1. MAY 1 ST, 2013 CATHERINE BARRETT PGY2 INTERNAL MEDICINE WESTERN UNIVERSITY Perioperative Management of Pheochromocytoma

2. Objectives (1) Understand the impact on catecholamine secretion and the resulting hemodynamic changes during surgical resection of pheochromocytoma (2)Review the use of alpha blockers, calcium channel blockers and metyrosine in the preoperative preparation of pheochromocytoma patients and their impact on intraoperative hemodynamics (3) Highlight the importance of anesthetic management and the evolution of surgical technique from laparotomy to a laporoscopic procedure (3) Highlight the need for long term follow up in patients with a history of resected pheochromocytoma

3. Pheochromocytoma Adrenal tumor originating from the chromaffin cells of the adrenal medulla Paragangliomas are closely related tumors originating from extra-adrenal sympathetic and parasympathetic tissue

4. Epidemiology Accounts for 0.05-0.1% of essential hypertension Incidence of sporadic pheochromocytoma peaks in the 4 th -5 th decade Familial causes of pheochromocytoma include:  VHL  NF1  MEN2  Germ line mutations in succinate dehydrogenase genes (SDHB, SDHD) Rule of “10”  10% bilateral  10% extraadrenal  10% familial  Closer to 25% in some reports  10% malignant

5. Clinical Presentation Symptomatic  Hypertension (paroxysmal or “essential hypertension”) most common presenting sign  Classic triad of headache, palpitations and sweating in 10-40%  Hypertensive crisis may develop in some patients resulting in cardiovascular shock with stroke, MI or multiorgan failure Incidental  Increasing incidence of incidental pheochromocytoma detected on routine imaging  Prior to 1985 25% Familial

6. Clinical Presentation Goldstein et al. 1999Kopetschke et al. 2009

8. Diagnosis Biochemical Diagnosis  Metanephrines (24h urine or plasma)  Catecholamines are metabolized in the chromaffin cells to metanephrines independent of catecholamine release Blood sampling should be performed at a supine position after about 15-20 minutes of IV catheter insertion Food, caffeine, strenuous physical activity or smoking are not permitted 8-12 hours prior to testing Imaging  CT or MRI for anatomic imaging  MIBG for functional imaging/metastases

10. Management Surgery mainstay or treatment First surgical resection occurred in 1926 by Dr. César Roux in Switzerland and Dr. Charles Mayo in the United States Prior to the introduction of adrenergic blocking agents and inotropes operative mortality reported up to 25%  Mortality rate up to 50% in operations on patients with unsuspected pheochromocytoma Current mortality ranges from 0 to 3.0% large tumor size, prolonged duration of anesthesia and increased levels of preoperative metanephrines are independent risk factors for adverse perioperative events

11. Norepinephrine <510 pg/ml and Epinephrine <170 pg/ml T0 = before induction of anesthesia T1 = after induction of anesthesia, laryngoscopy, orotracheal intubation T2 = end of pneumoperitoneal insufflation T3 = adrenal gland manipulation T4 = after adrenal gland resected T5 = recovery room All times significantly different with P< 0.05 Tauzin-Fin et al. 2004

12. Joris et al. 1999 Investigated hemodynamics in 8 consecutive patients undergoing laparoscopic adrenalectomy. Significant catecholamine release associated with pneumoperitoneum and adrenal gland manipulation.

13. Challenges Challenges of pheochromocytoma management  No randomized control trials  Few prospective studies  Approach to blockade varies widely by institution and mainly based on preference and availability of medications Unanswered Questions  Is preoperative blockade necessary in light of advances in anesthesia and surgical technique?  What is the preferred method of preoperative blockade?  Choice of medication  Duration of therapy prior to surgery

14. Management Goals Normalize blood pressure, heart rate, and function of other organs Restore volume depletion Prevent surgery-induced catecholamine storm and its consequences on the cardiovascular system

15. Current Recommendations NANETS 2010 North America Neuroendocrine Tumor Society  Recommend that all patients with pheochromocytoma or paraganglioma receive appropriate preoperative medical management to block the effects of released catecholamines  Choice of agent may include combined α1/2 blocker, selective α1 receptor blocker or calcium channel blocker  Beta blockade should be reserved for arrhythmias or angina and should not be initiated until appropriate alpha blockade achieved  Volume expansion recommended to decrease postoperative hypotension after tumor removal

16. No Preoperative Treatment Goldstein et al. 1999 Retrospective review of 104 patients from 1950 to 1998 Sixteen patients in the early years of the series underwent surgical resection without preoperative blockade Subjectively, the surgical course was classified as relatively smooth in 5 patients and complicated in 11 (69%) Nevertheless, there was no perioperative complications attributable to hemodynamic instability.

