2. 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%
3. 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
4. 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
8. 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
9.
10. 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
11. - ? 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
12. 1) α adrenoceptor antagonists
a) 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
13. 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
14. 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
15. 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 effects
3) 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
16. 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
17.
18. 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
19. - 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
20. - 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
21. - 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
22. 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
23. - 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
24. 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
25. 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
26. Case scenario
57 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.
27. 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.
28. 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.
29. 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.
30. 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.
31. 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.
32. References
1) 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)
