Anesthetic Implications of Anesthetic Implications of Pheochromocytoma & Pheochromocytoma &

Cushing syndrome Cushing syndrome &Addison’s disease&Addison’s disease

Moderator-Dr Jyoti Pathania

Presented by-Dr Kamal Prakash Sharma

PheochromocytomaPheochromocytoma

0.01-0.1% of HTN population Found in 0.5% of those screened

M = F 3rd to 5th decades of life Rare, investigate only if clinically suspicion:

Signs or Symptoms Severe HTN, HTN crisis Refractory HTN (> 3 drugs) HTN present @ age < 20 or > 50 ? Adrenal lesion found on imaging (ex. Incidentaloma)

Pheo: Signs & SymptomsPheo: Signs & Symptoms

The five P’s: Pressure (HTN) 90% Pain (Headache) 80% Perspiration 71% Palpitation 64% Pallor 42%

• Paroxysms (the sixth P!)

The Classical Triad: Pain (Headache), Perspiration, Palpitations Lack of all 3 virtually excluded diagnosis of pheo in a series of

> 21,0000 patients

Pheo: Paroxysms, ‘Spells’Pheo: Paroxysms, ‘Spells’

10-60 min duration Frequency: daily to monthly Spontaneous Precipitated:

Diagnostic procedures, I.A. Contrast (I.V. is OK) Drugs (opiods, unopposed -blockade, anesthesia induction,

histamine, ACTH, glucagon, metoclopramide) Strenuous exercise, movement that increases intra-abdo

pressure (lifting, straining)

Pheo: HypPheo: Hypootension!tension!

Hypotension (orthostatic/paroxysmal) occurs in many patients

Mechanisms: ECFv contraction Loss of postural reflexes due to prolonged

catecholamine stimulation Tumor release of adrenomedullin (vasodilatory

neuropeptide)

Pheo: Signs & SymptomsPheo: Signs & Symptoms

N/V, abdo pain, severe constipation (megacolon) Chest-pains

Anxiety Angina/MI with normal coronaries:

– Catecholamine induced: myocardial oxygen consumption or coronary vasospasm

CHF HTN hypertrophic cardiomyopathy diastolic dysfn. Catechols induce dilated cardiomyopathy systolic dysfn.

Cardiac dysrhythmia & conduction defects

Pheo: Signs (metabolic)Pheo: Signs (metabolic)

Hypercalcemia Associated MEN2 HPT PTHrP secretion by pheo

Mild glucose intoleranceLipolysis

Weight-loss Ketosis > VLDL synthesis (TG)

Pheo: ‘Rule of 10’Pheo: ‘Rule of 10’

10% extra-adrenal 10% occur in children10% familial 10% bilateral or multiple (more if familial)10% recur (more if extra-adrenal)10% malignant10% discovered incidentally

Tyrosine L-Dopa Dopamine

Norepinephrine

Epinephrine

Catecholamines

Normetanephrine

Metaneprine

PNMT

DBH

COMT

COMT

Metabolites

Homovanillic acid(HVA)

MAO, COMT

Vanillymandelic Acid(VMA)

MAO

MAO

TH

Familial PheoFamilial Pheo MEN 2a

50% Pheo (usually bilateral), MTC, HPT MEN 2b

50% Pheo (usually bilatl), MTC, mucosal neuroma, marfanoid habitus

Von Hippel-Landau 50% Pheo (usually bilat), retinoblastoma, cerebellar

hemangioma, nephroma, renal/pancreas cysts NF1 (Von Recklinghausen's)

2% Pheo (50% if NF-1 and HTN) Café-au-lait spots, neurofibroma, optic glioma

Familial paraganglioma Familial pheo & islet cell tumor Other: Tuberous sclerosis, Sturge-Weber, ataxia-telangectgasia,

Carney’s Triad (Pheo, Gastric Leiomyoma, Pulm chondroma)

24h Urine Collection24h Urine Collection24h urine collection:

Creatinine, catecholamines, metanephrines, vanillymandelic acid (VMA), +/-dopamine

HPLC with electrochemical detection or mass spect

Positive results (> 2-3 fold elevation): 24h Ucatechols > 2-fold elevation

• ULN for total catechols 591-890 nmol/d 24h Utotal metanephrines > 1.2 ug/d (6.5 umol/d) 24h UVMA > 3-fold elevation

• ULN 35 umol/d for most assays Sensitivity increased if 24h urine collection begun at onset of a paroxysm

Plasma CatecholaminesPlasma Catecholamines

Drawn with patient fasting, supine, with an indwelling catheter in place > 30 min

Plasma total catechols > (2000 pg/mL) SEN 85% SPEC 80%

False positives: same as for 24h urine testing, also with diuretics, smoking

CRF & ESRD: Oliguric to Anuric 24h Urines inaccurate Plasma epinephrine best test for pheo in ESRD Plasma norepi and metanephrines falsely elevated in ESRD

Plasma MetanephrinesPlasma Metanephrines

Not postural dependent: can draw normallySecreted continuously by pheoSEN 99% SPEC 89%False Positive: acetaminophenAssay not readily available in Canada

Suppression/Stimulation TestingSuppression/Stimulation Testing

Clonidine suppression May precipitate hypotensive shock! Unlike normals, pheo patients won’t suppress their

plasma norepi with clonidine

Glucagon stimulation May precipitate hypertensive crisis! Pheo patients, but not normals, will have a > 3x

increase in plasma norepi with glucagon

Localization: ImagingLocalization: ImagingCT abdomen

Adrenal pheo SEN 93-100% Extra-adrenal pheo SEN 90%

MRI > SEN than CT for extra-adrenal pheo

MIBG Scan SEN 77-90% SPEC 95-100%

111Indium-pentreotide Some pheo have somatostatin receptors

PET 18F-fluorodeoxyglucose (FDG) 6-[18F]-fluorodopamine

Pheo ManagementPheo Management

Prior to 1951, reported mortality for excision of pheochromoyctoma 24 - 50 %

HTN crisis, arrhythmia, MI, stroke Hypotensive shock

Currently, mortality: 0 - 2.7 % Preoperative preperation, -blockade? New anesthetic techniques?

• Anesthetic agents• Intraoperative monitoring: arterial line, EKG monitor, CVP

line, Swan-Ganz

Experienced & Coordinated team: Endocrinologist, Anesthesiologist and Surgeon

Preoperative WorkupPreoperative Workup

CBC, Electroytes, creatinine, INR/PTTFBSCa (if one of MEN syndrome is suspected)CXREKGEcho (r/o dilated CMY 2º catechols)

Preop Preperation RegimensPreop Preperation Regimens

Combined + blockade Phenoxybenzamine Selective 1-blocker (ex. Prazosin) Propanolol

Metyrosine Calcium Channel Blocker (CCB)

Nicardipine

No Randomized Clinical Trials to compare various regimens!

Preop: Preop: + + blockadeblockade Start at least 10-14d preop

Allow sufficient time for ECFv re-expansion

Phenoxybenzamine Drug of choice (noncompetitive & long acting) Covalently binds -receptors (1 > 2) Start 10 mg po bid increase q2d by 10 mg/d Maintenance 40-80 mg/d (some need > 200 mg/d)

End points indicating adequate preop preparation are- 1) Increase until BP control and no more paroxysms ,no in hospital BP

higher than 165/90 should be evident for 48 hours before surgery

2) FBS will return to normal

3) PCV will decline to around 40-43%

4) Orthostatic hypotension should be present, but BP on standing mg/d)should not be lower than 80/45 mm of Hg

5) ECG must be free of ST-T changes that are not permanent

6) No > 1 premature ventricular contraction should occur every 5 minutes

Preop: Preop: + + blockadeblockade

Phenoxybenzamine (cont’d) Side-effect: orthostasis with dosage required to normalized

seated BP, reflex tachycardia Drawback: periop hypotension/shock unlikely to respond to

pressor agent.