17. Case series of 30 pheochromocytoma resections. First 13 patients received no preoperative preparation. Phentolamine used during surgery to control blood pressure variations. This patient illustrates the wide variation in blood pressure that can be seen in a patient who has not undergone pretreatment prior to surgery. Ross et al. 1967

18. 113 patients, retrospective study from the Cleveland Clinic (1977 to 1994) This paper argues that preoperative preparation is not necessary as they found no difference in intraoperative hemodynamics with pretreatment. However, this paper only accounts for medications in the 24 hours prior to surgery and does not document the doses of medications. Ulchaker et al. 1999

19. Phenoxybenzamine Dibenzyline In use since the 1950s Irreversible, noncompetitive alpha 1/2 adrenoreceptor blocker Long-lasting effect that diminishes only after de novo receptor synthesis Oral and IV titration protocols The initial dose of phenoxybenzamine is usually 10 mg twice a day and is increased up to a total daily dose of 1 mg/kg Side effects  Postural hypotension  Reflex tachycardia  Nasal congestion  Somnolence  Postoperative hypotension

20. Prys-Roberts 2002

21. 62 patients with pheochromocytoma from 1956-1982  51 patients received preoperative pheonoxybenzamine  Median dose was 160mg/day  42 patients received IV infusion of phenoxybenzamine the evening before or morning of surgery  11 patients from 1956-1963 received no preoperative treatment  Operative and six month mortality was zero Stenstrom et al. 1985

22. DayPXB (10mg) PP (40mg) Supine BP Standing BP Supine HR Standing HR Weight (kg) 10-0-10-0 AM: PM: 21-0-10-0 31-1-10-0 41-1-20-0 52-1-21-1 62-2-21-1-1 72-2-31-1-1 83-2-31-1-1-1 93-3-31-1-1-1 103-3-31-1-1-1 113-3-31-1-1-1 123-3-31-1-1-1 133-3-31-1-1-1 143(-3)1(-1) PXB = Phenoxybenzamine; PP = Propranolol

23. Selective Competitive α1 Receptor Blockers Specific, competitive alpha 1 adrenergic antagonist  Doxazosin (Cardura)  In use since 1988  Half life 16-30 hours  Dose range: 1-16mg per day  Prazosin (Minipress)  Half life 2-3 hours  Dose range: 2-5mg BID-TID  Terazosin (Hytrin)  Half life 12 hours  Dose range: 2-5mg per day  Urapidil  Continuous infusion 10-15mg/hour 3 days prior to OR  Half life 2-4.8hours

24. Selective Competitive α1 Receptor Blockers Side effects  Postural hypotension Advantages:  No reflex tachycardia  Absence of alpha 2 blockade on presynaptic receptors  Decreased risk of hypotension postoperatively

25. Prys-Roberts 2002

26. Phenoxybenzamine vs Doxazosin 73 patients from 1995-2007  From 1995 to 2003:  31 patients blocked with phenoxybenzamine 25 also received propranolol  55% achieved adequate pretreatment with target MAP < 100  From 2003 to 2007:  42 patients blocked with doxazosin 37 also received propranolol  53% achieved adequate pretreatment with target MAP < 100 All patients received saline preoperatively (2L/day) x 2 days

27. Bruynzeel et al. 2010 No statistical difference between the intraoperative hemodynamics in the patients treated with phenoxybenzamine vs doxazosin. Higher doses of esmolol were required in the phenoxybenzamine group (P<0.05) but dosages of other drugs did not differ.

