Recognition and management of phaeochromocytoma

Endocrinology

Recognition and management of phaeochromocytomaSimon lewis

AbstractPhaeochromocytomas are potentially lethal catecholamine secreting

tumours. clinical presentation depends on the pattern of catecholamine

secretion. The symptoms are diverse, but the most common are headache,

diaphoresis and palpitations. These tumours represent a challenge to the

anaesthetist because they can present unexpectedly perioperatively and

the mortality is up to 50%. diagnosis relies on the demonstration of exces-

sive catecholamine production by 24-hour urine measurement. The tumour

is usually localized by cT or Mri imaging. Excision of the tumour can be

undertaken safely only when pharmacological control of the sympathetic

nervous system and normovolaemia have been achieved. A number of

antihypertensive agents have been used successfully in the perioperative

period to maintain cardiovascular stability. Preoperative preparation should

also include an assessment of myocardial function to exclude the presence

of phaeochromocytoma-associated cardiomyopathy. Adrenalectomy can be

performed using an open or laparoscopic approach, with each procedure

having implications for the anaesthetist. Management of intraoperative

hypertensive surges and arrhythmias requires an understanding of the

physiology and pharmacology of phaeochromocytomas. This article details

the clinical presentation, diagnosis and perioperative anaesthetic manage-

ment of elective and emergency phaeochromocytomas.

Keywords adrenal; antihypertensives; catecholamines; endocrinology;

perioperative; phaeochromocytoma; tumour

Phaeochromocytomas are pharmacologically volatile, potentially lethal, catecholamine-containing tumours of chromaffin cells. Although 90% are found in the adrenal medulla, they can occur wherever chromaffin tissue is located. Other sites include para-ganglia cells of the sympathetic nervous system and the organ of Zuckerkandl. Phaeochromocytomas follow the rule of 10%; in other words, 10% are extra-adrenal, 10% are bilateral and 10% are metastatic. These tumours are important to the anaesthetist as 25–50% of hospital deaths in patients with phaeochromocy-toma occur during induction of anaesthesia or during operative procedures for other causes.

The sympathetic nervous system

The sympathetic nervous system (SNS) comprises the sympa-thetic chain, a number of peripheral plexuses and the adrenal

Simon Lewis, FRCA, is a Consultant Anaesthetist at North Bristol NHS

Trust. His interests include vascular anaesthesia and perioperative

echocardiography.

AnAESTHESiA And inTEnSiVE cArE MEdicinE 9:10 44

medulla. The axons of the sympathetic preganglionic neurons leave the spinal cord with the ventral roots of T1–L2. They pass via the white rami communicantes to the paravertebral sympa-thetic chain where most of them end on the cell bodies of the postganglionic neurons. This sympathetic chain lies posterior to the aorta on either side of the thoracic column and the neu-rotransmitter at the ends of these preganglionic axons is acetyl-choline. The axons of some of the postganglionic neurons pass to the viscera in the various sympathetic nerves. Others re-enter the spinal nerves via the grey rami communicantes from the sym-pathetic chain and are distributed to autonomic effectors in the areas supplied by these spinal nerves. Some preganglionic neu-rons pass through the sympathetic chain without synapsing and form the splanchnic nerves that extend to, and terminate in, the outlying prevertebral ganglia. Sympathetic preganglionic fibres also extend to the adrenal medullae. Developmentally, the adre-nal medullae are modified sympathetic ganglia that are derived from chromaffin cells. Upon stimulation by these sympathetic cholinergic preganglionic neurons, the adrenal medullae release a mixture of catecholamine hormones – about 80% epinephrine, 20% norepinephrine and a trace amount of dopamine.

