Pheochromocytoma and Anesthesia

Blood pressure optimization is important in pheochromocytoma patients before going to surgery. It is important for the anesthesia providers to diagnose, optimize and manage those patients..

1. pheochromocytoma Dr tenzin yoezer Anesthesia resident Khesar gyalpo university medical sciences of Bhutan

2. What is pheochromocytoma ? Catecholamine secreting tumors of chromaffin tissue Precise etiology is unknown Located in the adrenal medulla or sympathetic para-ganglia but, can be found where chromaffin tissue exist(from anus to skull) Traditionally 90% were adrenal medulla and 10% elsewhere But now prevalence of extra adrenal is > 20% Accounts for 0.1% cause of HTN

3. prevalence Prevalence – 0.005% to 0.01% Occurs in both sexes Peak in 3 rd to 5th decades Rule of 10: 10% B/L, 10% extra-adrenal, 10% familial, 10% malignant ( but with advances and genetic diagnosis, it is untrue) In some familial >10% B/L Familial – autosomal dominant, usually b/L, if extra-adrenal appears same anatomical area over successive generation >20% extra-adrenal (organ of Zuckerkandl near aortic bifurcation is the most common extraadrenal site) ~25% hereditary > 33% malignant

4. Syndrome associated MEN type 11a( Sipple syndrome) – Parathyroid ademona hyperplasia, medullary Ca of thyroid, pheochromocytoma MEN type 11b – medullary ca of thyroid, mucosa adenomas, marfanoid appearance, pheo Almost 100% of pt with MEN II have or will develop b/L benign medullary pheochromocytoma Von- Hipple - Landau syndrome – heamangioblastoma of retina, cerebellum, or other parts of CNS, Pheo Neurofibromatosis – neurofibromas , café-au- lait spot, axillary or inguinal freckling, optic nerve lioma , pheo

5. Substances secreted by adrenal gland Primarily secrete 3 substances: Epinephrine Norepinephrine Dopamine These substances are found in chromaffin cells of sympathetic NS Most pheo secrete norepinephrine, either alone or, more commonly in combination with smaller amount of epinephrine in the ratio of 85:15

6. Mechanism of action of epinephrine and norepinephrine Exert their effect by acting on beta and alpha adrenergic receptors Beta receptor – G-protein meditation – increase cAMP levels Alpha1 receptor – G-protein – increase cytoplasmic Ca level – increase muscle contraction Alpha 2 receptor – inhibits adenylate cyclase – decrease cAMP

7. Synthesis and breakdown of catecholamine Synthesis: Active transport of Tyrosine from circulation to posthganglionic sympathetic nerve ending Hydrolysis of Tyroxine – rate limiting step Breakdown: Reuptake at nerve ending Diffusion and metabolism by catechol-O-methyltransferase(COMT) and monoamine oxidase

8. Clinical features of pheochromocytoma Classic traid : severe headache, diaphoresis, palpitation Sudden headache Perspiration Weight loss Paroxysmal HTN Orthostatic HTN Pallor, Diabetic like syndrome Nausea and vomiting Fever Encephalopathy Anxiety MI Stroke AKI Precursor response to drugs like histamine, droperidol , tyramine, metoclopramide, cytotoxic drugs, saralasin , TCA, phenothiazine

9. Hemodynamic sign depends on the predominate catecholamine With Norepinephrine – alpha adrenergic predominant effect Systolic and diastolic HTN with reflex bradycardia With epinephrine – beta adrenergic predominate affect Systolic HTN, diastolic hypotension, tachycardia CVS changes – cadiomyopathy , IHD, LVOT obstruction ECG – ST elevation/depression, T wave flattening or inversion, peaked P wave, QT prolongation, LAD, dysarhythmia

10. Preop evaluation and preparation

11. Biochemical diagnosis Urine test Norepinephrine Epinephrine Dopamine Total metaneohrines Fractionated metanephrines Vanilylmandelic acid Plasma test Norepinephrine Epinephrine Dopamine Plasma-free metanephrines Clonidine suppression of norepinephrine secretion

12. Biochemical diagnosis 24 h urine test is superior than plasma test – intermittently secreted and have short t1/2 Metanephrine test – high true positive (98-99%) and best test for familial From the evidence- initial test should be plasm-free metanephrines or urine fractionated metanephrines Plasma test advantages – predict size, adrenal vs extra-adrenal, metastasis, offer underlying germline mutation of susceptibility genes CT with or without 1 131 labelled MIBG- extremely accurate I diagnosing and localizing the tumour MRI – pregnant women and extra-adrenal localization Caution – use of arteriography(once popular)- stimulates catecholamine release

13. Pharmacological preparation for surgery Goal – control hypertension and to facilitate intravascular volume expansion Alpha blocker – Phenoxybenzamine , Prazosin, Terazosin, Doxazosin Phenoxybenzamine (nonselective and binds irreversibly) – commonly preferred ( long acting, ease administration) Started 1-3 weeks prior to surgery(during this period encouraged to take salt and water- voume expansion and to prevent postural hypotension) Titrated according to symptoms, BP and age