28. Phenoxybenzamine vs Doxazosin Retrospective review from March 2003 to June 2008 31 patients treated with phenoxybenzamine  Initial dose 5-10mg BID and increased by 10-20mg every 2-3 days to maximum dose of 60mg/day 36 patients treated with doxazosin  Initial dose was 4mg daily and increased by 4mg increments every 3-5 days to maximum dose of 16mg/day If the blood pressure was not <160/100 then additional antihypertensive agent added (CCB or ACE) Beta blockers were used to control tachycardia Zhu et al. 2010

30. Fourteen patients (38.9%) pretreated with DOX required supplementary antihypertensive therapy vs five patients (16.1%) in the PXB group (P<0.05). Fewer patients required beta blocker treatment in the DOX group vs PXB group (11.1 vs 77.4%, P<0.05) Zhu et al. 2010

31. Mayo Clinic vs Cleveland Clinic Mayo clinic (October 2003 to November 2006)  Phenoxybenzamine 1-4 weeks prior to surgery titrated to achieve orthostatic hypotension  2-3 days prior to surgery, beta blocker added if heart rate > 80  If BP still elevated, a CCB was added (nicardipine)  If the tumor was large, metyrosine was added 2-3 days prior to surgery Cleveland clinic (July 2005 to May 2009)  Normotensive or intermittent hypertensive patients received CCB  Alpha1 receptor antagonist was added in increments of 2mg every third day to a maximum of 10mg  If tachycardia developed and/or the patient had a history of CAD then a beta blocker was used

32. Mayo Clinic vs Cleveland Clinic Anesthesia records were electronic Intraoperative hemodynamics  Greatest intraoperative BP  Interval in minutes SBP > 30% of preinduction baseline  Interval in minutes that the SBP was 200mmHg  Lowest intraoperative BP  Interval in minutes that the systolic BP was 30% than the preinduction baseline  Greatest and lowest heart rates  Duration of tachycardia (>100 beats/min) and bradycardia (50 beats/min)

33. Weingarten TN et al. 2010

34. Mayo Clinic: -49 patients treated with PXB -1 patient treated with alpha 1 antagonist Cleveland Clinic: -5 patients treated with PXB -24 patients treated with alpha 1 antagonist (prazosin, doxazosin, terazosin) -1 patient with losaratan -4 patients received no treatment Weingarten TN et al. 2010

36. Postoperative course similar between both sites. The complication rates were low: -1 pneumothorax at MC -1 case of surgical re-exploration for bleeding at the CC -1 case of pulmonary edema at the CC -1 case of pneumonia at CC

37. Adequate Alpha Blockade No blood pressure reading >160/90 for 24 hours prior to surgery Orthostatic hypotension with readings > 80/45 should be present ECG should be free of ST changes for at least one week No more than one PVC q5 minutes

38. Patients with a MAP above 100 (n=25) experienced more and longer intraoperative episodes of SBP above 160 (true after adjustment for tumor size, pathology, procedure type). Bruynzeel et al. 2010

39. Calcium Channel Blockers Block NE-mediated calcium influx into vascular smooth muscle, controlling hypertension and tachyarrhythmias Generally felt to be less effective than alpha blockade Indications:  Supplement adrenoceptor blockers in patients with inadequate blood pressure control  Replace adrenoceptor blockers in patients with intolerable side effects Advantages  Decreased orthostatic hypotension and postoperative hypotension

40. Nicardipine 105 patients from 1991 to 2002 Nicardipine 20-60mg/day divided TID x 3-10 days All patients received nicardipine 20mg one hour prior to surgery and a continuous infusion at 0.5-2.0mg/kg/min  Hypertensive crises were treated by increasing the infusion rate from 2-10mg/kg/min or by IV boluses of 1-2mg Tachycardia (HR > 120) were treated with esmolol boluses (0.5mg/kg) Once the main vein of the tumor was clamped infusions were stopped If hypotension occurred, an infusion of colloid + IV ephedrine (3- 9mg) was administered  Persistent hypotension treated with continuous EPI/NE

41. All hypertensive episodes were controlled with nicardipine. Persistent hypotension in 13 patients requiring volume expansion and ephedrine. Two patients required NE infusion. Three deaths occurred in this series. One patient died secondary to massive hemorrhage. The second patient died from cardiovascular collapse in the OR followed by multiorgan failure in the ICU. The final patient died from a postop pulmonary embolism. Lebuffe G et al. 2005

42. Metyrosine Used since the late 1970s Alpha methyl tyrosine 0r metyrosine (Demser) Inhibits tyrosine hydroxylase It significantly but does not completely depletes catecholamine stores

