CASE REPORT

Cardiac and Abdominal Pheochromocytomas: Anesthetic Management for a Combined Cardiac and Hepatobiliary Procedure Francesca Rawlins, MBBS, BSc, FANZCA,* Craig Johnston, MBBS, FANZCA,* and Kerstin Wyssusek, PhD, FANZCA*†

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heochromocytomas are functionally active tumors arising from chromaffin cells. They produce and secrete biogenic amines. The majority of pheochromocytomas are intra-adrenal, with only 10% to 20% found outside the adrenal medulla.1 Pheochromocytomas are a rare cause of hypertension (0.1%0.6%)2 and are familial in 15% to 20% of cases. The incidence of metastatic pheochromocytomas varies between 3% and 36% as summarized by Pacak et al.3 Mediastinal paragangliomas, however, are extremely uncommon, representing only 2% of all catecholamine-secreting tumors.4 Without treatment, pheochromocytomas are associated with high mortality from hypertension, cardiomyopathy, and stroke. Their metabolic effects include hyperglycemia, weight loss, and lactic acidosis. CASE PRESENTATION A 29-year-old Indigenous Australian was referred to the authors’ tertiary referral hospital after presenting to his local hospital in hypertensive crisis following a rugby tackle. He complained of severe right-sided abdominal pain, diaphoresis, dizziness and dyspnea. His blood pressure on presentation was 220/110 mmHg. All symptoms resolved spontaneously. He had a 2-year history of right-sided abdominal pain, nausea, and vomiting on playing sports. His hypertension had not been diagnosed or investigated. He had a 15 pack-year smoking history and did not take any regular medication. He weighed 74 kg and had a BMI of 25. Investigation of his hypertension revealed elevated urine metadrenaline levels of 56,000 pmol/L (Normal o900). Computed tomography (CT) showed a 30  24 mm right-sided abdominal retrocaval mass suspicious for pheochromocytoma in the absence of an adrenal tumor. As routinely performed at the authors’ institution, followup transthoracic echocardiogram demonstrated a large mass abutting the right atrium. Cardiac magnetic resonance imaging (MRI) demonstrated a 40 mm x 32 mm highly vascular mass situated in the right atrioventricular groove (Fig 1). A small apical infarct was apparent. The anatomy was further delineated with coronary angiography, which demonstrated 2 feeding vessels coming off the right coronary artery (Fig 2). According to the authors’ hospital imaging protocol, they performed radioisotope M-iodobenzylguanidine (MIBG) scintigraphy, which showed uptake in both tumors (retrocaval and intracardiac) confirming the diagnosis of extra-adrenal pheochromocytomas. The patient was started on the alpha-blocker, phenoxybenzamine, 10 mg twice a day 3 weeks preoperatively. The dose was increased until blood pressure was controlled and postural hypotension developed. Phenoxybenzamine is the drug of choice for preoperative blood pressure management in pheochromocytoma at the authors’ institution as it produces a noncompetitive blockade of alpha-receptors by covalent binding. As per hospital protocol, metoprolol, a betablocker, was added to control reflex tachycardia.

After obtaining informed written consent from the patient, he was premedicated with 20 mg of temazepam the night before and the morning of surgery. His morning dose of phenoxybenzamine, 40 mg, and metoprolol, 50 mg, had been given. Anesthesia was induced after insertion of a 14G intravenous catheter and 20G radial arterial catheter. Prior to induction, a 30 mg/kg loading dose of magnesium sulfate (MgSo4) was given intravenously to aid cardiovascular stability. Fentanyl, 7 µg/kg, midazolam 0.1 mg/kg, and rocuronium, 0.6 mg/kg, were given together with propofol Marsh model target-controlled infusion (TCI) and remifentanil Minto model TCI to facilitate orotracheal intubation with a cuffed endotracheal tube. Anesthesia was maintained with propofol and remifentanil TCI, midazolam, 1 mg/h infusion, and cisatracurium, 4 mg/h infusion. It is standard to use infusions in the authors’ institution during cardiopulmonary bypass. The patient was ventilated with positive pressure in a circle system until cardiopulmonary bypass (CPB) was established. To ensure appropriate central venous access, an introducer sheath, as well as a multi-lumen central venous catheter, were inserted into the right internal jugular vein post induction of anesthesia. Although the patient was sufficiently premedicated, the authors elected to place the catheters after induction to prevent the risk of hypertensive crisis. Additionally, transesophageal echocardiography (TEE) was performed to analyze ventricular function and visualize the tumor intraoperatively (Fig 3). Several vasoactive drugs were prepared, namely norepinephrine and phenylephrine, to alleviate vasoplegia due to alpha-receptor blockade and to supplement blood pressure following the removal of the catecholamine-secreting tumors. Magnesium sulfate, sodium nitroprusside, phentolamine, and esmolol were at hand to be administered if needed in case of a catecholamine surge due to surgical manipulation of the tumors. Remifentanil was titrated to maintain a systolic blood pressure of 100 mmHg off CPB. The authors elected to perform acute normovolemic hemodilution (ANH) on the patient prior to the instigation of CPB. Approximately 300 mL of blood were removed from the central venous catheter and

