Pheochromocytoma is a catecholamine-secreting tumor that increases the complexity of anesthetic care.1 Sympathomimetics and medications that cause histamine release (such as morphine and atracurium) are known triggers of intraoperative pheochromocytoma crises. Our case underscores the caution one should use during all medication administration and highlights the critical thinking that is a hallmark of anesthetic care. A written HIPAA authorization to use/disclose existing protected health information was obtained.
A 75-year-old woman with medical history of anxiety, gastroesophageal reflux disease, ovarian cysts, and recently diagnosed endometrial adenocarcinoma presented for a robotic-assisted laparoscopic total abdominal hysterectomy and tumor debulking. The surgical plan included a hysterectomy, bilateral salpingectomy, omentectomy, bilateral pelvic lymphadenectomy, and ureterolysis. The patient had previously undergone bilateral oophorectomies for ovarian cysts. Her presurgical evaluation included a transvaginal ultrasound and endometrial biopsy for postmenopausal bleeding. Given her good functional status, she did not require preanesthetic cardiac investigations. The preoperative anesthetic history and physical examination were unremarkable, and preinduction vital signs were a noninvasive blood pressure (NIBP) of 140/70 mm Hg and a pulse rate of 84 beats per minute (bpm).
Intraoperative monitors included NIBP (right upper extremity), pulse oximetry, electrocardiogram, end-tidal (Et) gases, and an esophageal temperature probe. General anesthesia was induced with 100 mg of propofol in 2 divided doses, 100 μg of fentanyl and rocuronium. Direct laryngoscopy and surgical incision led to an abrupt rise in NIBP to 220/125 and 208/110 mm Hg, respectively (Figure 1). During this time, Et sevoflurane was 1.9%. NIBP returned to a baseline of 130/70 mm Hg after increasing the depth of anesthesia and administration of divided fentanyl doses, respectively. Subsequently, the intraoperative hemodynamics was stable on 2% Et sevoflurane, muscle relaxant, and fentanyl. One dose of 10 mg labetalol and 1 dose of 10 mg hydralazine were administered for raised systolic blood pressures to 150 mm Hg. The patient was normothermic, and a mild increase in Et carbon dioxide secondary to insufflation was managed with increasing minute ventilation. Toward the conclusion of the surgery, 10 mL of 1% methylene blue was administered to assess ureteral patency. Within minutes of methylene blue administration, the patient developed acute hypertension to 235/105 mm Hg. Consequently, the anesthesiologist attempted to treat hypertension by increasing the depth of anesthesia (Et Sevoflurane 2.9%) and administering divided doses of labetalol (90 mg) and hydralazine (20 mg) (Figure 2). Heart rate remained between 60 and 70 bpm. The intraoperative differential diagnosis consisted of undiagnosed preexisting hypertension, inadequate depth of anesthesia, surgical stimulation, inadequate analgesia, pneumoperitoneum, hypercarbia, malignant hyperthermia, fluid overload, and an adverse event from methylene blue administration. After completion of the surgery, the patient was emerged and extubated without complications. She received a total of 4 L of crystalloids, 350 μg fentanyl, and 1 mg hydromorphone intraoperatively.
During her 5-hour postanesthetic care unit stay, the patient remained hypertensive with NIBPs of 134–212/58–100 mm Hg and pulse rates ranging from 64 to 108 bpm. She received 2 doses of fentanyl 25 μg and divided doses of antihypertensives totaling 90 mg labetalol, 10 mg metoprolol, and 10 mg hydralazine.
Postoperatively, the patient was admitted to the Surgical Intensive Care Unit for further management of her blood pressure. Overnight, she required 20 mg labetalol, 10 mg hydralazine, and 0.4 mg of hydromorphone. No antihypertensive infusion was required. Our postoperative differential for hypertension included sympathetic response to pain, hypoxia or hypothermia, undiagnosed hypertension, pheochromocytoma, serotonin syndrome, thyroid storm, and bilateral renal artery stenosis. Hypertension as a result of methylene blue was also on our differential. At this time, the patient was alert, awake, and oriented to time, place, and person. She denied headaches, nausea, chest pain, dyspnea, palpitations, and muscular rigidity. A sympathetic response to hypoxia, hypercarbia, hypothermia, or pain was unlikely because she had appropriate oxygenation, ventilation, and acceptable analgesia (4/10 pain on numeric pain scale). Serum thyroid-stimulating hormone levels and urine metanephrines were sent as part of the workup. Her postoperative electrocardiogram showed normal sinus rhythm with atrial premature complexes. Her echocardiogram showed normal biventricular size, thickness, systolic function, and wall motion.