43. Metyrosine Maximum effect seen after about 3 days of treatment Typically used in combination with an alpha blocker Start at 250mg BID-TID, increasing by 250-500mg q2-3 days to max 1.5 to 2.0g per day Readily crosses the blood-brain barrier Side effects (more common if age > 65)  Sedation  Depression  Anxiety  Extrapyramidal signs (rare)  Diarrhea

44. Metyrosine 25 patients from 1982-1989 Phenoxybenzamine started at 10mg BID and titrated to 0.5mg/kg/day in divided doses  Mean dose: 28mg/day (10-60mg/day)  Mean duration: 15 days (1-35 days) Propranolol or atenolol added in 5 patients with persistent tachycardia 19 patients were also treated with metyrosine, initial dosage of 250mg every 6 hours increased up to max 4g/day  Mean dose: 833mg/day (500-1500mg/day)  Mean duration: 10 days (4-21 days) Perry et al. 1990

45. Meytrosine Adequate preparation:  Absence of symptoms  Normalization of BP and HR  Presence of mild (<20mmHg) orthostatic hypotension The total dose of phenoxybenzamine was reduced after the addition of metyrosine in some patients On the day of surgery patients received 1mg/kg phenoxybenzamine and 1g metyrosine 1 patient received prazosin Perry et al. 1990

47. There was no statistically significant difference in the intraoperative hemodynamic measurements between the two groups. The authors felt the OR was smoother in the metyrosine treated group with less need for intraoperative medications but this was not significant. Patients treated with metyrosine required less crystalloid during the OR but not in the postoperative period. Perry et al. 1990

48. Beta Blocker Atenolol, propranolol Loss of beta receptor mediated vasodilation in a patient with unopposed alpha induced vasoconstriction can lead to dangerous increases in blood pressure Useful for preoperative control of tachyarrhythmias or angina Particularly useful in combination with phenoxybenzamine as tachycardia is a common side effect of alpha blockade Labetalol (PO) has a fixed ratio of α to β antagonist activity that is about 1:7 and therefore should not be used for preoperative blockade unless another alpha blocker used

49. Pacak 2007

50. Volume Expansion Patients are volume constricted b/c of alpha 1 stimulation Normalization of blood volume minimizes the possibility of protracted hypotension at the time of tumor removal Historically patients received blood transfusions preoperatively Standard now is a high salt diet +/- preoperative saline infusion

51. Pacak 2007

52. Anesthesia Increasing depth of anesthesia and muscle relaxation common practice to reduce blood pressure variations Nicardipine  Arterial vasodilation  Reduced afterload  Improvement left ventricular function  Preservation venous return  Response in 1-3 min  Half life is 3-7 min Phentolamine  Competitive alpha 1 and weak alpha 2 adrenergic receptor antagonist with short duration action Sodium nitroprusside  Decreases preload and afterload  Onset immediate, recovery in 1-2 min

53. Anesthesia Nitroglycerin  Rapid venodilator  Reduces preload  Increases coronary blood flow by dilating the collateral vessels and suppressing coronary vasospasm  High doses produce arteriolar vasodilation Esmolol  Ultra short acting cardiac selective beta blocker  Onset in 60sec  Duration 10-20min Phenylephrine Norepinephrine

54. Advances in Surgical Approach Laparotomy  Prior to advances in imaging technique, manual exploration was required to exclude accessory tumor deposits  Still useful in large tumors or metastatic disease Laparoscopic surgery  Since 1992  Initial concern of increased cardiovascular risks with CO2 insufflation, increased abdominal pressure and manipulation of adrenal gland  Up to 10cm tumors can be removed  Less pain, reduced hospital stay and more rapid return to normal activity

55. Postoperative Care May need monitored setting such as the ICU Blood glucose monitoring as increased risk of developing hypoglycemia

56. Long Term Follow Up Recurrence rate of 17% More common in the setting of:  Extraadrenal disease (33%) vs adrenal disease (14%)  Familial (33%) vs nonfamilial (13%) Pathology does not determine malignant potential of pheochromocytoma  Requires presence of tumor deposit outside of chromaffin tissue

57. Pacak et al. 2006 Algorithm for genetic testing for genes associated with pheochromocytoma. The algorithm should be applied if there is a family hx of pheochromocytoma, the patient is < 50 years old or there are multiple, malignant or bilateral tumors. The biochemical phenotype of the tumor should also be considered in selection of the most appropriate genes to test.

