Journal of Pediatric Critical Care P - ISSN: E - ISSN: Year: 2017 Volume: 4 Issue: 4 DOI /

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1 Journal of Pediatric Critical Care P - ISSN: E - ISSN: Year: 2017 Volume: 4 Issue: 4 DOI / Case Report Medical management and Perioperative issues in Pediatric Pheochromocytoma A case report with review of literature Naresh Lal*, Ankur Ohri**, Vibin kumar Vasudevan **, Rachna Sharma***, Praveen Khilnani**** * Consultant PICU, **Fellow PICU, *** Senior Consultant PICU, BLK Superspeciality hospital, Delhi, India, **** Director, Pediatric Intensive Care Services, Rainbow Children s Hospital, New Delhi, India Received: 26-Sep-17/Accepted: 24-Oct -17/Published online: 01-Nov -17 Correspondence: Dr Naresh Lal, Consultant Pediatric Intensivist, BLK Superspeciality hospital, Delhi, India. Phone: , E mail: doclal2009@gmail.com ABSTRACT: Pheochromocytoma is a tumor arising out of embryological neural crest, being a tumor of adrenal medulla secreting predominantly norepinephrine as well as epinephrine(about 20% cases) leading to frequent surges of vasopressor catecholamines leading to systemic hypertension, hypertensive emergencies and associated cardiac, neurological, and renal sequalae. Though somewhat rare in pediatric age group, it remains an important etiological factor to think about when there is intractable hypertension or rapid swings of blood pressures leading to headaches and palpitations with family history of hypertension or as a part of familial endocrine neoplasia. Treatment remains laproscopic or open surgical resection under general anesthesia, however perioperative care remains a challenge for the anesthesiologist,intensivist requiring adequate medical control of hypertension with alpha blockers such as phenoxybenzamine before undertaking anesthetic induction and important monitoring measures instituted during intraoperative and postoperative period for close monitoring of blood pressure and intravascular volume status as well as hemodynamics.we review a case report with literature review regarding perioperative management of pheochromocytoma. Key words: pheochromocytoma, adrenal medulla, neural crest tumor, chromaffin cells, norepinephrine, epinephrine, hypertensive emergency

2 Case report A 9 year old developmentally normal male child was admitted with complaint of headache for days which had increased for last 3 days. The child also had complaints of polydipsia and polyuria with abdominal pain off and on for last 2 months. In the Emergency room, he was found to have tachycardia (pulse rate - 160/min) with Blood pressure of 170/100 mm of Hg (stage 2 hypertension-hypertensive emergency). He had normal saturation (98%) in room air and pulse volume and character were normal. Urine output was adequate. His GCS was 15/15 and had no focal neurological deficit. Meningeal sign were absent and planters were flexors (Babinsky negative). Fundus examination was normal. Rest of the examination was unremarkable. He was well built child (weight-24 kg). The child was shifted to PICU in view of acute hypertensive emergency and was seen by a pediatric neurologist who reviewed the case. The child had a history of seizures 2 months back. He was investigated at that time and treated as ADEM with methylprednisolone. The seizures were controlled with sodium valproate and leveracetam. The neurologist was against the diagnosis of ADEM made previously. There was also a significant family history of sudden death of grandfather at the age of 38 years and paternal uncle at 10years and aunt at 20 years of age. His father was operated for bilateral pheochromocytoma at the age of 12 years. Fig 1a

3 Fig Fig 1b 1b Fig 1c Figure 1a/1b/1c- MRI Brain of the patient showing T2 hyperintensities and increased ADC signal intensities in water shed areas In the PICU child was started on sodium nitroprusside for controlled BP reduction as per standard protocols. Later, oral amlodipine was started. Besides routine workup, evaluation was done for the malignant hypertension. He had normal CBC (HB -12.3gm%; TLC 10,400

