Anaesthetic Management Of Pheochromocytoma Mohd Faizal Zainuddin Supervisor: Dr Abdul Karim Othman
Pheochromocytoma- major disorder of adrenal medulla: excessivecatecholamine secretion- Secondary cause of hypertension in 0.1% ofhypertensive patients- Incidence is very low, age: 20 and 50 year old- A proportion diagnosed during induction ofanesthesia hypertensive crisis mortalityclose to 80%
Adrenal medulla:- reddish-brown central layer of adrenal gland- accessary medullary tissues – retroperitoneum near thesympathetic ganglia or along the abdominal aorta (paraganglia)- embryogically neural crest cells, innervated by cholinergicpreganglionic fibers- most (~80%) of catecholamine output of adrenal medulla isepinephrine, 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 + normetanephrine and as VMA
Normal plasma level of catecholamines…- free epinephrine= 30 pg/ml (0.16 n mol/L)- free norepinephrine= [200 – 1700 mcg/ml] 300pg/ml (1.8 n mol/L)- free dopamine= [<30 mcg/ml] 35 pg/ml (0.23 nmol/L)- T 1/2 ~ 2 minutes
Preoperative assessment- close cooperation between physician, cardiologist,surgeon and anaesthetist- relevant history, severity of hypertension, look for endorgan damage- full blood count and hematocrit: adequacy of volumeexpansion- renal function: urea, creatinine and electrolytes- electrocardiography: hypertrophy, arrhythmias,cardiomyopathy, ischemia or infarction, left ventriculardysfunction, improvement after adrenergic blockade- chest x-ray: cardiomegaly, pulmonary edema- insulin may be needed if hyperglycemia
Preoperative management- All patients with a biochemically positive pheochromocytomashould receive appropriate preoperative medical managementto block the effects of released catecholamines (FirstInternational Symposium on Pheochromocytoma)- Main goals:1) normalize blood pressure, heart rate and functions of otherorgans2) restore volume depletion3) prevent patient from surgery induced catecholamines storms
- ? which drugs: wide ranging practices, internationaldifferences in available or approved therapy, scarcityof evidence based studies- α adrenoceptor antagonists, β adrenoceptorantagonists, calcium channel blockers, angiotensinreceptor blockers were recommended- adrenergic blockade usually starts 7-14 dayspreoperatively to normalize blood pressure andheart rate and to expand the contracted volume- those with organ damage, adrenergic blockade canbe initiated earlier
1) α adrenoceptor antagonistsa) phenoxybenzamine (irreversible, noncompetitive)- initial dose 10 mg bd/day, increased till clinicalmanifestations are controlled or side effects appear(usually total 1 mg/kg/day is sufficient)- side effects: postural hypotension with reflextachycardia, dizziness, syncope, nasal congestion- another option: infusion 0.5 mg/kg/day for 5hours/day, 3 days before operation requiresclose monitoring, not cost effective, no correlationbetween duration of treatment withphenoxybenzamine and cardiovascularintraoperative stability
b) prazosin, terazosin, doxazosin(specific, competitive, short acting α1 adrenergicantagonists)- prazosin: 2-5 mg bd/tds a day, terazosin: 2-5mg/day, doxazosin: 2-8 mg/day- less side effects: no reflex tachycardia, less postoperative hypotension ! use with caution involume depleted patients- should be given before sleeping as patient maydevelop severe postural hypotension
2) β adrenoceptor antagonists- used after adequate pretreatment with α adrenoceptorantagonists to avoid hypertensive crisis from unopposed αadrenoceptor overstimulation - inhibition of β2adrenoceptor mediated vasodilatation leaving αadrenoceptor mediated vasoconstriction unopposed- cardioselective β1 adrenoceptor blockers are preferable- atenolol: 12.5 -25 mg 2-3 times/day; metoprolol: 25- 50mg 3-4 times/day; propranolol (non selective βadrenoceptor blocker): 20-80 mg 1-3 times/day- labetalol (combined α and β adrenoceptor blocker): notas primary choice paradoxical episodes of hypertension/ hypertensive crisis , except when patient on α and βadrenoceptor blockers that need to be replaced
3) calcium channel blocker- block noradrenaline mediated calcium influx intovascular smooth muscle control hypertension andtachyarrhythmias- main roles:1) inadequate blood pressure control with adrenoceptorblockers2) replace adrenoceptor blockers in patients with severeside effects3) prevent adrenoceptor blocker induced sustainedhypotension 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 depletescatecholamine stores- for extensive metastatic disease and patients withbiochemically active tumors- when used with α adrenoceptor blockers: less labileblood 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 increasedby 250 to 500 mg every 2 – 3 day or as necessary up tototal 1.5 to 2.0 g/day
intraoperative management- close communication between surgeon andanaesthetist success of intraoperativemanagement- regional anaesthesia versus regional combinedwith general anaesthesia and neurolept technique- main aim: avoid straining that may causecatecholamine release- standard monitoring: ECG, pulse oxymeter, noninvasive blood pressure, inspired oxygenconcentration, neuromuscular blockade,temperature, urine output
- central venous and arterial catheter: immediateidentification of hemodynamic fluctuation duringinduction, maintenance, surgical manipulation andguide for pharmacologic intervention- pulmonary artery catheter: severe left ventriculardysfunction and pre operative cardiovascularcompromise- at least two large bore intravenous catheter forfluids and medications administration- epidural catheter at T10-T11 to T12-L1:intraoperative and postoperative analgesia