Catecholamine synthesis and metabolismThe principal catecholamines synthesized in the chromaffin cells of the adrenal medulla are epinephrine, norepinephrine and dopamine. They are formed by the hydroxylation and decar-boxylation of the amino acid tyrosine. Some of the tyrosine is formed from phenylalanine, but most is of dietary origin. Within the chromaffin cell tyrosine is hydroxylated to dopa, which is then transported to the nerve terminals. Dopa is decarboxyl-ated to dopamine and accumulates in granulated vesicles in the nerve terminal. The membranes of these vesicles contain dopa-mine β-hydroxylase that converts dopamine to norepinephrine (Figure 1). No further conversion takes place in the peripheral sympathetic nerve terminals; however, in the adrenal medulla norepinephrine is converted to epinephrine by phenylethanol-amine-N-methyltransferase (PNMT).

After release from the adrenal medulla the catecholamines are rapidly eliminated. Up to 90% of the norepinephrine released at the synapse is taken up by the presynaptic nerve endings (uptake 1). This process is blocked by cocaine, tricyclic antidepressants (TCAs), metaraminol and phenothiazines. Although circulating catechol-amines can be metabolized by this route, 70% of epinephrine is methoxylated by catechol-O-methyltransferase (COMT) in the liver and kidney (uptake 2).

Predisposition

Phaeochromocytomas are usually classified as being sporadic or familial in origin. The majority are sporadic and benign. Familial conditions associated with phaeochromocytoma include multiple endocrine neoplasia (MEN) IIA and IIB, von Hippel–Lindau dis-ease, neurofibromatosis type I (von Recklinghausen’s disease), tuberous sclerosis and Sturge–Weber syndrome.

Presentation

Hypertension is the most common sign in patients present-ing with phaeochromocytomas; however, only 0.04% of all

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Endocrinology

hypertensive patients have a phaeochromocytoma. The three most commonly expressed symptoms are headache, diaphoresis and palpitations. Presentation is usually dependent on the pat-tern of catecholamine secretion by the tumour. Those secreting predominantly norepinephrine present with sustained hyperten-sion, headaches and slow, thudding palpitations. Predominantly epinephrine-secreting tumours make up between 10% and 17% of all tumours and present with the paroxysmal symptoms of palpitations, trembling, sweating and anxiety. Other less com-mon features include nausea and vomiting (dopamine secretors), cerebrovascular accident and cardiac failure. Symptoms may be precipitated by postural changes, increases in intra-abdominal pressure, trauma, exercise and certain medications.

Phaeochromocytoma multisystem crisis is an unusual and life-threatening complication that comprises multiorgan failure, hyperpyrexia, encephalopathy and hypertension or hypotension. Prompt diagnosis and aggressive medical and supportive therapy are required.

Diagnosis

The definitive diagnosis of phaeochromocytoma relies on the demonstration of an excessive, inappropriate production of catecholamines. Difficulty arises in distinguishing the normally functioning sympathetic nervous system from the episodic over-activity of a phaeochromocytoma because catecholamines are rap-idly reabsorbed or metabolized following release. Measurements

Catecholamine biochemistry

COMT, catechol-O-methyltransferase

MAO, monoamine oxidase

HO

HOCOMT

MAO

COMT

COMT

MAO

MAO

C C

H H

H

HO COOHC

H

HH

NH2

HO

HO C C

OH H

H H

NH2

HO

HO C C

OH H CH3

H H

NH

CH3O

HO COOHC

OH

H

CH3O

Dopamine

Norepinephrine

Epinephrine

Homovanillic acid

Vanillylmandelic acid

Metanephrine

Normetanephrine

Figure 1


of plasma and urinary catecholamines have the highest sensitiv-ity and urinary vanillylmandelic acid the lowest. Plasma levels of the metabolites normetanephrine and metanephrine also have a high sensitivity. Biochemical testing can confirm the diagnosis in >95% of patients. In the rare situation that the diagnosis cannot be confirmed the clonidine suppression test is available. Cloni-dine is an α2-agonist and usually causes a decrease in physiologi-cal release of norepinephrine from sympathetic nerve terminals by negative feedback inhibition. Lack of suppression is sugges-tive of a phaeochromocytoma in the absence of reuptake inhibi-tors (TCAs, cocaine, metaraminol, phenothiazines).

