Anaesthetic Management Of Pheochromocytoma

Mohd Faizal Zainuddin

Supervisor: Dr Abdul Karim Othman

Pheochromocytoma - major disorder of adrenal medulla: excessive catecholamine secretion- Secondary cause of hypertension in 0.1% of hypertensive patients- Incidence is very low, age: 20 and 50 year old- A proportion diagnosed during induction of anesthesia hypertensive crisis mortality close to 80%

Adrenal medulla: - reddish-brown central layer of adrenal gland - accessary medullary tissues – retroperitoneum near the sympathetic ganglia or along the abdominal aorta (paraganglia)- embryogically neural crest cells, innervated by cholinergic preganglionic fibers - most (~80%) of catecholamine output of adrenal medulla is epinephrine, the rest being norepinephrine and dopamine- Catecholamine metanephrine + nor metanephrine (methoxylation)- Catecholamine 3-methoxy-4-hydroxymandellic acid/VMA (oxydation)- Excreted in urine as free or conjugated metanephrine + nor metanephrine and as VMA

Normal plasma level of catecholamines…- free epinephrine= 30 pg/ml (0.16 n mol/L)- free norepinephrine= [200 – 1700 mcg/ml] 300 pg/ml (1.8 n mol/L)- free dopamine= [<30 mcg/ml] 35 pg/ml (0.23 n mol/L)- T 1/2 ~ 2 minutes

24 hour urine…- Normetanephrine = 50 – 840 mcg/ml- Metanephrine = 0 – 370 mcg/ml- Vanillimandelic acid = <7.2 mcg/ml- Norepinephrine = 13 – 107 mcg/ml- Epinephrine = 0 – 15 mcg/ml

Preoperative assessment- close cooperation between physician, cardiologist, surgeon and anaesthetist- relevant history, severity of hypertension, look for end organ damage- full blood count and hematocrit: adequacy of volume expansion- renal function: urea, creatinine and electrolytes- electrocardiography: hypertrophy, arrhythmias, cardiomyopathy, ischemia or infarction, left ventricular dysfunction, improvement after adrenergic blockade- chest x-ray: cardiomegaly, pulmonary edema- insulin may be needed if hyperglycemia

Preoperative management- All patients with a biochemically positive pheochromocytoma should receive appropriate preoperative medical management to block the effects of released catecholamines (First International Symposium on Pheochromocytoma)

- Main goals: 1) normalize blood pressure, heart rate and functions of other organs 2) restore volume depletion 3) prevent patient from surgery induced catecholamines storms

- ? which drugs: wide ranging practices, international differences in available or approved therapy, scarcity of evidence based studies- α adrenoceptor antagonists, β adrenoceptor antagonists, calcium channel blockers, angiotensin receptor blockers were recommended- adrenergic blockade usually starts 7-14 days preoperatively to normalize blood pressure and heart rate and to expand the contracted volume - those with organ damage, adrenergic blockade can be initiated earlier

1) α adrenoceptor antagonistsa) phenoxybenzamine (irreversible, non competitive)- initial dose 10 mg bd/day, increased till clinical manifestations are controlled or side effects appear (usually total 1 mg/kg/day is sufficient)- side effects: postural hypotension with reflex tachycardia, dizziness, syncope, nasal congestion- another option: infusion 0.5 mg/kg/day for 5 hours/day, 3 days before operation requires close monitoring, not cost effective, no correlation between duration of treatment with phenoxybenzamine and cardiovascular intraoperative stability

b) prazosin, terazosin, doxazosin (specific, competitive, short acting α1 adrenergic antagonists)- prazosin: 2-5 mg bd/tds a day, terazosin: 2-5 mg/day, doxazosin: 2-8 mg/day- less side effects: no reflex tachycardia, less post operative hypotension ! use with caution in volume depleted patients- should be given before sleeping as patient may develop severe postural hypotension

2) β adrenoceptor antagonists- used after adequate pretreatment with α adrenoceptor antagonists to avoid hypertensive crisis from unopposed α adrenoceptor overstimulation - inhibition of β2 adrenoceptor mediated vasodilatation leaving α adrenoceptor mediated vasoconstriction unopposed- cardioselective β1 adrenoceptor blockers are preferable- atenolol: 12.5 -25 mg 2-3 times/day; metoprolol: 25- 50 mg 3-4 times/day; propranolol (non selective β adrenoceptor blocker): 20-80 mg 1-3 times/day- labetalol (combined α and β adrenoceptor blocker): not as primary choice paradoxical episodes of hypertension / hypertensive crisis , except when patient on α and β adrenoceptor blockers that need to be replaced

