MAY 1 S T , 2013CATHERINE BARRETT

PGY2 INTERNAL MEDICINE WESTERN UNIVERSITY

Perioperative Management of Pheochromocytoma

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  

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

Epidemiology

Accounts for 0.05-0.1% of essential hypertensionIncidence of sporadic pheochromocytoma peaks in the

4th-5th 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

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 <10% of pheochromocytoma incidental, now

>25% Familial

Clinical Presentation

Goldstein et al. 1999 Kopetschke et al. 2009

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

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

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 resectedT5 = recovery room

All times significantly different with P< 0.05 Tauzin-Fin et al. 2004

Joris et al. 1999

Investigated hemodynamics in 8 consecutive patients undergoing laparoscopic adrenalectomy.

Significant catecholamine release associated with pneumoperitoneum and adrenal gland manipulation.

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

Management Goals

Normalize blood pressure, heart rate, and function of other organs

Restore volume depletionPrevent surgery-induced catecholamine

storm and its consequences on the cardiovascular system

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

No Preoperative Treatment

Goldstein et al. 1999Retrospective review of 104 patients from 1950

to 1998Sixteen 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.

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

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

Phenoxybenzamine

DibenzylineIn 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/kgSide effects

Postural hypotension Reflex tachycardia Nasal congestion Somnolence Postoperative hypotension

Prys-Roberts 2002

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

Day PXB(10mg)

PP(40mg)

Supine BP

Standing BP

Supine HR

Standing HR

Weight (kg)

1 0-0-1 0-0 AM: PM:

AM: PM: AM: PM:

AM: PM:

2 1-0-1 0-0

3 1-1-1 0-0

4 1-1-2 0-0

5 2-1-2 1-1

6 2-2-2 1-1-1

7 2-2-3 1-1-1

8 3-2-3 1-1-1-1

9 3-3-3 1-1-1-1

10 3-3-3 1-1-1-1

11 3-3-3 1-1-1-1

12 3-3-3 1-1-1-1

13 3-3-3 1-1-1-1

14 3(-3) 1(-1)PXB = Phenoxybenzamine; PP = Propranolol

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

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

Prys-Roberts 2002

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 < 100All patients received saline preoperatively (2L/day) x 2

days

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.

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/day36 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

Zhu et al. 2010

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

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

Mayo Clinic vs Cleveland Clinic

Anesthesia records were electronicIntraoperative 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)

Weingarten TN et al. 2010

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

Weingarten TN et al. 2010

Weingarten TN et al. 2010

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

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

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

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 effectsAdvantages

Decreased orthostatic hypotension and postoperative hypotension

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

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

Metyrosine

Used since the late 1970s

Alpha methyl tyrosine 0r metyrosine (Demser)

Inhibits tyrosine hydroxylase

It significantly but does not completely depletes catecholamine stores

Metyrosine

Maximum effect seen after about 3 days of treatmentTypically used in combination with an alpha blockerStart 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 barrierSide effects (more common if age > 65)

Sedation Depression Anxiety Extrapyramidal signs (rare) Diarrhea

Metyrosine

25 patients from 1982-1989Phenoxybenzamine 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

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

Perry et al. 1990

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

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 anginaParticularly 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

Pacak 2007

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

Pacak 2007

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

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

PhenylephrineNorepinephrine

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

Postoperative Care

May need monitored setting such as the ICUBlood glucose monitoring as increased risk of

developing hypoglycemia

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

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.

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 metastasesCombination 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

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

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

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

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

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/endmet

Kinney MAO et al. Perioperative Management of Pheochromocytoma. Journal of Cardiothoracic and Vascular Anesthesia. 2002. 359-369

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

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