From the *Department of Anesthesiology, Princess Alexandria Hospital and †School of Medicine, University of Queensland, Brisbane, Australia. Address reprint requests to Francesca Rawlins, Department of Anesthesia, Princess Alexandria Hospital, 199 Ipswich Road, Woolloongabba, Brisbane 4201, QLD, Australia. E-mail: [email protected] Crown Copyright © 2014 Published by Elsevier Inc. All rights reserved. 1053-0770/2602-0033$36.00/0 http://dx.doi.org/10.1053/j.jvca.2013.12.023 Key words: pheochromocytoma, cardiac paraganglioma, hypertensive crisis, anesthetic management of pheochromocytoma

Journal of Cardiothoracic and Vascular Anesthesia, Vol ], No ] (Month), 2014: pp ]]]–]]]

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Fig 1. MRI axial section through heart demonstrating mass in right atrioventricular groove. RCA, right coronary artery.

stored in a saline-, adenine-, glucose-, and mannitol-containing blood bag at room temperature. The chest was opened by midline sternotomy. The tumor was apparent in the right atrium. There was no evidence of metastatic disease within the pericardium or mediastinum. The right atrial appendage and left superficial femoral vein were cannulated to provide venous drainage and isolation of the inferior vena cava should the abdominal tumor be adherent to it. The ascending aorta was cannulated, and CPB was instituted. The patient was cooled to 34°C, and the heart was arrested with antegrade cold-blood- and potassium-containing crystalloid cardioplegia in a 4-to-1 ratio after application of a crossclamp to the ascending aorta. The right atrial tumor was excised with a 1-cm portion of the right coronary artery. A saphenous vein graft was used to bypass from the aorta to the posterior descending artery.

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Fig 3. Modified TEE bicaval view showing large tumor associated with the right atrium (RA). The tip of the central venous line (CVL) is visible in the superior vena cava. Also labelled are left atrium (LA) and inferior vena cava (IVC).

The cross-clamp time was 47 minutes. After removal of the clamp, the patient reverted to sinus rhythm spontaneously. The second procedure was carried out by the hepatobiliary surgeons who performed a midline laparotomy with right subcostal extension. An encapsulated noninvasive paraganglioma was dissected out intact from the infrahepatic inferior vena cava. No evidence of metastatic disease was found. After completion of both surgical procedures, the patient was weaned and separated from CPB after 184 minutes. The authors anticipated the patient would become hypotensive once both tumors were resected. A norepinephrine infusion was started during CPB and briefly increased to 20 µg/min coming off bypass. The predicted hypotension also was treated with aggressive intravascular filling. A total of 5 liters of crystalloid plus 300 mL of autologous blood and 900 mL of pump blood were infused. The use of TEE allowed real-time evaluation of ventricular contractility and filling and guided the authors’ decision-making. Moderate coagulopathy, confirmed by a thromboelastograph, was treated with 2 units of fresh frozen plasma and 2 units of pooled platelets at the end of the case. The norepinephrine was weaned rapidly at the end of surgery, and the patient was transferred to the intensive care unit. An anticipated perioperative hypoglycemia was treated with an infusion of 50% glucose at 5 mL per hour after tumor removal. The patient was extubated on day 1 postoperatively and discharged home on day 7. He continued to be hypertensive postoperatively and was treated with atenolol, 25 mg daily. Followup at his local hospital found his serum catecholamine levels to have normalized at 2 weeks postoperatively, and the atenolol was stopped. DISCUSSION

Fig 2. Coronary angiogram demonstrating highly vascular tumor at the right atrioventricular groove associated with the right coronary artery (RCA).