Localization

Computed tomography (CT) and magnetic resonance imaging (MRI) provide accurate and consistent identification of most pha-eochromocytomas. CT has a sensitivity of 93–100% for detec-tion of adrenal tumours but decreases to 90% for extra-adrenal tumours (Figure 2). MRI is better at detecting extra-adrenal phaeochromocytomas. It is also the investigation of choice in

Computerized tomography scan of large phaeochromocytoma

Case study. This 78-year-old patient presented with malignant

hypertension (blood pressure 230/130 mm Hg), acute coronary

syndrome (troponin I 5.95 µg/ml) and hyperglycaemia. Twenty-four hour

urine catecholamines were markedly elevated and showed a mixed

secreting tumour (normetanephrine 124 µmol/24 hours (0.2–2.8);

metanephrine 127 µmol/24 hours (0.2–2.2)). Computerized tomography

imaging revealed a large (20 cm) phaeochromocytoma (arrow).

Transthoracic echocardiogram showed moderate left ventricular

hypertrophy with no regional wall motion abnormality. The raised

troponin I level was attributed to catecholamine-induced myocardial

necrosis. The patient was stabilized with phenoxybenzamine and

atenolol. The tumour was removed 5 weeks later through a thoraco-

abdominal incision. A vasopressin infusion was required postoperatively

to treat hypotension secondary to residual α-blockade and contralateral

adrenal suppression. The patient’s diabetes also resolved

Figure 2


Endocrinology

pregnancy because it avoids exposure of the fetus to radiation. Both CT and MRI have poor specificity, but, if there is doubt, nuclear imaging using 123I-metaiodobenzylguanidine (MIBG) scintigraphy enhances the ability to identify and localize the cate-cholamine source. MIBG is concentrated by the tumour’s uptake of precursor amines; the process takes 24–48 hours.

Preoperative management

Excision of the pheochromocytoma can safely be undertaken only when pharmacological stability of the sympathetic nervous system has been achieved. The perioperative mortality decreased from 13–45% to 0–3% when preoperative α-adrenergic blockade was instigated and when it was recognized that these patients often have hypovolaemia preoperatively. The main priorities are therefore to ensure stable blood pressure and heart rate and to restore a normal blood volume. Pharmacological control can be produced by the interruption or antagonism of catecholamine synthesis, release or receptor action. The traditional approach is to institute α-adrenergic blockade and then to add in β-adrenergic blockade if required. The use of β-adrenoceptor blockade alone can lead to hypertension due to unopposed α-adrenoceptor action (Table 1).

Phenoxybenzamine has been considered by many to be the drug of choice for controlling blood pressure alterations and associ-ated symptoms. It binds covalently to α1- and α2-adrenoceptors thereby blocking catecholamine-induced vasoconstriction and catecholamine reuptake. Orthostatic hypotension and reflex tachycardia occur, the latter secondary to inhibition of presyn-aptic α2-adrenoceptors resulting in an increase in norepinephrine at the unopposed β-receptors. Therefore, adjuvant β-blockade is normally required to control the tachycardia. Preoperative control is good; however, postoperatively patients remain sleepy (owing to persistent central α2-adrenoceptor blockade) and may require large volumes of intravenous fluid to maintain blood pressure until the blockade has worn off. The effects of phenoxybenza-mine dissipate over approximately 36 hours and patients usually stop the drug 24–48 hours before surgery.

Selective α1-adrenoceptor antagonists offer several potential advantages when compared with phenoxybenzamine. They do not produce reflex tachycardia (because the α2-adrenoceptors

Adrenoreceptor effects

Receptor Principal effects

α1 Vasoconstriction, uterine contraction, increased

sweating, decreased insulin release, decreased

glucagon release

α2 inhibition of further norepinephrine release

β1 chronotropy, ionotropy, arrhythmogenicity,

renin secretion

β2 Smooth muscle relaxation in bronchi, vascular

wall, uterus, insulin and glucagon secretion

Table 1


are not inhibited) and have a shorter duration of action result-ing in less postoperative hypotension. Preoperative β-blockade is unnecessary unless the patient has an epinephrine-secret-ing tumour. Doxazosin has a long duration of action and can be given in once-daily doses up to and including the eve of the surgery. Prazosin and terazosin can also be considered but both require more frequent dosing.