3) calcium channel blocker- block noradrenaline mediated calcium influx into vascular smooth muscle control hypertension and tachyarrhythmias- main roles: 1) inadequate blood pressure control with adrenoceptor blockers 2) replace adrenoceptor blockers in patients with severe side effects3) prevent adrenoceptor blocker induced sustained hypotension in patients with intermittent hypertension- may prevent catecholamine associated coronary spasm- amlodipine: 10-20 mg/day; nicardipine: 60-90 mg/day; nifedipine: 10-30 mg/day; verapamil: 180-540 mg/day

4) metyrosine (α Methyl ʟ Tyrosine)- competitively inhibits tyrosine hydroxylase and depletes catecholamine stores- for extensive metastatic disease and patients with biochemically active tumors- when used with α adrenoceptor blockers: less labile blood pressure and reduced blood loss intra operatively - limited availability and side effects evident at high dose- sedation, sleepiness, depression, anxiety, galactorrhea, diarrhea, crystalluria, extrapyramidal signs - suggested dose: initial 250 mg bd/tds, can be increased by 250 to 500 mg every 2 – 3 day or as necessary up to total 1.5 to 2.0 g/day

intraoperative management- close communication between surgeon and anaesthetist success of intraoperative management- regional anaesthesia versus regional combined with general anaesthesia and neurolept technique- main aim: avoid straining that may cause catecholamine release- standard monitoring: ECG, pulse oxymeter, non invasive blood pressure, inspired oxygen concentration, neuromuscular blockade, temperature, urine output

- central venous and arterial catheter: immediate identification of hemodynamic fluctuation during induction, maintenance, surgical manipulation and guide for pharmacologic intervention- pulmonary artery catheter: severe left ventricular dysfunction and pre operative cardiovascular compromise - at least two large bore intravenous catheter for fluids and medications administration- epidural catheter at T10-T11 to T12-L1: intraoperative and postoperative analgesia

- induction: preoxygenation followed by fentanyl 1-2 mcg/kg and propofol 1-2 mg/kg- alfentanil/ sufentanil: replace fentanyl, midazolam: co-induction- thiopentone histamine release, etomidate cardiovascular stability but produces involuntary movements- vecuronium, rocuronium & cisatracurium: cardiovascular stability and release least histamine- atracurium & mivacurium histamine release- suxamethonium: produce fasciculation, but successfully used in pregnant patient with pheochromocytoma- lung then ventilated with volatile agent for 3-5 minutes followed by tracheal intubation

- TV=7-10 ml/kg, rate=10-12, ETCO2=35 mmHg- maintenance: isoflurance/sevoflurance in air-oxygen mixture with FiO2 around 0.5 (halothane – sensitizes myocardium to catecholamines); nitrous oxide not contraindicated- if epidural is used: initial bolus 8-10 ml of 0.25% bupivacaine in divided doses followed by infusion bupivacaine 0.1-0.2% with fentanyl 2 mcg/ml at 6-12 ml/h- reversal: neostigmine + glycopyrrolate tachycardia associated with atropine hypertensive spike- to reverse or ventilate patient in ICU preoperative state and intraoperative course - even if extubated, monitor hemodynamic stability at least 24 hours in ICU/HDW

Perioperative catecholamine release- manipulation of tumor hemodynamic response perioperative catecholamine release- sodium nitroprusside: potent arterio-venodilator, rapid and brief action, minimal reflex tachycardia and tachyphylaxis, titratable infusion (0.5 mcg/kg/min)- phentolamine: competitive α adrenergic blocking agent (3-5 times as active at α1 as at α2 receptors), fast onset with short half life, given in incremental doses of 1-2 mg or infusion 0.1-0.2 mg/min, associated with tachycardia and tachyphylaxis, may result in hypertension

- esmolol: rapid effect and short duration easily titrable to control heart rate and blood pressure, 1 mg/kg or 50-150 mcg/kg/min, peak effect observed within 6-10 minutes and attenuated 20 minutes completely after cessation of infusion

- magnesium sulphate: inhibits catecholamine release from chromaffin cells and alters adrenergic receptors response, loading dose 40-60 mg/kg followed by infusion 1-2 g/h