4 /cmm, platelets- 5.4lac/cmm) and Renal function tests (urea- 13.5mg/dl, creatinine- 0.48mg/dl) with normal electrolytes (Na meq/dl, K+-3.5 meq/dl, Ca ,Phosporus- 2.9mg/dl).His Liver function test was normal. Urine routine was normal and cultures were sterile. ECHO was also normal study with no left ventricular hypertrophy. USG Abdomen revealed a hypoechoic nodular lesion (3.5 x 2.9cm) at the left renal hilum. CT abdomen revealed multiple nodular enhancing lesions in the right suprarenal region and left suprarenal region anterior to left renal vein. These features were s/o bilateral pheochromocytoma. No evidence of renal artery stenosis was seen. Plasma Metanephrine was 2484pg/ml (range ) and 24 h Urinary catecholamine level- Epinephrine µg/day (range ), Nor-epinephrine-65084µg/day (range 22-73), Dopamine-30µg/day (range ) were significantly elevated. 25 hydroxy vitamin D- 42ng/ml (range 30-75), Serum Parathyroid pg/ml (range 15-65), S.Calcitonin-4.30pg/ml (normal <8.8) and T3/T4/TSH- 3.41/1.01/3.95 were normal. MIBG Scan showed high uptake in supra-renal glands in both sides but no metastasis. Figure 2(a) 2(b) Figure 2 (a) Hyperintense lesions on T2 imaging in MRI abdomen and 2(b) 123I-labeled metaiodobenzylguanidine (MIBG )scan showing high uptake of tracer in supra-renal glands A multidisciplinary team approach comprising Pediatric endocrinologist, Pediatric Neurologist, Pediatric surgeon, Pediatric anesthesia and Pediatric intensivist was sought. Patient was prepared for surgery in collaboration with anesthetist. He was started on Phenoxybenzamine (10 mg twice daily increased to thrice daily) then subsequently after about 6 days atenolol was added. His blood pressure was gradually lowered and maintained (Systolic BP / Diastolic BP mm Hg). During the hospital stay in preoperative period the child developed gait abnormalities and he could walk only with support. S.CPK and NCV study was normal. It was probably due to catecholamine-induced myocyte dysfunction which is a known entity. Muscle biopsy was not done. Physical therapy was initiated, and the child showed gradual improvement. Laparoscopic Bilateral adrenalectomy was done later. Intra-operative period was uneventful (managed with fluids, sodium nitroprusside drip and norepinephrine drip as required). Stress dose of hydrocortisone was given at the end of surgery. He remained stable in the post op period. Histopathology report was consistent with neuroendocrine tumors.

5 Figure 3: Laparoscopic surgery for Pheochromocytoma- retroperitoneal approach Figure 4: Specimen of Pheochromocytoma

6 Figure 5: Post-operative clinical photograph of Patient Recovery was uneventful. BP gradually settled down to 130/80 and he was discharged on seventh day post op on steroids and antiepileptics. Review of Literature Pheochromocytomas (PHEO) and Paragangliomas (PGL) are rare neuroendocrine tumors that arise from neural crest-derived cells or organs, known as paraganglia, and can occur in all locations where paraganglia are found. PHEO is the term used for a catecholaminesecreting tumor that occurs in the adrenal medulla, the most common location, whereas PGL are extra-adrenal tumors that arise from both sympathetic and parasympathetic paraganglia. PGL are located anywhere from the base of the skull to the pelvis, but most commonly arise in the head and neck or in the abdomen near the renal vessels or the organ of Zuckerkandl, which is localized around the origin of the inferior mesenteric artery and is the largest extraadrenal collection of chromaffin tissue. The clear majority of these tumors in childhood are PHEO, and they synthesize and secrete catecholamines (dopamine, norepinephrine, and epinephrine) and their metabolites (homovanillic acid, normetanephrine, and metanephrine, respectively). Most pheochromocytomas (more than 80%) mainly secrete norepinephrine and in rare cases may produce epinephrine predominantly. Some tumours may secrete dopamine and various peptides and ectopic hormones. Epidemiology 1,2 Incidence rates are around 0.3 cases per million per year or less. Approximately 10 20% of cases are diagnosed during childhood at an average age of 11 yr with a slight predominance in boys, particularly under the age of 10 yrs. In children diagnosed with hypertension, upto 1.7% have a catecholamine-secreting neoplasm

