Written by: Rita Agarwal, MD, FAAP; and Echo Rowe, MD, FAAP

Case Presentation

A 10-year-old boy was scheduled for a CT-guided biopsy of a thoracic mass. The otherwise healthy child presented with a 3- to 4-month history of back pain. MRI revealed a right posterior paraspinal mass anterior to the costovertebral junction extending from T3 to T5 and measuring approximately 3.3×2.8×3.6 cm. In the preoperative holding room, the child was tearful and clingy to his mother. His blood pressure (BP) was 135/69 mm Hg; his heart rate was 92 beats per minute.

After induction and endotracheal intubation, the patient was positioned prone for the biopsy. During the procedure his BP increased significantly (up to 185/127 mm Hg) and did not respond to additional IV fentanyl, propofol bolus administration, or increasing the concentration of isoflurane. Labetalol was administered in 5-mg increments to a total of 45 mg, and although BP decreased during the procedure, hypertension persisted in the recovery period.

image

The World Health Organization defines pheochromocytomas (PCs) as intra-adrenal paragangliomas (PGs). All other catecholamine-producing tumors are classified as extra-adrenal PGs. They have an incidence of 0.05% to 0.1% and can occur anywhere along the sympathetic chain, most commonly in the abdomen, neck, mediastinum, bladder, or ureters. PCs occur most frequently in the adrenal medulla.1-3 In adults, the typical distribution is 10% malignant and 90% nonmalignant.1

In children, PC is much rarer and more often bilateral and extra-adrenal and can be found in multiple locations, most commonly in the thorax; most are nonsecreting tumors.1-3 In children there is a male preponderance, whereas in adults women slightly outnumber men. PCs can occur as part of familial multiple endocrine neoplasia syndromes, or in isolation. Syndromes that are associated with PC include Carney’s triad, familial PG type 2, MAX gene mutations, multiple endocrine neoplasia syndrome type 2a (Sipple’s), multiple neoplasia syndrome 2b/3 (RET proto-oncogene), neurofibromatosis type 1, succinate dehydrogenase complex mutations, TMEM127gene mutations (tumor suppressor gene), tuberous sclerosis, and Von Hippel-Landau disease.2-4Almost all PCs and PGs secrete, store, or metabolize catecholamines or their metabolites in various amounts and combinations. They arise from chromaffin cells, and presenting symptoms vary according to the amount and type of catecholamines released.

The classic triad of headache, palpitations, and hypertension is present in many patients, but may occur intermittently.4 Other less specific symptoms include lethargy, anxiety, anemia, pallor, abdominal pain, visual disturbances, excessive sweating, weight loss, polydipsia, polyuria, hyperglycemia, and paroxysmal hypertension. Nausea is a more common symptom in children.5Hypertension is more commonly sustained in children (vs paroxysmal attacks) and may be severe, causing cardiomyopathy, encephalopathy, or other neurologic injury. Symptoms may occur intermittently or continuously. They may be increased or worsened by common activities or unrelated surgery.1-6

Twenty-five percent to 50% of deaths in patients with PC occur during anesthesia and surgery, making it important to establish a diagnosis before induction of anesthesia.4,7 The literature describing the presentation and management of PC/PG is sparse in children and tends to be based on case reports. Anesthesiologists typically are involved in these patients’ care in several circumstances: The child may present in crisis or with a new diagnosis; during an unrelated surgery; during the workup for a suspected tumor; during radiological or other “minor” procedures; and when the child presents for curative surgery.

The diagnosis of PC/PG is confirmed by measuring plasma or urine catecholamines.1-5 In children, norepinephrine-secreting tumors are more common than epinephrine-secreting tumors. Urine catecholamines are proportional to circulating levels, so 24-hour urine collections are necessary to help establish diagnosis. Plasma-free metanephrine levels have better sensitivity and specificity, and it is important to use age-specific norms. O-methylated dopamine metabolites can aid in the identification of exclusively dopamine-secreting tumors, which are often asymptomatic.1,8

There is no gold standard on whether plasma or urine samples should be measured, as both have advantages and disadvantages. Use of medications such as tricyclic antidepressants, caffeine, phenoxybenzamine, and a diet of catecholamine-rich foods—such as nuts, cheese, and some fruits—can interfere with plasma levels.