Selective 1-blockers Prazosin, Terazosin, Doxazosin Some experience with Prazosin for Pheo preop prep Not routinely used as incomplete -blockade Less orthostasis & reflex tachycardia then phenoxybenzamine Used more for long-term Rx (inoperable or malignant pheo)

Preop: Preop: + + blockadeblockade

-blockadeUsed to control reflex tachycardia and

prophylaxis against arrhythmia during surgery

Start only after effective -blockade (may ppt HTN)

If suspect CHF/dilated CMY start low dose Propanolol most studied in pheo prep

• Start 10 mg po bid increase to cntrl HR

Preop: Preop: + + blockadeblockade

If BP still not cntrl despite + blockade Add Prazosin to Phenoxybenzamine Add CCB, ACE-I Avoid diuretics as already ECFv contracted Metyrosine

Preop: Preop: + + blockadeblockade

Medications given on Morning of surgery Periop HTN:

1) IV phentolamine– Short acting non-selective -blocker

2) IV Nitroprusside (NTP)

Periop arrhythmia: IV esmolol Periop Hypothension: IV crystalloid +/- colloid

Pheo: Rx of HTN CrisisPheo: Rx of HTN Crisis

IV phentolamineIV NTPIV esmololIV labetalol – combined + blocker

Preop: MetyrosinePreop: Metyrosine

Synthetic inhibitor of Tyrosine Hydroxylase (TH) Start 250 mg qid max 1 gm qid S/E’s: sedation, extra pyramidal, diarrhea,, anxiety,

renal/cholelithiasis, galactorrhea N/V Alone may insufficiently control BP and reported HTN

crises during operation Restrict use to inoperable/malignant phaeochromocytoma

or as adjunct to + blockade or other preoperative prep

Tyrosine L-Dopa Dopamine

Norepinephrine

Epinephrine

PNMT

DBH

TH

Preop: CCBPreop: CCB

Nicardipine Block norepi mediated ca uptake into vascular smooth muscles

Started po 24h to few weeks preop to control BP and allow ECFv restoration

After intubation IV Nicardipine (start 2.5 ug/kg/min) IV Nicardipine adjusted to SBP Stopped prior to ligation of tumor venous drainage Tachycardia Rx with concurrent IV esmolol

Advantage: periop hypotension may still respond to presser agents as opposed to those patients who are completely -blocked

PerioperativePerioperativeAdmit night before for overnight IV saline2 large bore I/V lines should be secured Arterial lineCVP lineRoutine Pulse oximetry,etCO2,EKG,Temperature probeKnown CHF: consider Swan-GanzRegardless of preop medications:

Have ready: IV phentolamine, IV NTP, IV esmolol Rx hypotension with crystalloid +/- colloid 1st

Aim for CVP 12 or Wedge 15 Inotropes may not work!

Intraoperative considerationsIntraoperative considerations

Three critical phases of tumor resection are1) Induction and intubation2) Surgical manipulation 3) After ligation of the tumors venous

drainage

Induction & IntubationInduction & IntubationEtomidate, thiopental, and propofol can all be used

to initiate anesthesia.Increase anesthetic depth by bag mask ventilation

with volatile anesthetic Lidocaine 1-2mg/kg 1 min prior to inductionNarcotics Fast acting antihypertensive readily availableAnesthetic choice:

En/Sevo/isoflurane: don’t sensitized myocardium to catecholamines

Halothane: may sensitize heart arrhythmia

Maintenance(During surgery)Maintenance(During surgery)Anesthesia is maintained with gases and

narcotics. VA are easy to titrate, can help with HTN (1.5-2 MAC)

Pt should be kept normovolemic. Blood glucose monitoring Hypertensive episodes managed by- Deepening volatile anesthetic level Nitroprusside @ 0.5-10ugm/kg/m via infusion Phentolamine mixed at 10mg/100ml

