad Sci. 2002;970:1-10.

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7. Pacak K. Preoperative management of the pheochromocytoma patient. J Clin Endocrinol Metab. 2007;92:4069-4079. 8. Prys-Roberts C. Phaeochromocytoma—recent progress in its management. Br J Anaesth. 2000;85:44-57. 9. Sprung J, O’Hara JF Jr, Gill IS, et al. Anesthetic aspects of laparoscopic and open adrenalectomy for pheochromocytoma. Urology. 2000;55:339-343. 10. Orchard T, Grant CS, van Heerden JA, et al. Pheochromocytoma— continuing evolution of surgical therapy. Surgery. 1993;114:11531159. 11. Janetschek G, Neumann HP. Laparoscopic surgery for pheochromocytoma. Urol Clin North Am. 2001;28:97-105. 12. Proye C, Thevenin D, Cecat P, et al. Exclusive use of calcium channel blockers in preoperative and intraoperative control of pheochromocytomas: hemodynamics and free catecholamine assays in ten consecutive patients. Surgery. 1989;106:1149-1154. 13. Ulchaker JC, Goldfarb DA, Bravo EL, et al. Successful outcomes in pheochromocytoma surgery in the modern era. J Urol. 1999;161: 764-767. 14. Pacak K, Eisenhofer G, Ahlman H, et al. Pheochromocytoma: recommendations for clinical practice from the First International Symposium, October 2005. Nat Clin Pract Endocrinol Metab. 2007; 3:92-102. 15. Havlik RJ, Cahow CE, Kinder BK. Advances in the diagnosis and treatment of pheochromocytoma. Arch Surg. 1988;123:626-630. 16. Hull CJ. Phaeochromocytoma: diagnosis, preoperative preparation and anaesthetic management. Br J Anaesth. 1986;58:1453-1468. 17. Kocak S, Aydintug S, Canakci N. Alpha blockade in preoperative preparation of patients with pheochromocytomas. Int Surg. 2002; 87:191-194. 18. Prys-Roberts C, Farndon JR. Efficacy and safety of doxazosin for perioperative management of patients with pheochromocytoma. World J Surg. 2002;26:1037-1042. 19. Pullerits J, Ein S, Balfe JW. Anaesthesia for phaeochromocytoma. Can J Anesth. 1988;35:526-534. 20. Sloand EM, Thompson BT. Propranolol-induced pulmonary edema and shock in a patient with pheochromocytoma. Arch Intern Med. 1984;144:173-174. 21. Bravo EL. Pheochromocytoma. Cardiol Rev. 2002;10:44-50. 22. Sjoerdsma A, Engelman K, Spector S, et al. Inhibition of catecholamine synthesis in man with alpha-methyl-tyrosine, an inhibitor of tyrosine hydroxylase. Lancet. 1965;2:1092-1094. 23. Cohen DL, Fraker D, Townsend RR. Lack of symptoms in patients with histologic evidence of pheochromocytoma: a diagnostic challenge. Ann NY Acad Sci. 2006;1073:47-51. 24. Kebebew E, Duh QY. Benign and malignant pheochromocytoma: diagnosis, treatment, and follow-up. Surg Oncol Clin North Am. 1998;7:765-789. 25. Werbel SS, Ober KP. Pheochromocytoma: update on diagnosis, localization, and management. Med Clin North Am. 1995;79:131153.

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