Co-existent abdominal and cardiac pheochromocytomas are exceptionally rare. There are relatively little data published on the management of mediastinal pheochromocytomas; however, the treatment of choice is surgical resection, being curative in the majority of cases.5,6 The authors’ literature search revealed no published data to date discussing the anesthetic management of a secreting cardiac pheochromocytoma. Patients with a diagnosed pheochromocytoma usually are referred to an endocrine surgeon who often works with an anesthesiologist with expertise in the perioperative management of those patients. The authors’ case mandated expertise in endocrine

SYNCHRONOUS CARDIAC AND ABDOMINAL PHEOCHOMOCYTOMAS

and cardiac anesthesia. Therefore, a multidisciplinary team of endocrinologists, cardiothoracic and hepatobiliary surgeons, and cardiac and endocrine anesthesiologists and perfusionist, managed the patient. A combined procedure to excise both tumors was planned. The anesthetic and surgical management had to be adapted to safely allow excision of both tumors in 1 operation by 2 different surgical teams. Due to the involvement of the right coronary artery, the operation was planned to be carried out on CPB. After biochemical confirmation, pheochromocytomas and paragangliomas usually are localized with different techniques, namely CT, MRI, and MIBG. According to Lumachi et al, a combination of MRI and MIBG can achieve 100% sensitivity and positive predictive value.7 Perioperative drug management regimens vary and are largely dependent on local institutional protocols. Calcium channel blockers, alpha-receptor blockers, magnesium sulfate, and angiotensin-converting enzymes have been discussed in the literature. The most common drug used in Australia is phenoxybenzamine. According to current expert view, perioperative alpha-blockade has a significant impact on surgical outcome, with diminished perioperative complications.3,8–10 In the authors’ patient, control of intraoperative blood pressure was paramount due to the risk of ascending aortic dissection after cannulation for cardiopulmonary bypass. The authors elected to administer MgSo4 preoperatively. Magnesium sulfate acts as a vasodilator by inhibiting catecholamine release, inhibiting catecholamine receptors, and behaving as a functional calcium antagonist. Administration of MgSo4 is relatively safe, and its use in modulating blood pressure in pheochromocytoma surgery has been described since the 1980s.11–14 Remifentanil is a rapidly titratable opioid with a short half-life. It has a dose-dependent effect on blood pressure and is known to suppress catecholamine secretion.15 Sodium nitroprusside also was prepared, its advantages being its rapid onset and short half-life, making it appropriate for controlling surges in blood pressure.16 After tumor excision, a period of relative hypotension can be anticipated. This is due mainly to the long half-life of phenoxybenzamine, the short half-life of catecholamines, and volume depletion. The hypotension in this patient’s case was confounded by the inflammatory response due to cardiopulmonary bypass.17 In their review article, Lentschner et al raised the question of whether medically treated pheochromocytoma patients are hypovolemic.18 Data in the literature are scarce. Mallat et al, however, suggested that during tumor removal, reduced preload associated with hypovolemia is not a key contributor to hypotension.19 They postulated that decreased arterial tone would be a more likely explanation. The authors’ management plan included appropriate intravascular filling and vasopressor support, which was guided by TEE images. It can be difficult to distinguish between hypovolemia and low afterload when assessing the left ventricle with TEE. Qualitatively, hypovolemia causes a decrease in left ventricular end-systolic and end-diastolic area when measured in the transgastric midshort axis, whereas low afterload causes a decrease in endsystolic area with a normal end-diastolic area and therefore, increased stroke volume.20 The authors observed the changes in left ventricular end systolic and end diastolic areas in response

