Phaeochromocytoma

The curriculum asks for knowledge on 'the principles of the peri-operative management of...resection of neuroendocrine tumours e.g. phaeochromocytoma'.

A 2018 SAQ on the question was 'surprisingly poorly answered' (39% pass rate).

Resources

Phaeochromocytomas are functionally active chromaffin cell tumours
They secrete catecholamine hormones alongside a variety of other peptides
Said secretion may be continuous or intermittent

Catecholamines	Other peptides
Noradrenaline (70%)	Chromogranin A
Adrenaline (25%)	Vasoactive intestinal peptide (VIP)
Dopamine	Neuropeptide Y
	ACTH
	Calcitonin
	Somatostatin

Rare; incidence 0.2/100,000

Responsible for 0.1% of cases of hypertension

Equal incidence in males and females
Presents in the 3^rd - 5^th decade of life

Malignant in 10 - 29% of cases
Extra-adrenal in 10 - 24% of cases

Can be found anywhere in association with the sympathetic ganglia
The organ of Zuckerkandl near the aortic bifurcation is the most common extra adrenal site

Bilateral in 10% of cases

The majority develop sporadically

Familial

10-30% are familial
Usually inherited in an autosomal dominant fashion
Tend to secrete more adrenaline
Familial phaeochromocytomas may be associated with other syndromes including:

Multiple endocrine neoplasia syndromes 2A and 2B
Von-Hippel Lindau syndrome
Neurofibromatosis
Succinate dehydrogenase deficiency

Paragangliomas are closely related neuroendocrine tumours arising from extra-adrenal paraganglia

Some produce catecholamine hormones
Management can be considered the same as phaeochromocytoma

Classic triad of symptoms is palpitations, headache and sweating

System	Symptoms	Signs
Respiratory	Dyspnoea Orthopnoea Reduced exercise tolerance	Pulmonary oedema due to heart failure from cardiomyopathy
Cardiovascular	Palpitations Ischaemic chest pain	Hypertension (90%) Tachycardia Dysrhythmias
Neurological	Headache Visual disturbance Anxiety	Tremor Focal neurology Focal neurology
Gastrointestinal	Nausea, vomiting and abdominal pain (Splanchnic vasoconstriction)
Metabolic	Sweating Weight loss	Hyperglycaemia

Paroxysms may be triggered by:

Stress: exercise | sneezing | anaesthesia | labour
Histamine-releasing drugs (morphine, atracurium), metoclopramide and nicotine

Organ sequelae include:

Hypertensive crises
MI and cardiomyopathy
Pulmonary oedema
CVA
Acute bleeding from the tumour

Biochemical

Raised plasma metanephrine or normetanephrine

However, difficult to measure plasma catecholamine levels as short half-lives and difficult to distinguish from venesection-induced stress response

24hr urinary collection of:

Catecholamines inc. dopamine
Metanephrine/normetanephrine
Vanillyl mandelic acid (VMA)
Homovanillic acid (HMA) levels in dopamine-secreting tumours

False positives can be induced by a number of factors, including:

Recent exercise
Diet
Venesection in sitting position
Renal impairment
Common medications including paracetamol, recreational drugs and caffeine, sympathomimetics, NARI's and MAO-I's

Imaging

MRI or CT of the abdomen to identify tumours

Although similar sensitivity, MRI has higher specificity and superior for identifying paragangliomas

MIBG scintigraphy to identify extra-adrenal tumours and metastatic spread

Meta-iodobenzylguanidine (MIBG) is a synthetic agent structurally similar to noradrenaline
It is taken up in adrenergic neurones and concentrated in phaemochromocytomas/paragangliomas

Alpha blockade

Start at least two weeks pre-operatively
Multiple benefits including:

Lowers blood pressure
Reverses vasoconstriction; need adequate fluid filling (can check with serial haematocrits)
Reduced afterload improves myocardial function
Reduces chances of hypertensive surges during surgery

E.g. phenoxybenzamine

Non-selective, non-competitive, long-acting alpha-antagonist
10mg BD increased up to 200mg until BP controlled
Has a half-life of 24hrs so is stopped 24 - 48hrs pre-operatively
Can lead to tachycardia by inhibiting noradrenergic feedback loop via ɑ₂-antagonism and subsequent over-activation of β₁-adrenoreceptors

If the tumour is non-adrenaline secreting, possible to use a selective alpha antagonist instead e.g. prazosin, doxazosin

Shorter half-lives
Lower risk of tachyarrhythmia as no ɑ₂-antagonism
However as they are competitive inhibitors and may be overwhelmed by catecholamine surges intra-operatively

Beta blockade

Initiated after ɑ-blockade due to concern regarding

Hypertensive crisis from unopposed ɑ-agonism if it were instigated first
Myocardial failure from high afterload (ɑ₁-agonism + β₂-antagonism) and reduced contractility (β₁-antagonism)

Benefit from lower heart rate and reducing arrhythmia risk
Used to avoid the tachycardia that can occur through ɑ₂-antagonism