β-Adrenergic antagonists are indicated for patients who have epinephrine-secreting tumours. They are contraindicated in the absence of established α-blockade because circulating catechol-amines would produce vasoconstriction without opposition by the vasodilating β2-receptors. The resulting hypertension can precipitate pulmonary oedema, which can be exacerbated by the negative ionotropic effects of the β-blockade. Suitable options include atenolol and bisoprolol. Labetalol (combined α- and β-blocker) can be used; however, it has been reported to precipi-tate hypertensive crisis.

α-Methyl-para-tyrosine competitively inhibits tyrosine hydroxy-lase, which is the rate-limiting step in catecholamine synthesis. By reducing the tumour’s catecholamine stores it decreases the ability of the phaeochromocytoma to react to stimulation. It can be used for patients with poor left ventricular function in whom β-blockade worsens cardiac performance and α-blockade leads to tachycardia.

Witteles et al.1 have recommended the following criteria for optimal preoperative conditions:• no blood pressure reading > 160/90 mmHg 24 hours before

surgery• orthostatic hypotension, with blood pressure > 80/45 mmHg

should be present• ECG should be free of ST-T changes for at least 1 week• no more than one ventricular ectopic every 5 minutes.

Cardiac evaluationHaving achieved preoperative cardiac stability, the main determi-nant of perioperative morbidity is the baseline myocardial status of the patient. The most common effect of phaeochromocytoma on the heart is the development of a hypertrophic cardiomyopa-thy secondary to chronic norepinephrine-induced hypertension. Less commonly a dilated cardiomyopathy and subsequent cardiac failure can occur. Therefore all patients with a phaeochromocy-toma should have a preoperative echocardiogram regardless of blood pressure levels. Pathological findings on the ECG are com-mon and these generally improve after aggressive medical treat-ment and surgery.

Intraoperative management

Close communication between the surgical, endocrine and anaes-thetic teams is a prerequisite to the successful management of patients undergoing phaeochromocytoma resection.

Surgical approachAdrenalectomy can be performed using an open lateral retro-peritoneal approach or by laparoscopic transperitoneal surgery. The open procedure is quicker and less likely to result in surges of catecholamine release. The postoperative period is, however,

© 2008 Elsevier ltd. All rights reserved.

Endocrinology

longer and more painful than the laparoscopic approach, after which patients can be discharged within 48 hours.

MonitoringPreoperative preparation with adrenoceptor antagonists blunts the cardiovascular response to catecholamine surges that occurs secondary to physical manipulation of the tumour. Reliable inva-sive monitoring of both arterial and central venous pressures is therefore essential. Measurement of pulmonary capillary wedge pressure (PCWP) and cardiac output can be helpful because these patients may exhibit a discrepancy between right-sided and left-sided filling pressure, particularly during tumour manipulation.

AnaesthesiaGeneral anaesthesia is the most common technique chosen with most anaesthetic agents having been used successfully. The depth of anaesthesia and associated vasodilatation is generally more important than the specific agent. Sevoflurane and isoflu-rane have been used extensively. Halothane can result in severe arrhythmias with high levels of circulating catecholamines. Des-flurane causes significant sympathetic stimulation and so may best be avoided.

Propofol, thiopentone and etomidate have all been suc-cessfully used for induction. Indirect sympathomimetic agents (e.g. ketamine and ephedrine) can stimulate the tumour to release catecholamines and should be avoided. Drugs that cause histamine release (e.g. morphine, tubocurarine and atracurium) have infrequently been reported to trigger a crisis.