D 5W(tachycardia can occur,small dose of esmolol/propranolol can treat it)

Maintenance(During surgery)Maintenance(During surgery)Propranolol/Short acting beta blocker Esmolol

may be required during this period if there is persistent tachycardia/premature ventricular contractions

Ligation of the tumors venous Ligation of the tumors venous drainagedrainage

↓ circulating catecholamine causing hypotensionAfter ligation of all venous drainage arterial

pressure commonly declines r/t ↑CO, ↓ SVR

Treatment↓ VA↑ IVFPhenylephrine or nor epinephrine

PostopPostop1) Invasive lines should stay intact. Pt still at risk

for liable BP. 2) Pt susceptible to hypotension that is refractory

to fluid volume expansion 3) Still have high volumes of circulating

catecholamine despite tumor resection 4) Catecholamine levels normalize after several

days. 75% of pts BP returns to normal after 10 days

5) Prone to Hypoglycemia. Secondary to suppression of β-cell function disappears after the tumor is removed

Pheo & PregnancyPheo & Pregnancy

Diagnosis with 24h urine collections and MRI No stimulation tests, no MIBG if pregnant 1st & 2nd trimester (< 24 weeks):

Phenoxybenzamine + blocker prep Resect tumor laprascopically

3rd trimester: Phenoxybenzamine + blocker prep When fetus large enough: cesarian section followed by tumor

resection

Addison's diseaseAddison's disease Addison's disease is characterized by decreased or absent glucocorticoid

secretion, usually combined with mineralocorticoid insufficiency. It can be primary or secondary and may present as an acute, chronic, or acute-on-chronic illness. The most common cause is autoimmune.

A) Clinical features Postural hypotension & dizziness Hyperkalemia & Hyponatremia

Hypoglycemia

Nausea, vomiting, diarrhea, and weight loss.

Decreased body hair.

Pigmentation especially in areas exposed to the sun.

Can be associated with pernicious anemia, myasthenia gravis, and vitiligo

May not be clinically obvious until a significant stress occurs

B) Investigations- 1) Low serum glucose.

2) Low Na+, raised K+ and urea

3) Low Bicarbonates,Nomocytic anemia

4) Plasma ACTH-measure simultaneously with plasma cortisol at 08:00h. Even if cortisol is normal the ACTH will be elevated.

5) Plasma renin activity and aldosterone—plasma renin activity is usually low with a low aldosterone.

6) Short Synacthen(Cosyntropin) stimulation test—250 µg of Synacthen dissolved in 1 ml of sterile water is given i/v or i/m. Serum cortisol is measured 30-60 min later. A serum cortisol >495 nmol/litre excludes the diagnosis.

C) Management- 1) Hydrocortisone 200 mg IV should be given immediately, then 100 mg 6-

hourly IM or 200 mg/24 h IV, until oral replacement is possible(Hydrocortisone orally: 20 mg in the morning and 10 mg at night)

2) Fludrocortisones to replace aldosterone:0.05- 0.1 mg daily orally. 3) To maintain NaCl daily intake to 3-4gm/d 4) Fluid resuscitation with CVP guidance. 0.9% saline is an appropriate fluid

with 50% dextrose infused if hypoglycaemia occurs. 5) Inotropes if hypotension persists. The choice of inotrope will depend on the

clinical picture, i.e. noradrenaline if the patient has severe vasodilatation.

Perioperative management of Perioperative management of patients with Addison's diseasepatients with Addison's disease

1)Give all medication up to the morning of surgery.

2)25 mg IV hydrocortisone should be given at induction.

3)Small or intermediate cases should be managed as per perioperative steroids

4)In major cases, hydrocortisone 200 mg/24 h should be used until the patient can be weaned back onto maintenance therapy.

5) Blood glucose and electrolytes.