On postoperative day 1, the NIBP decreased to 109–164/40–71 mm Hg after hydralazine 10 mg and hydromorphone 2.2 mg, and the patient was transferred to the floor. On postoperative day 2, her NIBP was within 20% of her baseline, no further antihypertensive medications were required, and she was discharged home with close follow-up. Her 24-hour total urine metanephrines were found to be raised at 20,708 µg per 24 hours (normal 224–832 µg/24 hours). She was subsequently followed by an endocrinologist with repeat total urine metanephrines raised at 5164 µg per 24 hours and a computed tomography abdominal scan significant for a 3.1 × 3.7 cm right adrenal mass (Figure 3). Five months after her initial surgery and after adequate medical optimization of her pheochromocytoma, the patient underwent uncomplicated right adrenalectomy with surgical pathology confirming 3.5 cm pheochromocytoma with an unremarkable adrenal cortex. Further genetic testing looking for hereditary cancer syndromes was negative.
Hypertension is anticipated and commonly encountered in the perioperative period. Our differential consisted of preexisting hypertension and sympathetic stimulation in the setting of surgical manipulation, hypercarbia, hypoxia, and inadequate depth of anesthesia/analgesia. A broader differential would further include raised intracranial pressure, cerebrovascular accident, pheochromocytoma, thyroid storm, malignant hyperthermia, bilateral renal artery stenosis, and serotonin syndrome. Inadequate inhibition of the sympathetic nervous system is the most probable explanation for the abrupt rise in blood pressure during direct laryngoscopy and surgical incision. Both these episodes were controlled with increasing depth of anesthesia. This is in contrast to the third episode of hypertension that was not associated with a noxious stimulus, was abrupt, and persisted into the postoperative period. While surgical stimulation and pneumoperitoneum could explain the hypertension, they fail to explain why raised blood pressures continued postoperatively. The patient’s 3500 mL positive fluid balance and steep Trendelenburg positioning could have contributed, but are unlikely to have been the sole cause of abrupt and sustained hypertension. Cerebrovascular accident and raised intracranial pressure were unlikely because our patient was successfully extubated, was alert, oriented, and had no headaches, vomiting, or focal neurological deficits. Malignant hyperthermia was thought unlikely because the patient was normothermic, did not have muscular rigidity, and had a manageable rise in Etco2 that resolved after completion of abdominal insufflation. Most of the intra-abdominal surgical resection had been completed by the time of methylene blue administration, although we cannot say with certainty if there was direct surgical manipulation of the tumor coinciding with methylene blue administration.
Our patient’s perioperative hypertension was temporally associated with the administration of methylene blue, and we therefore evaluated whether methylene blue could have triggered a pheochromocytoma crisis. Methylene blue is a potent vasoconstrictor, and literature supports its use in refractory vasoplegic shock.2 It decreases cyclic guanosine monophosphate levels within vascular smooth muscle, which in turn increases intracellular calcium concentrations and vasoconstriction. Moreover, methylene blue is a monoamine oxidase inhibitor (MAOI) and has been known to cause serotonin syndrome when administered to a patient on other MAOIs.3–6 Our patient did not have hyperthermia, neuromuscular signs, or selective serotonin reuptake inhibitor/tricyclic antidepressant use. Hence, methylene blue–associated serotonin syndrome is an unlikely etiology. Perhaps methylene blue’s MAOI properties triggered a hypertensive crisis secondary to high circulatory catecholamines in this patient with pheochromocytoma. The dose of 100 mg of methylene blue that our 61-kg patient received is in line with the 1.5–2 mg/kg dosing used in vasoplegia. Refractory hypertension in our case lasted around 40 minutes, which is comparable to the plasma pharmacokinetics of methylene blue in previous literature.7 This is the first case of an association between methylene blue and hypertensive urgency in a patient with pheochromocytoma on our literature search.