Hypertension during tumour resection has two distinct aeti-ologies. Noxious stimuli such as intubation, skin incision and abdominal exploration cause increased catecholamine release. Use of epidural analgesia (T9–L1), opioid infusions (e.g. remi-fentanil, alfentanil) and deep anaesthesia can help to blunt these responses. Tumour manipulation can produce a more marked hypertensive response, which is associated with significant increases in plasma catecholamine levels, increases in systemic vascular resistance, PCWP and occasionally a fall in cardiac output secondary to left ventricular dysfunction. Hypertension secondary to tumour palpation is best treated with systemic vasodilators.

Phentolamine is a competitive α1-adrenoceptor and weak α2- adrenoceptor antagonist that can be given intravenously by infusion or increments of 1–2 mg. It has a short onset of action (one circulation time) and short duration of action (10–15 min-utes). Side effects include a tachycardia secondary to presynaptic α2-adrenoceptor blockade.

Sodium nitroprusside is a mixed vaso- and venodilator that reduces preload and cardiac output afterload. It acts by stimu-lating the formation of cyclic guanosine monophosphate (GMP) that relaxes vascular smooth muscle. Its onset is immediate and duration of action is 1–2 minutes. At infusion rates of greater than 2 μg/kg/min, toxic metabolites such as cyanide and thio-cyanate can accumulate.

Magnesium sulphate has several potentially beneficial actions. It has anti-arrhythmic properties due to calcium channel block-ade, regulation of intracellular potassium and ATP activation. It


causes vasodilatation by blocking the adrenoreceptor response to norepinephrine and angiotensin II. It also inhibits catecholamine release from the adrenal medulla and peripheral adrenergic nerve terminals. The effective therapeutic plasma concentration is 2–4 mmol/litre, which can usually be achieved with an intra-venous loading dose of 40–60 mg/kg followed by an infusion of 2 g/hour. Side-effects include a potentiation of neuromuscular blockade and inhibition of platelet activity.

Labetalol is a combined α- and β-adrenoreceptor antagonist. Incremental doses of 5 mg are given to treat surges in blood pressure. When used intravenously it causes 7:1 β:α-blockade and therefore hypotension and bradycardia can be observed. It is a useful second-line agent to treat epinephrine-induced tachydysrhythmias.

Towards the end of the operation the anaesthetist should anticipate the sudden fall in blood pressure that usually signals the clamping of the final vessels draining the phaeochromocy-toma. Ensuring euvolaemia prior to this event limits the degree

General principles of elective phaeochromocytoma surgery

Preoperatively

• determine the tumour location and its pattern of

catecholamine secretion

• Echocardiogram to assess myocardial function with or

without the presence of cardiomyopathy

• Establish α1-adrenergic blockade to control hypertension

• Add β-blocker to control heart rate or rhythm (especially with

epinephrine secretors)

Peroperatively

• Sedative premedication

• insert invasive arterial monitoring before induction

• obtund pressor response to intubation

• Establish central venous pressure monitoring

• Maintain anaesthesia with moderate degree of vasodilatation

(e.g. isoflurane)

• Ensure adequate surgical analgesia by T9–l1 epidural (open

procedure) or opioid infusion (laparoscopic)

• Treat hypertensive surges during tumour manipulation with

phentolamine (1–2 mg boluses) or magnesium sulphate

infusion (therapeutic range 2–4 mmol/litre)

• control tachydysrhythmias with β-blockade (e.g. esmolol,

labetalol)

• Predict hypotension in response to clamping of veins

draining tumour

Postoperatively

• HdU/iTU care with invasive monitoring

• Aim for early extubation to ensure awake and functioning

reticular activating system

• Use posture and intravenous fluids to maintain BP;

vasopressors can be ineffective

BP, blood pressure; HdU, high-dependency unit; iTU, intensive therapy unit

Table 2


Endocrinology

Intraoperative presentation and treatment of an unsuspected phaeochromocytoma precipitated by abdominal palpation

1 Pre-induction blood pressure and heart

rate. 2 Marked hypotension post-induction

that responded to fluid resuscitation.