- induction: preoxygenation followed by fentanyl 1-2mcg/kg and propofol 1-2 mg/kg- alfentanil/ sufentanil: replace fentanyl, midazolam: co-induction- thiopentone histamine release, etomidate cardiovascular stability but produces involuntarymovements- vecuronium, rocuronium & cisatracurium:cardiovascular stability and release least histamine- atracurium & mivacurium histamine release- suxamethonium: produce fasciculation, but successfullyused in pregnant patient with pheochromocytoma- lung then ventilated with volatile agent for 3-5 minutesfollowed by tracheal intubation
- TV=7-10 ml/kg, rate=10-12, ETCO2=35 mmHg- maintenance: isoflurance/sevoflurance in air-oxygenmixture with FiO2 around 0.5 (halothane – sensitizesmyocardium to catecholamines); nitrous oxide notcontraindicated- if epidural is used: initial bolus 8-10 ml of 0.25%bupivacaine in divided doses followed by infusionbupivacaine 0.1-0.2% with fentanyl 2 mcg/ml at 6-12 ml/h- reversal: neostigmine + glycopyrrolate tachycardiaassociated with atropine hypertensive spike- to reverse or ventilate patient in ICU preoperativestate and intraoperative course- even if extubated, monitor hemodynamic stability atleast 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 tachycardiaand tachyphylaxis, titratable infusion (0.5mcg/kg/min)- phentolamine: competitive α adrenergic blockingagent (3-5 times as active at α1 as at α2 receptors),fast onset with short half life, given in incrementaldoses of 1-2 mg or infusion 0.1-0.2 mg/min,associated with tachycardia and tachyphylaxis, mayresult in hypertension
- esmolol: rapid effect and short duration easily titrable tocontrol heart rate and blood pressure, 1 mg/kg or 50-150mcg/kg/min, peak effect observed within 6-10 minutes andattenuated 20 minutes completely after cessation of infusion- magnesium sulphate: inhibits catecholamine release fromchromaffin 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 thecondition 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 anddiscontinuation of vasodilator and β blockers, bloodtransfusion may be needed, infusion of vasopressor maybe required temporarily- uncommon if adequately prepared preoperatively withpharmacological control and volume expansion- ? residual effects of preoperative adrenergic blockade ?intra abdominal bleeding- hypertension: recovery from anaesthesia, pain, residualtumor- treatment: analgesic, reinstitute anti hypertension
Conclusion- The anesthetic management of patients withpheochromocytoma remains a challenge to eventhe most experienced anesthesiologist in view of itsrarity although the perioperative mortality hasreduced remarkably- Preoperative control of hypertension withadrenergic blocking agents and adequate volumeexpansion is important for reducing the mortalityand morbidity associated with this surgery- To ensure the successful of management ofpatients with pheochromocytoma, closecommunication between endocrine, surgical,medical, oncology, radiology and anesthesia teamsis essential
Case scenario57 year old male with underlying hypertension,benign prostatic hypertrophy, umbilical herniaand bilateral knee osteoarthritis presented to EDwith 3/52 history of presyncopal and syncopalepisodes, as well as abdominal pain andintermittent nausea. Patient also complained ofbrief episode of light headedness and faintingepisode upon standing.
Upon further questioning, patient gave history ofepisodes of sweating lasting 1-2 minutes,palpitation and dizziness (all three usually occurringonce every 1-2 weeks for past six months), andblurred vision for last 2-3 months. Patient alsohaving labile and difficult to control hypertension(patient was on amlodipine 10 mg OD andmetoprolol 50 mg OD). Patient also had a history ofsevere weight gain (over 49 kg) during last twoyears compounded by low energy level. He wasthen put on diet and weight loss medicationresulting in 30 kg weight loss but continued to behypertensive.
At ED a work up for cardio and cerebrovascular eventsand a possible small bowel obstruction was initiated. CTof the abdomen revealed a 6.4 cm left adrenal mass inaddition to a small umbilical hernia with partial smallbowel obstruction. ECG did not show any ischemia.Patient was taken to operating theatre for urgentumbilical hernia repair. Upon induction, patientdeveloped a hypertensive crisis with a blood pressure of250/150 mmHg and tachycardia with a heart rate of 95bpm. Surgery was immediately aborted and patient wastransferred to intensive care unit.
Further investigations revealed elevated urinenorepinephrine of 738 mcg/24 h and epinephrine of 779mcg/24 h. Two days later patient underwent hernia repairwith blood pressure and heart rate controlled with IV α-and β- adrenoceptor blockade.Pateint was then discharged with phenoxybenzamine,metoprolol and amlodipine. Further investigationsconfirmed the diagnosis of pheochromocytoma. Patientwas started on phenoxybenzamine 10 mg OD, whichgradually titrated up to 30 mg TDS. He was also put onatenolol 25 mg per day, which was gradually titrated upto 50 mg BD and Metyrosine 250 mg TDS.
ECG revealed first degree AV heart block with QTinterval of 464 msec. A transthoracic echocardiogramshowed a mildly dilated left atrium and ventricle, butno further recommendations were given by cardiologyteam.Patient was admitted one day prior operation. Hisaverage blood pressure and heart rate were 134/76mmHg and 65 bpm. At midnight, he was given an extradose of 40 mg phenoxybenzamine, 12.5 mg atenololand 500 mg metyrosine. He was also received 1 liter ofdextrose saline.
During surgery in the following day, there wasno significant change in blood pressure duringtumor manipulation and removal. Postoperatively, he developed few hours of lastinghypotension (average blood pressure of 83/49mmHg and heart rate of 87 bpm) which wastreated with IV Dopamine. Otherwise he madean uneventful recovery.
References1) An overview of anaesthetic issues in pheochromocytoma: 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)