The perioperative management of a patient with undiagnosed pheochromocytoma is challenging with a reported 80% mortality rate in an extensive review of 50 patients from 1985.1,8 Even with advances in medicine, undiagnosed pheochromocytoma resulted in perioperative deaths during a hysterectomy and cesarean delivery in 2007 and 2011, respectively.9,10 With the introduction of preoperative α-adrenergic blockade, operative mortality and cardiovascular instability have declined substantially.11 β-Adrenergic blockade without adequate α-blockade is known to cause hypertensive crises because of unrestricted α-receptor–mediated vasoconstriction.12,13 Labetalol, a nonselective β-blocker, has 7:1 β-blockade to α-blockade properties and has been used safely in pheochromocytoma patients.14,15 For our patient, the underlying pheochromocytoma was undiagnosed, and divided doses of labetalol and hydralazine were used throughout her perioperative care. Our patient’s NIBP did respond to successive labetalol dosages, perhaps because of downregulation of α-receptors from longstanding circulating catecholamines or because the α-blockade provided by labetalol was sufficient to inhibit vasoconstriction. It is unlikely that the persistent hypertension was a result of unrestricted α-adrenergic vasoconstriction (even though labetalol is a nonselective β-blocker) because our patient’s NIBP responded to divided doses of labetalol.
The intraoperative administration of methylene blue and subsequent persistent hypertension led to the discovery of a previously undiagnosed pheochromocytoma in our patient. This case as a whole highlights the importance of vigilance during medication administration and underscores the need for perioperative critical thinking.
Garrett Sendlewski, BFA, from Yale Anesthesiology Media Lab, Yale University School of Medicine, New Haven, Connecticut, helped to create the figures in this manuscript.
Name: Shikha Shukla, MBBS.
Contribution: This author helped prepare and edit the manuscript.
Name: Richard Zhu, MD.
Contribution: This author helped prepare the manuscript.
Name: Philip Rubin, MD.
Contribution: This author helped prepare the manuscript.
Name: Ranjit Deshpande, MBBS.
Contribution: This author helped prepare and edit the manuscript.
This manuscript was handled by: Kent H. Rehfeldt, MD.
1. Myklejord DJ. Undiagnosed pheochromocytoma: the anesthesiologist nightmare. Clin Med Res. 2004;2:59–62.
2. Del Duca D, Sheth SS, Clarke AE, Lachapelle KJ, Ergina PL. Use of methylene blue for catecholamine-refractory vasoplegia from protamine and aprotinin. Ann Thorac Surg. 2009;87:640–642.
3. Francescangeli J, Vaida S, Bonavia AS. Perioperative diagnosis and treatment of serotonin syndrome following administration of methylene blue. Am J Case Rep. 2016;17:347–351.
4. Hencken L, To L, Ly N, Morgan JA. Serotonin syndrome following methylene blue administration for vasoplegic syndrome. J Card Surg. 2016;31:208–210.
5. Top WM, Gillman PK, de Langen CJ, Kooy A. Fatal methylene blue associated serotonin toxicity. Neth J Med. 2014;72:179–181.
6. Schick PK, Yu BP. Methylene blue-induced serotonin release in human platelets. J Lab Clin Med. 1973;82:546–553.
7. Evora PR, Ribeiro PJ, Vicente WV, et al. Methylene blue for vasoplegic syndrome treatment in heart surgery: fifteen years of questions, answers, doubts and certainties. Rev Bras Cir Cardiovasc. 2009;24:279–288.
8. Sellevold OF, Raeder J, Stenseth R. Undiagnosed phaeochromocytoma in the perioperative period. Case reports. Acta Anaesthesiol Scand. 1985;29:474–479.
9. Dabbous A, Siddik-Sayyid S, Baraka A. Catastrophic hemodynamic changes in a patient with undiagnosed pheochromocytoma undergoing abdominal hysterectomy. Anesth Analg. 2007;104:223–224.
10. Kuok CH, Yen CR, Huang CS, Ko YP, Tsai PS. Cardiovascular collapse after labetalol for hypertensive crisis in an undiagnosed pheochromocytoma during cesarean section. Acta Anaesthesiol Taiwan. 2011;49:69–71.
11. Roizen MF, Hunt TK, Beaupre PN, et al. The effect of alpha-adrenergic blockade on cardiac performance and tissue oxygen delivery during excision of pheochromocytoma. Surgery. 1983;94:941–945.
12. Mannelli M. Management and treatment of pheochromocytomas and paragangliomas. Ann N Y Acad Sci. 2006;1073:405–416.
13. Pacak K. Preoperative management of the pheochromocytoma patient. J Clin Endocrinol Metab. 2007;92:4069–4079.
14. Van Stratum M, Levarlet M, Lambilliotte JP, Lignian H, de Rood M. Use of labetalol during anesthesia for pheochromocytoma removal. Acta Anaesthesiol Belg. 1983;34:233–240.
15. Bailey RR. Labetalol in the treatment of a patient with phaechromocytoma: a case report. Br J Clin Pharmacol. 1979;8suppl 2141S–142S.