Pheochromocytomas are tumors arising from catecholamine producing chromaffin cells in the adrenal medulla (1). They almost always produce, store, metabolize and secrete catecholamines. Currently the only way to cure pheochromocytoma is its surgical removal. Roux and Mayo were the first to remove pheochromocytoma in 1926 and 1927, respectively (2). Unfortunately, due to the lack of understanding of pathophysiology of catecholamine secreting tumors and no antihypertensive medication adrenalectomy for pheochromocytoma was associated with extremely high mortality exceeding 50% (2). Only in 1956 priestly used alpha-blockers perioperatively which resulted in dramatic reduction in postoperative mortality (3). In 1996 Gagner et al. published a series of laparoscopic cases showing that minimally invasive access is safe and feasible (4). Over the last two decades adrenal gland surgery has transformed, so that laparoscopic access has become the gold standard in the surgical treatment of adrenal tumors, including pheochromocytomas (5,6). The advances in operative technique and perioperative management have lowered mortality rates to 0–3% with complications occurring in 5% to 22% of patients (4,7-9). Although these numbers are now relatively low, perioperative hemodynamic instability still remains the biggest surgical and anesthetic challenge which apart from intraoperative bleeding is responsible for serious adverse events. The aim of this review was to discuss pre-, intra- and postoperative factors that may impact on hemodynamic condition of a patient.
Currently the gold standard in the assessment of adrenals before surgery includes imaging studies (computed tomography, magnetic resonance, 131I-MIBG scintigraphy) (10,11). Additionally, hormonal activity of each tumor has to be evaluated. In case of pheochromocytoma urine or plasma catecholamines and metanephrines levels are routinely used. Vanillylmandelic acid, although very specific for pheochromocytoma (95%) is characterized by rather low sensitivity (65%) (12). Both the size of the tumor and degree of catecholamines production correlates strongly with intraoperative hypertension (13). It is generally accepted that every patient with suspected pheochromocytoma requires appropriate preoperative optimization with antihypertensive drugs and blood volume expansion fluids. These precautions should be taken in every patient irrespective of clinical symptoms because undiagnosed pheochromocytoma or inadequately prepared patient may develop hypertensive crisis. In this situation mortality is close to 80% (14). In 1982 Roizen published a paper describing so-called Roizen criteria for adequate preoperative patient optimization with antihypertensive drugs (15). They include:
- No in-hospital blood pressure >160/90 mmHg for 24 h prior to surgery;
- No orthostatic hypotension with blood pressure <80/45 mmHg;
- No ST or T wave changes for 1-week prior to surgery;
- No more than five premature ventricular contractions per minute.
The most commonly used drug for patients’ preparation is phenoxybenzamine (irreversible, noncompetitive, alpha-blocker) (16,17). The initial therapy is introduced 10–14 days prior to surgery. The initial dose of phenoxybenzamine is 10 mg twice a day and is gradually increased until the clinical symptoms are controlled or side effects appear (usually the total daily dose is 1 mg/k/d). Phenoxybenzamine can be administered intravenously or orally and the dose is increased every 48 hours (16,18). There are alternative α-adrenoreceptor blockers such as: prazosin, terazosin and doxazosin. Although according to some studies they can be as effective as phenoxybenzamine, other studies did not support these conclusions (13,17). Moreover, in patients with coexisting tachyarrhythmia beta-blockers may be necessary. Currently, cardioselective beta1-blockers are preferred (metoprolol, atenolol) (18). In summary, appropriate preoperative alpha or/and beta-blockade allows significant reduction in cardiovascular morbidity and mortality as demonstrated by Goldstein et al. from 69% to 3% (19).
Although less effective, calcium channel blockers (amlodipine, nicardipine, nifedipine) are sometimes used as an alternative to alpha-blockers (16,18). However, they are mostly combined with the latter in patients with uncontrolled hypertension despite alpha-blockade or as an alternative in patients with severe side-effects (18). In some hospitals they are also used as primary preoperative agent in normotensive patients with pheochromocytoma (7). Moreover, in some institutions catecholamine synthesis blockers are sometimes introduced (alpha-Methyl-L-tyrosine or metyrosine) (20-22). It significantly lowers the level of serum catecholamines (23). Although it has been shown to provide satisfactory results in blood pressure control preoperatively as well as intraoperatively (especially during induction of anesthesia or manipulation of the tumor when the most prominent catecholamines secretion occurs), its use is rather uncommon and reserved for patients with metastatic disease or as a combination with other alpha-blockers (21,22,24). According to previously published studies such combination allows better blood pressure stabilization, reduced intraoperative blood loss and volume replacement during surgery compared to alpha-blockers alone (21,22).