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to fluid challenges and used this to guide fluid therapy. Initially, high doses of norepinephrine were used to support separation from CPB, but the dose was weaned rapidly in response to TEE-guided fluid administration. Vasopressin was also available were the hypotension to become refractory to norepinephrine as described by Lord at al.11 A more quantitative method of assessing left ventricular filling is the use of the superior vena cava collapsibility index described by Vieillard-Baron et al.21 This technique has the advantage that it can be used to predict fluid responsiveness before fluids are administered. In their publication, Vieillard-Baron et al reported that a collapsibility index of greater that 36% can predict fluid responsiveness, as measured by an increase in cardiac index of greater than 11% with a 100% specificity and 90% sensitivity. While this technique would be very useful in an intensive care setting, in the authors’ experience, the rapidly changing hemodynamics associated with cardiac surgery require a faster response with fluids, inotropes, and vasopressors. The authors, therefore, used the TEE images as a qualitative guide. The rationale for ANH in this instance was to minimize allogeneic blood product transfusion after a predicted long bypass run with associated high risk of coagulopathy. ANH has been practiced since the 1970s with the advantages being minimizing exposure of the patient to allogeneic blood products and potential infection, decreasing the number of red blood cells lost during surgery secondary to hemodilution, and potential benefits of transfusing whole blood with clotting factors and platelets.22 Over the years, multiple studies have been carried out into ANH. A meta-analysis by Segal et al23 looking at randomized control trials from 1966-2002 concluded that patients showed modest benefits from hemodilution in the form of less allogeneic blood transfusion. Taketani et al24 reviewed data from 243 patients undergoing cardiac or thoracic aortic surgery on CPB and concluded that ANH can be an effective means of reducing the risk of homologous blood transfusion. Furthermore, Sarin et al25 described a decrease in postoperative mortality and morbidity associated with decreased blood product usage in patients undergoing ANH for cardiac surgery. The authors’ patient had a starting hemoglobin of 16g/dL and hematocrit of 48%. Taking into account the 2 liters of prime that would be given on bypass, they chose to remove 1 bag of blood (approximately 300 mL) before CPB, which ensured that the platelets were not activated by contact with the bypass circuit. The volume was replaced with crystalloid. The blood was given back to the patient after protamine reversal of heparin. During bypass, the hemoglobin did not fall below 8g/dL and after the pump blood and autologous blood had been returned following heparin reversal, the patient had a hemoglobin of 9.7g/dL and a hematocrit of 29%. Care should be taken in selecting patients to have ANH to avoid hemodiluting already anemic patients or providing additional cardiovascular stress to patients who are septic or have cardiac ischemia. It is of note that Licker et al conducted a study of ANH in patients undergoing on-pump coronary artery bypass grafting and found it to, in fact, provide additional cardioprotective effects.26 The abdominal tumor was removed while on CPB, which lengthened the duration of the bypass run. The relatively long,

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184-minute CPB time resulted in a moderate degree of coagulopathy, which was treated with fresh frozen plasma and platelets. Despite the patient having a normal platelet count prior to surgery, the use of CPB is recognized to cause platelet dysfunction through platelet activation and a decrease in the overall number of platelets.17 Post-bypass coagulopathy may be secondary to platelet dysfunction and factor consumption on CPB with the degree of platelet dysfunction increasing with bypass time.17 Point–of-care testing in the form of thromboelastography was performed on rewarming to assess the degree of coagulopathy. The thromboelastography suggested coagulation factor deficiency and platelet deficiency; hence, fresh frozen plasma and platelets were administered. The experience of the surgeon is also a significant factor in determining blood

product usage. In this case, persistent ooze at both surgical sites prompted the surgeons to request blood products. Intraoperative and postoperative hypoglycemia have to be anticipated. Masako et al suggested that endogenous secretion of insulin is suppressed by high plasma catecholamine level and that a rebound insulin secretion after tumor removal may cause severe hypoglycemia.27 In conclusion, the anesthetic management of patients with pheochromocytomas and paragangliomas is often challenging. To date, there is no evidence-based recommendation on intraoperative anesthetic care. Close cooperation among all members of the multidisciplinary team is vital. The authors’ perioperative treatment of this patient with meticulous attention to hemodynamics helped ensure a favorable result.