Selective β_1-antagonists are used e.g. atenolol, metoprolol

Calcium channel blockade

Used as an adjunct to those already on alpha-blockers, not as monotherapy
Examples include prolonged-release nicardipine

Perioperative management of the patient with phaeochromocytoma

Phaeochromocytomas should be operated on in specialist centres
With appropriate management, morbidity and mortality of surgery is <2%

History and examination

Focus pre-operatively is on:

Cardiovascular evaluation
End-organ effects from hypertension

Historically, the 1982 Roizen criteria were used as targets, although this may no longer be necessary

Investigations

FBC to measure serial haematocrits; helps establish adequacy of alpha-blockade

May need 24hr tape to exclude arrythmia
Ideally there should be evidence of ST-segment or T-wave changes for 7 days pre-operatively and ≤1 ectopic beat every 5 mins

Diastolic dysfunction occurs in the majority of patients
LV systolic dysfunction occurs in ~10% of patients
50% may have hypertensive cardiomyopathy

Blood pressure

Blood pressure recording with a 24hr ambulatory monitor, aiming for:

BP <160/90mmHg
HR <100bpm

Assess for postural hypotension, aiming for postural BP >80/45

Glucose monitoring

Hyperglycaemia often occurs due to a blend of:

ɑ₁ agonism - glycogenolysis
ɑ₂ agonism - impairs insulin release
Β₁ agonism - lipolysis
Β₂ agonism - increased glucagon release and insulin resistance

Is managed in a standard fashion e.g. metformin, insulin, gliclazide

Optimisation

Historically deemed suitable for surgery if:

Nasal congestion is present
NIBP is <160/90mmHg
Postural hypotension is present, but not <80/45mmHg
No ST-segment or T-wave changes for 7 days pre-operatively
≤1 ectopic beat (PVC) every 5 minutes

The main aim peri-operatively is to prevent haemodynamic compromise and arrhythmia due to catecholamine surges
Surgery is mostly laparoscopic (trans-abdominal or retroperitoneal approaches); both performed in the lateral position ± table break

Monitoring and access

AAGBI monitoring as standard; consider CM5 position for ECG leads
Arterial line
CVC to assess preload, administer centrally-acting drugs
Transoesophageal CO monitoring to optimise fluid therapy/vasopressors
PA catheter may be needed if severe cardiomyopathy

Anaesthetic technique

GA ± thoracic epidural is common

Catecholamine surges

Such surges occur during:

Induction of anaesthesia and tracheal intubation
Laparoscopic insufflation
Manipulation of the tumour
Ligation of the venous drainage of the adrenal gland
Administration of histamine-released or catecholamine-releasing drugs

Management options include:

Adequate pre-operative medical management
Benzodiazepine premedication
Attenuating the response to laryngoscopy with short-acting opioids

E.g. remifentanil infusion
E.g. 3 - 5μg/kg fentanyl + 40 - 60mg/kg magnesium prior to intubation

Avoid histamine-releasing drugs e.g. morphine, atracurium, pancuronium
Avoid catecholamine-releasing or mimetic drugs e.g. ephedrine, ketamine, pethidine, cocaine
Rapid, short-acting anti-hypertensives:

Drug	Dose
Magnesium	2 - 4g/hr
Phentolamine	1-2mg
Labetalol	5 - 10mg
Esmolol	500μg/kg over 1 min loading 50 - 200μg/kg/min infusion for ∽4mins
Sodium nitroprusside	0.5 - 1.5μg/kg/min to start Up to 4μg/kg/min
GTN	10 - 400μg/min

Tachyarrhythmias

Magnesium
Esmolol (dose as above)
Labetalol (as above)
Amiodarone (300mg)

Hypotension

After tumour removal, hypotension can occur due to:

Hypovolaemia
Relative hypovolaemia due to splanchnic pooling of blood
Persisting ɑ blockade
Down-regulation of adrenoreceptors
Suppression of the contralateral adrenal medulla

Management is with:

Fluid therapy (guided by CVP/CO monitoring/TOE)
Vasopressor therapy
Consideration of angiotensin if resistant to vasopressors due to receptor down-regulation
Steroids

Extubation at the end of surgery is usually ok in uncomplicated surgery
Patients may require HDU/ITU post-operatively for ongoing cardiovascular management and fluid balance management
Require steroid therapy if bilateral adrenalectomy has been performed

Complications

Hypertension

Typically from pain, fluid overload, urinary retention or pre-existing essential hypertension
May be due to hyper-reninism associated with inadvertent renal artery ligation
Persistent hypertension raises concerns about incomplete resection or metastatic disease

Hypoglycaemia due to removal of ɑ₂-medicated suppression of pancreatic β-cell insulin release

Regular blood glucose monitoring and appropriate titration of dextrose infusions is recommended

Hypoadrenalism can occur, especially if there is bilateral adrenal resection; steroid supplementation may be required