7 About 90% of pheochromocytomas occur sporadically and are benign. In 10% of patients, the adrenal tumour is part of a familial disorder such as the multiple endocrine neoplasia (MEN) syndrome, von Recklinghausen disease or von Hippel-Lindau syndrome. VHL disease is the major cause of chromaffin tumors diagnosed in childhood. Percentage of cases with hereditary disease is as high as 70% in children less than age 10yr. Hereditary PHEO/PGL are often multifocal and, in the case of PHEO, frequently bilateral. Clinical Presentation 1,2 Pheochromocytoma presents with classical triad of paroxysmal episodes of palpitation headache and sweating. The presentation of pheochromocytoma can range from normotensive and asymptomatic in patients with hereditary pheochromocytoma or small incidentalomas to potentially lethal symptoms in patients with larger, more functional, sporadic tumors. Most of pediatric patients present clinically with sustained hypertension and less often, due to tumor mass effects (e.g. pain), as an incidental radiographic finding, or because of family screening for one of the hereditary syndromes listed above. The released catecholamines cause significant hypertension, often severe and refractory to conventional treatment. Cardiovascular symptoms include ventricular arrhythmias, cardiac failure with cardiomyopathy, acute pulmonary oedema, and peripheral vasoconstriction with pallor. Others: symptoms like orthostatic hypotension, syncope, pancreatitis, stroke, seizures, tremor, anxiety and certain nonspecific symptoms like blurred vision, abdominal pain, diarrhea, weight loss, hyperglycemia, polyuria and polydipsia can occur. Given their neuroendocrine origin, PHEO/PGL can also rarely cosecrete other hormones, resulting in a clinical syndrome of ectopic hormone excess, such as gigantism (GHRH), Cushing syndrome (CRH or ACTH), hypercalcemia (PTHrP), SIADH and secretory diarrhoea (vasoactive intestinal peptide).differential diagnosis could be panic attacks, labile hypertension and conditions causing secondary elevation in plasma catecholamines like intracranial lesions, seizure, acute abdomen, eclampsia, shock, carcinoid syndrome etc. Diagnosis 1,2,3 Once there is a clinical suspicion, diagnosis is confirmed by biochemical and radiological methods. Biochemical- The best confirmatory test is to measure free catecholamines and their metabolites ((metanephrines and normetanephrines) in a 24-hour urine collection. These measurements include epinephrine, norepinephrine, dopamine, metanephrine, and vanillylmandellic acid (VMA). An elevation of these analytes greater than 4-fold above the reference range is associated with almost 100% probability of the presence of a catecholamine-secreting tumor. To avoid a false-positive result from exercise and procedure induced stress, plasma metanephrines are best measured in the supine position 30 min after an indwelling needle or catheter is inserted into the vein Radiological- Once the diagnosis has been established, the tumour must be localized to facilitate its surgical removal. Although larger tumours may be located with Ultrasonography, most tumours require CT or MRI scans especially when located outside the adrenal gland.

8 Both provide an accurate identification of the majority of pheochromocytomas. PHEO/PGL are vascular tumors that commonly contain necrotic, cystic, and/or hemorrhagic areas. On MRI, they may exhibit a classic hyperintense appearance on T2-weighted images. Tumours in unusual sites (not seen with cross-sectional imaging) and metastases may have to be identified with functional testing using nuclear scintigraphy with 123 I-labeled metaiodobenzylguanidine (MIBG), which has a high specificity for pheochromocytoma as MIBG is concentrated by the tumour's avid uptake of precursor amines. Because MIBG testing is not 100% sensitive, other nuclear imaging modalities like 18 F DOPA and 18 F FDA PET can be considered and are likely to be superior to scanning with MIBG. Treatment 3,4,5 Optimal therapy for pheochromocytoma is surgical resection of the tumor. Medical therapy should be initiated for 1 2 week before surgery. No universal algorithm exists for medical management. Preoperative Assessment Multi-specialty team involvement including cardiologist, anesthetist, intensivist and surgeon should be involved. Adequate blood pressure (BP) control is important for 1-2 weeks prior to surgery. This is done to minimize the complications that may arise from acute catecholamine surges during induction of anaesthesia and manual manipulation of the tumor. Relevant history and examination to assess the severity of hypertension and look for any end-organ damage, especially catecholamine induced cardiomyopathy and cardiac failure, which is associated with a high mortality, should be undertaken. For a detailed assessment of cardiovascular status electrocardiography (ECG), chest X-ray and M-mode echocardiography should be advised. ECG might show hypertrophy, arrhythmias, cardiomyopathy, ischaemia or infarction. Chest X-ray may reveal cardiomegaly or pulmonary oedema. M-mode echocardiography should be used to assess left ventricular dysfunction, evaluate improvement after alpha adrenergic blockade, and determine the optimal timing of surgery. A baseline full blood count and haematocrit followed by serial monitoring provides an assessment of the adequacy of volume expansion when alpha adrenergic blockade has been