- ? best medications for hemodynamic control, rarity of the condition familiarity of drugs to anesthesiologist, availability and affordability

post operative management- most important complications: hypotension, hypertension and hyperglycemia- after adrenal veins ligated and tumor removed, hypotension may occur amenable to fluid load and discontinuation of vasodilator and β blockers, blood transfusion may be needed, infusion of vasopressor may be required temporarily- uncommon if adequately prepared preoperatively with pharmacological control and volume expansion- ? residual effects of preoperative adrenergic blockade ? intra abdominal bleeding - hypertension: recovery from anaesthesia, pain, residual tumor- treatment: analgesic, reinstitute anti hypertension

Conclusion- The anesthetic management of patients with pheochromocytoma remains a challenge to even the most experienced anesthesiologist in view of its rarity although the perioperative mortality has reduced remarkably- Preoperative control of hypertension with adrenergic blocking agents and adequate volume expansion is important for reducing the mortality and morbidity associated with this surgery- To ensure the successful of management of patients with pheochromocytoma, close communication between endocrine, surgical, medical, oncology, radiology and anesthesia teams is essential

Case scenario57 year old male with underlying hypertension, benign prostatic hypertrophy, umbilical hernia and bilateral knee osteoarthritis presented to ED with 3/52 history of presyncopal and syncopal episodes, as well as abdominal pain and intermittent nausea. Patient also complained of brief episode of light headedness and fainting episode upon standing.

Upon further questioning, patient gave history of episodes of sweating lasting 1-2 minutes, palpitation and dizziness (all three usually occurring once every 1-2 weeks for past six months), and blurred vision for last 2-3 months. Patient also having labile and difficult to control hypertension (patient was on amlodipine 10 mg OD and metoprolol 50 mg OD). Patient also had a history of severe weight gain (over 49 kg) during last two years compounded by low energy level. He was then put on diet and weight loss medication resulting in 30 kg weight loss but continued to be hypertensive.

At ED a work up for cardio and cerebrovascular events and a possible small bowel obstruction was initiated. CT of the abdomen revealed a 6.4 cm left adrenal mass in addition to a small umbilical hernia with partial small bowel obstruction. ECG did not show any ischemia.

Patient was taken to operating theatre for urgent umbilical hernia repair. Upon induction, patient developed a hypertensive crisis with a blood pressure of 250/150 mmHg and tachycardia with a heart rate of 95 bpm. Surgery was immediately aborted and patient was transferred to intensive care unit.

Further investigations revealed elevated urine norepinephrine of 738 mcg/24 h and epinephrine of 779 mcg/24 h. Two days later patient underwent hernia repair with blood pressure and heart rate controlled with IV α- and β- adrenoceptor blockade.

Pateint was then discharged with phenoxybenzamine, metoprolol and amlodipine. Further investigations confirmed the diagnosis of pheochromocytoma. Patient was started on phenoxybenzamine 10 mg OD, which gradually titrated up to 30 mg TDS. He was also put on atenolol 25 mg per day, which was gradually titrated up to 50 mg BD and Metyrosine 250 mg TDS.

ECG revealed first degree AV heart block with QT interval of 464 msec. A transthoracic echocardiogram showed a mildly dilated left atrium and ventricle, but no further recommendations were given by cardiology team.

Patient was admitted one day prior operation. His average blood pressure and heart rate were 134/76 mmHg and 65 bpm. At midnight, he was given an extra dose of 40 mg phenoxybenzamine, 12.5 mg atenolol and 500 mg metyrosine. He was also received 1 liter of dextrose saline.

During surgery in the following day, there was no significant change in blood pressure during tumor manipulation and removal. Post operatively, he developed few hours of lasting hypotension (average blood pressure of 83/49 mmHg and heart rate of 87 bpm) which was treated with IV Dopamine. Otherwise he made an uneventful recovery.

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G Singh, P Kam (1998)2) Perioperative management of pheochromocytoma:

anaesthetic implications: Aliya Ahmed (2007)3) Anaesthetic management of pheochromocytoma: Ahmed

Turkistani (2009)4) Approach to the patient: preoperative management of the

pheochromocytoma patient: Karel Pacak (2007)5) Undiagnosed pheochromocytoma: the anaesthesiologist

nightmare: Duane J. Myklejord (2004)6) Pathophysiology of disease: an introduction to clinical

medicine (third edition)7) Clinical anesthesiology (fourth edition)