Treatment

The primary goal is to control catecholamine secretion and treat end-organ damage in order to allow the patient to undergo safe surgical resection. Surgical resection is curative in many cases. These patients will often have intravascular volume depletion and abnormal electrolytes, all of which should be normalized before surgery. Glucose metabolism and homeostasis are frequently abnormal and should be monitored closely.8,9

Alpha-blockade: start phenoxybenzamine at 5 mg orally twice a day (0.25 mg/kg/day). Given the long half-life of phenoxybenzamine, the dose should be titrated slowly every 48 to 72 hours until effective alpha-blockade is reached, as evidenced by reduction in symptoms, reduction in BP (20 mm Hg systolic or 10 mm Hg diastolic), or orthostatic changes in heart rate (>15 beats/minute). Once an effective dose is established, this should be continued for 7 to 14 days before surgical resection.

Plasma-free catecholamine levels should be checked to elucidate whether the mass is secreting epinephrine, norepinephrine, dopamine, or some combination.

Common practice in most institutions is to start beta-blockade after adequate alpha-blockade has been established; however, at least 1 institution starts them together and reports no increase in complications.4

Perioperative Management

Be prepared! Avoiding hypertension and hypotension is the main concern in perioperative management of these patients. Each patient will need careful evaluation for preexisting end-organ injury. Despite excellent alpha-blockade before surgery, patients with PC are exquisitely sensitive to vasoactive medications and surgical manipulation. There is no good evidence to support the use of a particular vasoactive agent over another, other than choosing fast-acting medications and ones with which the anesthesiologist is most familiar. Our patient required 2 months to reduce his BP with 40 mg of phenoxybenzamine twice a day. We had clevidipine, esmolol, epinephrine, and vasopressin prepared for his surgical resection.

Key Points

  • Children with PC are often very anxious and will benefit from premedication.
  • Crucial in these cases are good peripheral IV access, a central line for administering vasoactive medications and central volume monitoring, and invasive BP monitoring.9
  • Transesophageal echocardiography (TEE) is very helpful for monitoring preload, contractility, and valvular function, especially in patients with cardiac dysfunction.9
  • Pain and stress can exacerbate cardiovascular instability; consider regional techniques to provide postoperative analgesia.
  • Prepare several vasoactive infusions and bolus doses to both increase and lower BP, as needed.
  • Consider need for blood and blood products transfusion.
  • Blood pressure often plummets after the mass is resected.
  • Blood pressure variations and volatility can continue for any days after resection.
  • Ketamine should be avoided.
  • Close hemodynamic monitoring will be required in the postoperative period.

Resolution of the Case

The child presented for surgical removal of the PC after stabilizing his BP. This patient required 1 lung ventilation, had a central line with a venous oximeter, an arterial line, TEE, 3 peripheral IV lines, and a paravertebral block for postoperative pain. His BP management was challenging; however, he tolerated the operation well, was extubated at the end of the procedure, and recovered in the pediatric ICU. He continued to have anxiety and difficult pain management for se veral days after the surgery. However, on follow-up several months later, he was symptom-free, and according to his mother, a “completely changed boy.”

References

  1. Lenders JW, Duh QY, Eisenhofer G, et al. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(6):1915-1942.
  2. Guo Z, Lloyd RV. Pheochromocytomas and paragangliomas: an update on recent molecular genetic advances and criteria for malignancy. Adv Anat Pathol. 2015;22(5):283-293.
  3. King KS, Pacak K. Familial pheochromocytomas and paragangliomas. Mol Cell Endocrinol. 2014;386(1-2):92-100.
  4. Hack HA. The perioperative management of children with phaeochromocytoma. Paediatr Anaesth. 2000;10(5):463-476.
  5. Martucci VL, Pacak K. Pheochromocytoma and paraganglioma: diagnosis, genetics, management, and treatment. Curr Probl Cancer. 2014;38(1):7-41.
  6. Chen H, Sippel RS, O’Dorisio MS, et al. The North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors: pheochromocytoma, paraganglioma, and medullary thyroid cancer. Pancreas. 2010;39(6):775-783.
  7. Pacak K. Preoperative management of the pheochromocytoma patient. J Clin Endocrinol Metab. 2007;92(11):4069-4079.
  8. Davison AS, Jones DM, Ruthven S, et al. Clinical evaluation and treatment of phaeochromocytoma. Ann Clin Biochem. 2018;55(1):34-48.
  9. Naranjo J, Dodd S, Martin YN. Perioperative management of pheochromocytoma. J Cardiothorac Vasc Anesth. 2017;31(4):1427-1439.