9 started. An assessment of renal function should be carried out by biochemical investigations such as urea, creatinine and electrolytes. Insulin therapy may be required if hyperglycaemia is present. If hypercalcaemia is present, the presence of MEN type 11 should be suspected. Preoperative Management Adrenergic crisis- leading to an uncontrollable situation may occur at induction of anaesthesia, intubation, and during tumour handling. Appropriate preoperative medical management dramatically decreases morbidity and mortality during the operative management of pheochromocytoma. Preoperative preparation is conventionally done with alpha adrenergic blockade over a period of days and subsequently, additional beta adrenergic blockade is required to treat any associated tachyarrhythmias. Phenoxybenzamine is a nonselective α-receptors blocker. Usual dose is mg/kg 8-12 hourly orally (adult dose 10-40mg). Major disadvantages would be tachycardia, persistent postoperative hypotension, somnolence, stuffiness of nose, headache, and postural hypotension requiring intravenous fluid replacement. More selective α1receptor blockers like Prazosin, Doxazosin and Terazosin can also be used. Prazosin is short acting and may require frequent dosing. Usual dose is mg/kg 6-12 hourly oral (adult 1-5mg). Calcium channel blocker like nifedipine (0.5mg/kg 12hrly upto 1 mg/kg 8hrly) can be used in low-risk patients to obviate the need to increase the dosage of α-blockers and it also does not interfere with plasma normetanephrine assays. Treatment with α-blockers improves symptoms, lowers blood pressure, and expands the vascular bed and blood volume. The choice of drug will depend not only on the physician's preference but also upon availability and cost effectiveness. It is important to introduce the drugs cautiously starting with small doses and increasing gradually until orthostatic hypotension develops indicating adequate alpha blockade. During alpha receptor blockade tachycardia and arrhythmias can occur due to resultant unopposed beta receptor activity. The tachycardia and arrhythmias are controlled by carefully introducing beta adrenergic blockers. Beta blockade should never be instituted until alpha adrenergic blockade is fully established as unopposed alpha stimulation may lead to severe hypertension. Caution is required in patients with cardiomyopathy who may develop pulmonary oedema due to withdrawal of beta stimulation. Thus, beta adrenergic blockade should be avoided in patients with catecholamine induced cardiomyopathy as it can lead to development of intractable hypotension, bradycardia and asystolic arrest. Selective beta I adrenoceptor antagonists such as atenolol (0.5-1mh/kg 12-24hrly orally, max 25-50mg) should be used to minimize undesirable side effects in the bronchi or peripheral vasculature. Non-selective beta 1 antagonists such as propranolol ( mg/kg gradually increased to 1.5 mg/kg orally, max 80 mg, 6-8hrly if required) or metoprolol (1-2 mg/kg 6-12hrly) can also be used but care must be taken in patients with history of obstructive airway disease. Labetalol has both alpha and beta blocker effects and is used sometimes. Its alpha blocking actions augments any pre-existing alpha block induced by phenoxybenzamine or prazosin.