3 Severe hypertension and ventricular

tachycardia following abdominal palpation

by surgeon. 4 Operation abandoned and

labetalol, 5 mg boluses given (total 40 mg).

5 Patient transferred to ICU – pulmonary

artery catheter inserted which showed ↑↑

systemic vascular resistance and ↓ cardiac

output. 6 Phentolamine, 2 mg boluses

(total 22 mg), with improvement in cardiac

indices. 7 Severe hypotensive episodes

and ↓ central venous pressure requiring

aggressive fluid resuscitation (4 litres over

5 hours). 8 24-hour urine catecholamine

analysis demonstrated epinephrine- and

norepinephrine-secreting tumour.

Doxazosin and bisoprolol therapy

commenced

He

art

ra

te

(be

ats

/min

)

Blo

od

pre

ssu

re

(mm

Hg

)

Day 1 (min) Day 2 (hours)

241812601301201101009080706050403020100

150

100

50

250

200

150

100

50

0

01 2 3 4 5 6 7 8

Figure 3

of hypotension, although even with central venous pressure monitoring it can be difficult to predict the final volume status of the patient, because the intermittently high catecholamine levels cause marked changes in central venous filling pressures.

Postoperative management

Hypotension is the main complication postoperatively and is usu-ally secondary to residual adrenergic blockade. Treatment may be difficult because the hypotension can be refractory to fluid resuscitation and adrenoceptor agonists. Attention to fluid bal-ance and posture are the most effective interventions. Early extu-bation ensures an awake reticular activating system that helps to maintain blood pressure by stimulating norepinephrine release from sympathetic nerve endings. Catecholamine secretion from the contralateral adrenal gland will have been suppressed by the phaeochromocytoma, and adrenoreceptors will be downregu-lated for some time. If hypotension persists, haemorrhage should be excluded. Postoperative blood glucose monitoring is recom-mended because hypoglycaemia has been reported (Table 2).

Emergency presentation

Phaeochromocytomas may present unexpectedly during coinci-dental surgery and the mortality is variously quoted as 33–50%. The precipitants of a perioperative catecholamine crisis include anaesthetic drugs (ephedrine, ketamine, pancuronium and dro-peridol have all been reported), inadvertent tumour manipula-tion during patient positioning or increases in intra-abdominal


pressure (e.g. laparoscopy). Their presentation can mimic other potentially catastrophic medical emergencies such as malignant hyperthermia and thyroid storm. If the diagnosis is suspected intraoperatively all stimulation should be stopped immediately. If the tumour secretes predominantly norepinephrine, systemic hypertension may be accompanied by a baroreceptor-mediated reflex bradycardia. The patient may have signs of excessive cat-echolamine secretion such as vasoconstriction, piloerection and mydriasis. Myocardial ischaemia may be evident on the ECG and tachydysrhythmias can occur especially with epinephrine- secreting tumours. Pulmonary oedema may develop as a result of pulmonary capillary vasoconstriction and catecholamine-induced myocardial dysfunction. There is no justification for proceeding with surgical excision of the tumour as mortality is unacceptably high without preoperative adrenoreceptor blockade. Control of the cardiovascular system should be attempted using the shorter-acting agents described above and the operation terminated with the minimum of surgical stimulation. The patient should be trans-ferred to intensive care and the diagnosis confirmed with 24-hour urinary catecholamine excretion. Adrenoceptor blockade should be introduced gradually and a multidisciplinary plan implemented for the excision of the phaeochromocytoma (Figure 3). ◆

REFEREnCE

1 Witteles rM, Kaplan El, roizen MF. Safe and cost-effective

preparation of patients with pheochromocytoma. Anesth Analg

2000; 91(2): 302–4.


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Recognition and management of phaeochromocytoma