POSTOPERATIVELY- To continue Hydrocortisone I/v until oral maintenance dose is

started To start fludrocortisone 0.05-0.1 mg/d Monitor Blood glucose Monitor daily electrolytes

Cushing's syndromeCushing's syndromeCushing's syndrome is a collection of signs and symptoms due to an excessively

high plasma cortisol. The most common cause of Cushing's syndrome is treatment with glucocorticoid drugs. Anesthetists will see this syndrome in:

1) Patients having pituitary or adrenal surgery to resects tumors causing a raised cortisol.

2) Patients with malignant tumors. These occasionally secrete an ACTH-like hormone that causes profound Cushinoid features. Oat cell carcinoma of the lung is a common cause.

3) Patients on high-dose steroid therapy.

Clinical features-Moon face and truncal obesity.

Proximal myopathy and osteoporosis.

Easy bruising and fragile skin.

Impaired glucose tolerance, diabetes.

Hypertension and left ventricular hypertrophy.

Hypernatremia and hypokalaemia.

Gastrointestinal reflux & Sleep apnea.

DiagnosisDiagnosis1)Classical clinical features are often seen but will not differentiate the various causes

of a raised cortisol level. Urinary free cortisol or lack of diurnal variation will confirm a pathological cause but will not define the etiology.

2)The ‘short dexamethasone suppression test’ (1 mg of dexamethasone is given at night and a cortisol sample taken in the morning) is a sensitive test to confirm abnormally raised serum cortisol. Serum cortisol will be suppressed in the morning if the HPA axis is working normally.

3)Serum ACTH levels will help determine if adrenal or pituitary pathology is the cause.

4)Very high ACTH levels suggest ectopic production, e.g. carcinoma of the lung, and very low levels suggest adrenal hyper secretion.

5)The ‘high dose dexamethasone suppression test’ (2 mg is given 6-hourly for 48 h and serum cortisol measured) will cause a fall in early morning and urinary free cortisol on the second day in pituitary-dependent Cushing's syndrome, but not in ectopic or adrenal causes.

6)Inferior petrosal venous sinus sampling following CRH stimulation is the final confirmatory test for pituitary Cushing's syndrome.

7)MRI scan of the pituitary fossa.

Treatment of cushing syndromeTreatment of cushing syndrome 1) Selective Transsphenoidal resection is treatment of choice for Cushing

disease(Pituitary micro/macroadenoma) 2) Adrenalectomy uni/bilateral needed( for adrenal adenoma/carcinoma) 3) Pt will be medically treated prior to surgery with focus on decreasing synthesis

of steroids by -Aminoglutethimide,Ketoconazole

-Mitotane

-Metyrapone & Cyproheptadine

4) Spirinolactone to control BP & restore electrolyte balance may be needed 5) Insulin to control plasma glucose levels may be required 6) All above measures contd. to the day of surgery

Preoperative assessmentPreoperative assessment 1) 85% of patients are hypertensive and are often poorly controlled. 2)

ECG abnormalities (high-voltage QRS and inverted T waves) can make IHD difficult to exclude but will revert to normal after curative surgery. These ECG changes seem to be related to the Cushing's disease itself.

3) 60% of patients have diabetes or impaired glucose tolerance and a sliding scale should be started before major surgery if glucose is >10 mmol.

4) Gastroesophageal reflux is common and preoperative acid suppression therapy and rapid sequence induction should be considered.

5)Venous access can be very difficult. 6) Patients can be obese and appropriately sized blood pressure cuffs, operating tables, and supports should be ordered.

INTRAOPERATIVELY- 1) Careful positioning of pt because of osteoporosis 2) Despite routine monitoring CVP is monitored as these pt tend to have higher CVP 3) Adequate control of blood sugar 4) We normally begin administering glucocorticoids at the start of resectioning of

tumor @ 100 mg of Hydrocortisone hemi succinate/phosphate i/v

POSTOPERATIVELY- 1) Hydrocortisone @ 100 mg/24 hr is contd. i/v on the day of surgery

& reduced over a period of 3-6 days until maintenance dose is reached

2 )Beginning on the day 3rd a mineralocorticoid fludrocortisone @ 0.05-0.1mg/day orally started