REFERENCES 1. Van Braeckel P, Carlier S, Steelant PJ, et al: Perioperative management of phaeochromocytoma. Acta Anaesth Belg 60:55-66, 2009 2. Lenders J, Eisenhofer G, Mannelli M, et al: Phaeochromocytoma. The Lancet 366:665-675, 2005 3. Pacak K, Eisenhofer G, Ahlman H, et al: Pheochromocytoma. Recommendations for clinical practice from the First International Symposium. Nat Clin Pract Endocrinol Metab 3:92-102, 2007 4. Young WF Jr.: Adrenal medulla, catecholamines, and pheochromocytoma, in Goldman L, Ausiello D (eds). Cecil Medicine. Philadelphia, PA, Saunders Elsevier, 2008, pp. 1721-1727 5. Brown ML, Zayas GE, Abel MD, et al: Mediastinal Paragangliomas: The Mayo Clinic experience. Ann Thorac Surg 86:946-951, 2008 6. Kim DD, Matsui C, Gozzanu JL, et al: Pheochromocytoma anesthetic management. Open J Anesthesiol 3:152-155, 2013 7. Lumachi F, Tregnaghi A, Zucchetta P, et al: Sensitivity and positive predictive value of CT, MRI and 123I-MIBG scintigraphy in localizing pheochromocytomas: A prospective study. Nucl Med Commun 27:583-587, 2006 8. Goldstein RE, O’Neill JA Jr, Holcomb GW 3rd: Clinical experience over 48 years with pheochromocytoma. Ann Surg 229:755-764, 1999 9. Pacak K: Preoperative management of the pheochromocytoma patient. J Clin Endocrinol and Metab 92:4069-4079, 2007 10. Chen H, Sippel RS, O’Dorisio MS, et al: The North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors pheochromocytoma, paraganglioma, and medullary thyroid cancer. Pancreas 39:775-783, 2010 11. Lord MS, Augoustides JGT: Perioperative management of pheochromocytoma: Focus on magnesium, clevidipine, and vasopressin. J Cardiothorac Vasc Anesth 26:526-531, 2012 12. Pace N, Buttigieg M: Phaeochromocytoma. Br J Anaesth CEACC Reviews 3, 1:20-23, 2003 13. Masumune T, Ishiyama T, Kawamura A, et al: Use of magnesium sulphate during resection of pheochromocytoma. Masui 51:515-517, 2002 14. James MF: Use of magnesium sulphate in the anaesthetic management of phaeochromocytoma: A review of 17 anaesthetics. Br J Anaesth 62:616-623, 1989

15. Dermitzaki E, Gravanis A, Stournaras C, et al: Opioids suppress basal and nicotine induced catecholamine secretion via a stablilizing effect on actin filaments. Endocrinology 142:2022-2031, 2001 16. Kinney M, Narr BJ, Warner MA: Perioperative management of phaeochromocytoma. J Cardiothorac Vasc Anesth 16:359-369, 2002 17. Rinder CS: Hematologic effects of cardiopulmonary bypass, in Gravlee G, Davis RF, Kurusz M, Utley J chapter 24. (2nd ed.). Cardiopulmonary bypass: Principles and practice. NewYork, NY, Lippincott Williams and Wilkins, 2000 18. Lentschener C, Gaujoux S, Tesniere A, et al: Point of controversy: Perioperative care of patients undergoing pheochromocytoma removal–time for a reappraisal? Eur J Endocrinol 165:365-373, 2011 19. Mallat J, Pironkov A, Destandau MS, et al: Systolic pressure variation (Deltadown) can guide fluid therapy during pheochromocytoma surgery. Can J Anaesth 50:998-1003, 2003 20. Sidebotham D, Merry AF, Legget ME, et al: Practical Perioperative Transesophageal Echocardiography, (2nd ed.). Elsevier Saunders, 2011 21. Vieillard-Baron A, Chergui K, Rabiller A, et al: Superior vena caval collapsibility as a gauge of volume status in ventilated septic patients. Intensive Care Med 30:1734-1739, 2004 22. Shander A, Rijhwani TS: Acute normovolemic hemodilution. Transfusion 44:26S-34S, 2004 23. Segal JB, Blasco-Colmenares E, Norris EJ, et al: Preoperative acute normovolemic hemodilution: A meta-analysis. Transfusion 44: 632-644, 2004 24. Taketani T, Motomura N, Toyokawa S, et al: Beneficial effect of acute normovolemic hemodilution in cardiovascular surgery. Jpn J Thorac Cardiovasc Surg 53:16-21, 2005 25. Sarin E, Speir A, Henry L, et al: Acute normovolemic hemodilution decreases blood product use and postoperative mortality and morbidity following cardiac surgery. J Am Coll Cardiol 59: E1843-E1843, 2012 26. Licker M, Ellenberger C, Sierra J, et al: Cardioprotective effects of acute normovolemic hemodilution in patients undergoing coronary artery bypass surgery. Chest 128:838, 2005 27. Akiba M, Kodama T, Ito Y, et al: Hypoglycemia induced by excessive rebound secretion of insulin after removal of pheochromocytoma. World J Surg 14:317-324, 1990