14. Reflex tachycardia – frequent side effect of alpha blocker Tachycardia – mx with addition of beta-blocker Caution – in the initial phase of treatment, avoid beta-blocker . In the absence of adequate alpha-blockade, inhibition of non selective beta-blocker mediated vasodilation(by beta 2) can result unopposed alpha-receptor mediator vasoconstriction due to catecholamine secreted by the tumour . ( i.e more vasoconstriction than vasodilation)This can precipitate a hypertensive crisis, HF, and possibly end-organ damage. In rare case , pheo with secreting soley epinephrine and with CAD, beta selective might benefit

15. Use of phenoxybenzamine might be limited by severe side effect profile (postural hypotension, reflex tachycardia, nasal stuffiness, syncope), high cost and uncommon Recent study has found use of oral Nicardipine has equivalent effect It is tolerated better, cheaper and more accessible

16. Adequate volume expansion Caution – decrease myocardial function and CCF Sedation in immediate preop is helpful to attenuate catecholamine release secondarily to anxiety. Also reduces vasodilator requirement in intraop Preop nebulization with lidocaine – significantly attenuate tracheal intubation response

17. Stopping of phenoxybenzamine Because of its prolong effect on alpha receptors, it is discontinued 24-48 hours before surgery to avoid vascular unresponsiveness immediately following removal of tumor Some anesthesiologist administer ½ to 2/3 of morning dose preceding surgery to address above problem Some surgeon request to discontinue 48 hours preop so they can use hypertensive episode intraop as cue in localizing areas of metastasis

18. Intraoperative management

19. Drugs to avoid Histamine releasing drugs – potent catalyst of catecholamine release from the tumour Eg : morphine, curare, atracurium , Vagolytic drugs – Atropine, Sux Indirect caecholamine release stimulant ( they are not absolute CI, can use judiciously) Eg : Pancuronium , ketmine , ephedrine Others: halothane, cocaine. metaclorpramide

20. monitoring ECG – V5 lead Core Temperature, SpO2, BP, CVP, urinary catheter Known/suspected Myocardial dysfunction – TEE, PAC, device that measure SV variation, CO

21. Anesthetic management GA preferred Laparoscopy is the technique if size 4-5 cm Induction – minimize the hemodynamic changes with adequate depth Lidocaine 4% spray via mucosal atomizer or 1.5 mg/kg IV 2 mins before intubation Caution with desflurane – provoke sympathetic stimulation and catecholamine release Halothane – may incite arrhythmias in the presence of high level of catecholamine

22. Na Nitroprusside – drug of choice(direct vasodilator, immediate onset of action, short duration)

23. Magnesium sulfate inhibits release of catecholamine from adrenal medulla and peripheral nerve terminal During tumor manipulation/ refractory HTN mixture of antihypertensive may be needed

24. Dysarhytmia are usually in ventricular in origin Mx with lidocaine or beta blocker( propanalol ) Amiodarone is an alternative due to long acting

25. Management concern after removal of tumor- Hypotension & hypoglycemia BP may decrease abruptly after venous drainage of tumor is interrupted Causes: immediate decrease in plasma catecholamine, vasodilation from residual alpha blockade with phenoxybenzamine , intraop fluid and blood loss, increase anesthetic depth Any vasodilating agent being administered should be discontinued BP mx – Adequate volume expansion with R/L or N/S before ligation norepinephrine, vasopressin – should be 2 nd line as its sensitivity is down regulated by residual alpha blockade Decrease the depth of anesthesia Norepinephrine requirement may be high in post tumor resection due to receptor insensitivity from chronic catecholamine release Continued vasodilator support requirement – inadequate resection of tumor or previously undiagnosed extra-adrenal tumor ** close communication between anesthetist and surgery is essential

26. Intraop blood transfusion – increases post resection HTN due to catecholamine contain in the blood Immediately after resection – insulin level increases Therefore dextrose containing solution is administered after resection If B/L or hypoadrenalism – glucocorticoid therapy

27. Concerns with laparoscopic adrenalectomy Pneumoperitoneum – elevates catecholamine level – increase CO and BP Therefore, close monitoring of vital signs is essential once pneumoperitoneum is initiated Lower intra-abdominal pressure – decrease release of catecholamine and less hemodynamic fluctuations If hemodynamic is sustained or refractory – terminate insufflation

28. Post op managemnt

29. Post op hypotension Common post op cause of death Due to reduced catecholamine level post resection Hypovolaemia Residual effect of phenoxybenzamin Down regulation of catecholamine receptors Mx – fluids, norepinephrine, vasopressin ** rule out post op bleeding

30. Other problems Somnolent – due to sudden removal of activating catecholamine Hypoglycemia – decrease catecholamine particularly if tumor is epinephrine secreting Neoglycogenesis and glycogenolysis is not present due to chronic beta agonism also due to chronic elevated insulin Thus close monitoring of blood glucose in first 24 h is essential Persistent HTN – residual pheochromocytoma ***Catecholamine level(norepinephrine) level may not decrease for many days even after removal of tumor

31. thanks Reference Yao 8 th edition Morgan Stoelting and coexisting disease