10 Patients often develop hypertensive swings during surgical manipulation of the tumour despite complete pharmacological blockade. Therefore, medication for alpha and beta blockade should be continued until the day of the operation except phenoxybenzamine which may be stopped the day before surgery as it has a long half-life and can cause postoperative hypotension. A few days before surgical intervention, oral salt loading (either via increased dietary intake or with sodium chloride tablets) is recommended to expand the blood volume to prevent severe postoperative hypotension. Intraoperative Management Adequate general anaesthesia and selective adrenergic antagonists to control haemodynamic surges in response to tumour manipulation is of utmost importance. Epidural analgesia (fentanyl and bupivacaine) is used for both intraoperative and postoperative pain control. Induction with midazolam, thiopentone, fentanyl, alfentanyl or remifentanil can be used along with neuromuscular blocking agent. Vecuronium, rocuronium and cisatracurium have shown cardiovascular stability and appear to be suitable agents for this purpose as they also release the least histamine which need to be avoided in these patients. Sodium nitroprusside (SNP), phentolamine, prazosin, nitroglycerine and various other agents like magnesium sulphate, nicardipine, diltiazem, esmolol etc, have been used to control intraoperative rises in blood pressure. Sodium nitroprusside is preferred for this purpose. It is a potent arteriovenodilator with a rapid and brief action and is used as a titratable intravenous infusion. Intraoperative use of beta adrenergic antagonists can help control tachycardia and tachyarrhythmias. Esmolol (30-300ug/k/min infusion) has haemodynamic effects that may be uniquely suited for the intraoperative management of pheochromocytoma. Its rapid effect and short duration makes it easily titratable, both to control heart rate and blood pressure. Magnesium sulphate inhibits catecholamine release from chromaffin cells and alters the adrenergic receptors response. Continuous infusion may also be used. Calcium channel blockers e.g. nifedipine and nicardipine have also been used for intraoperative haemodynamic control. The procedure of choice for most PHEO is laparoscopic adrenalectomy, either using transperitoneal or retroperitoneal approach. Laparotomy should be contemplated in patients with large PHEO and/or a concern for underlying malignancy. In the setting of bilateral PHEO, cortical-sparing procedures should be considered for the adrenal with the least tumor bulk. The cortical-sparing approach is particularly attractive in young children and children at risk for noncompliance with the lifelong glucocorticoid and mineralocorticoid replacement required after bilateral adrenalectomy but carries the risk of recurrent PHEO in the remnant Postoperative Management The three most important complications in the immediate postoperative period are hypertension, hypotension and hypoglycaemia. After the adrenal veins are ligated, there is a sudden decrease in the circulating catecholamines which may lead to hypotension. At this point the vasodilators and blocker should be discontinued and a modest fluid bolus should be given. An eye must be kept on the blood loss and blood given if required. Infusion of a

11 vasopressor such as norepinephrine or phenylephrine may be required temporarily. Approximately 50% of patients remain hypertensive for a few days, most likely related to elevated catecholamine levels which may persist for one week after pheochromocytoma resection. Therefore, restarting or continuation of antihypertensive medication may be required for a few days. Presence of residual tumour must be considered in cases of persistent hypertension and catecholamine levels should be repeated. Persistent hypotension may be due to residual effects of preoperative adrenergic blockade. There should also be a high index of suspicion for intra-abdominal bleeding. After removal of the tumour the pancreatic beta cell suppression is no longer present and insulin levels increase. The lipolysis and glycogenolysis is also absent due to removal of tumour and alpha blockade. This may lead to hypoglycaemia which may be associated with encephalopathy and the residual adrenergic blockade may mask its signs and symptoms. Therefore, blood glucose levels should be monitored in the perioperative period and glucose containing intravenous fluids should be started after tumour removal. It is advisable to perform a high-dose cosyntropin stimulation test before hospital discharge to determine the need for adrenal steroid replacement. Follow up Long-term follow-up with biochemical screening (i.e. plasma or urine metanephrines) and intermittent imaging studies are required to assess for recurrence especially in cortical sparing surgeries. Annual screening is advised in cases with specific gene mutation. Conclusion Although PCC is a rare neoplasm, it should be considered as a possible diagnosis in children presenting with malignant hypertension. Genetic tests should be done in patients with pheochromocytoma who are young, have a positive family history, and with bilateral disease. Preoperative preparation is of utmost importance prior to surgery. Adrenal sparing surgery can be considered in bilateral tumors in young children. Patients should ideally be managed by an experienced team of endocrinologists, surgeons, intensivists and anesthetics Conflict of Interest: None Source of Funding: None References: 1. Waguespack T, Grubbs E, Ying A, Perrier N, Ramirez M, Jimenez C. Current Review of the Etiology, Diagnosis, and Treatment of Pediatric Pheochromocytoma and Paraganglioma. J Clin Endocrinol Metab 2010;95: Martin M, Hammer G. Pheochromocytoma: An Update on Risk Groups, Diagnosis, and Management. Hospital Physician 2006; 42(2): Ahmed A. Perioperative Management of Pheochromocytoma: Anaesthetic Implications. J Pak Med Assoc 2007; 57(3): Adler J, Rochow G, Chen H, Benn D, Robinson B, Sippel R, et al. Pheochromocytoma: Current Approaches and Future Directions. The Oncologist 2008, 13: Roberts P. Pheochromocytoma recent progress in its management. Br J Anaesh 2000; 85;44-57.