58. Malignant Pheochromocytoma Incidence ranges 3-36% depending on genetic background and tumor localization Overall five year survival 34-60%  Longer survival in metastatic bone disease  Shorter survival with liver or lung lesions External beam radiation for bony metastases Combination chemotherapy with cyclophosphamide, vincristine and dacarbazine  Tumor regression and symptom relief in up to 50% of patients  Response short lived MIBG therapy  Dosing regimen still unclear

59. Conclusions Surgery is the mainstay of treatment for pheochromocytoma but is associated with secretion of catecholamines which can lead to hemodynamic compromise Preoperative blockade does not completely eliminate blood pressure variation during surgery but ensures a relatively smoother course than without treatment Further advances in the care of pheochromocytoma patients will be based on preoperative preparation, anesthetic management and surgical technique as all are important components of its management

60. Conclusions All patients with pheochromocytoma will require long term follow up as there remains a life long risk of recurrence Special considerations to genetic testing should be made in the appropriate clinical circumstance

61. References Goldstein RW et al. Clinical Experience Over 48 Years with Pheochromocytoma. Annals of Surgery. 1999. 229(6):755-766 Guerrero et al. Clinical Spectrum of Pheochromocytoma. J Am Coll Surg. 2009 209:727-732 Chen H et al. The NANETS Consensus Guideline for the Diagnosis and Management of Neuroendocrine Tumors: Pheochromocytoma, Paraganglioma and Medullary Thyroid Cancer. Pancreas. 2010. 39(6):775-783 Pacak K. Preoperative Management of the Pheochromocytoma Patient. The Journal of Clinical Endocrinology and Metabolism. 2007. 92(11):4069-4079

62. References Tauzin-Fin P et al. Effects of perioperative alpha 1 block on haemodynamic control during laparoscopic surgery for pheochromocytoma. British Journal of Anesthesia. 2004. 92 (4):512-517 Kopetschke R et al. Frequent incidental discovery of pheaochromocytoma: data from a german cohort of 201 pheochromocytoma. European Journal of Endocrinology. 2009. 161:355-361 Joris JL et al. Hemodynamic Changes and Catecholamine Release During Laparoscopic Adrenalectomy for Pheochromocytoma. Anesth Anal 1999. 88:16-21

63. References Stenstrom G et al. Influence of Pre-operative Treatment with Phenoxybenzamine on the Incidence of Adverse Cardiovascular Reactions during Anesthesia and Surgery for Pheochromocytom. Acta Anaesthesiol Scand. 1985. 29: 797-803 Pacak K et al. Pheochromocytoma: recommendations for clinical practice from the first international symposium. 2006. www.nature.com/clinicalpractice/endmetwww.nature.com/clinicalpractice/endmet Kinney MAO et al. Perioperative Management of Pheochromocytoma. Journal of Cardiothoracic and Vascular Anesthesia. 2002. 359-369

64. References Lenders JWM et al Pheochromocytoma. Lancet. 2005. 366:665-675 Bruynzeel H et al. Risk factors for hemodynamic instability during surgery for pheochromocytoma. J Clin Endocrinol Metab. 2010. 95(2) 678-685 Ulchaker JC et al. Succesful outcomes in pheochromoctoma surgery in the modern era. The Journal of Urology. 1999. 161:764-767 Zhu Y et al. Selective a1-adrenoceptor antagonist (controlled release tablets) in preoperative management of pheochromocytoma. Endocr. 2010, 38:254–259

65. References Weingarten TN et al. Comparison of Two Preoperative Medical Management Strategies for Laparoscopic Resection of Pheochromocytoma. 2010. 76: 508.e6 –508.e11 Prys-Roberts C et al. Efficacy and Safety of Doxazosin for Perioperative Management of Patients with Pheochromocytoma. World J. Surg. 2002. 26, 1037–1042. Perry RR et al. Surgical Management of Pheochromocytoma with the use of Metyrosine. Annal Surgery. 1990. 212(5): 621– 628 Lebuffe G. et al. The effect of calcium channel blockers on outcome following the surgical treatment of phaeochromocytomas and paragangliomas. 2005. (60):439– 444