Interestingly, there are studies showing that preoperative medication seems unnecessary in case of pheochromocytoma. For instance, Boutros et al. basing on 63 cases suggested that pheochromocytoma patients can undergo successful surgery without preoperative alpha adrenergic blockade (25). Similar conclusions were drawn by Desmonts et al. (26). However, these results must be interpreted with caution. They comprise relatively small groups of patients with not entirely clear pre- and intraoperative anesthetic protocol, which does not allow drawing unequivocal conclusions.
Preoperative intravenous fluid administration before adrenalectomy for pheochromocytoma still remains the major dogma. In 1954 Thompson reported improved outcomes after whole blood transfusions at the level greater than estimated intraoperative blood loss (27). However, the surgery for pheochromocytoma at that time was associated with massive blood loss due to inadequate alpha-blockade and open approach. Later, Ulchaker reported zero mortality after 127 consecutive adrenalectomies in patients receiving intraoperatively large volumes of crystalloids and colloids (7). On the contrary, Gosse limited the amount of preoperatively administered fluids to 2,000 mL with satisfactory results (28). Moreover, Lebuffe et al. and Lentschener et al. transfused fluids intraoperatively only when blood pressure dropped during surgery (29,30). They did not report deaths related to hemodynamic instability. According to the most recent observations preoperative intravenous fluid administration is not supported by any evidence-based study and does not improve outcomes in adrenalectomy for pheochromocytoma (17).
As already mentioned surgery remains the only possible way to cure pheochromocytoma. The anesthetic protocol in this type of tumor has been previously extensively studied and it can be found elsewhere (16,31). There are several steps during surgery that are directly associated with sudden increase in blood pressure. They comprise changing the patient’s position on the operating table; induction of general anesthesia and intubation; intraabdominal pressure changes (associated with cough, light sedation, and insufficient relaxation or initiation of mechanical ventilation); creation of pneumoperitoneum or when the tumor is directly manipulated (32-35). According to current recommendations laparoscopic or retroperitoneoscopic approach should be preferred since it has been shown to be safe also in cases of pheochromocytoma (6). Like in other surgical disciplines minimally invasive adrenalectomy is associated with reduced pain, decreased blood loss, faster recovery and shortened length of stay (36-39). Although it is generally accepted that tumors smaller than 6 cm are most suitable for laparoscopic removal, it has been shown feasible also in cases of bigger lesions (40). There are several studies documenting the use of robotic surgery in adrenal glands pathology. Although it is associated with additional costs the intraoperative blood loss and length of stay may be reduced comparing classical laparoscopy (41-44). Importantly, pheochromocytomas may also carry a malignant potential. We have demonstrated that laparoscopic access can be used also in cases of potentially malignant pheochromocytomas (PASS scale >6) and is not associated with inferior long-term outcomes (45). However, our observations suggest that surgery for pheochromocytoma is more difficult than for other adrenal tumors (46). Although the operative time was longer and blood loss was higher, complication rates remained unchanged. A study by Parnaby et al. showed that laparoscopic adrenalectomy for pheochromocytoma was indeed associated with increased episodes of severe intraoperative hypertension (SBP >200–220 mmHg) when compared to the laparoscopic resection of other adrenal tumors (47). Interestingly, a creation of peritoneum has been shown to increase catecholamines release which may result in hemodynamic instability (35,48,49). Moreover, case control studies confirmed that in terms of hemodynamic instability laparoscopic approach is equal to open procedure (50,51). Moreover, a study by Kiernan et al. demonstrated that after open surgery the risk of increased number of episodes of systolic blood pressure >200 mmHg was 27 times higher comparing to laparoscopy (52). Minimally invasive surgery requires gentle, meticulous dissection. Otherwise uncontrolled bleeding precludes good visualization of proper surgical planes. This fits in perfectly with the principles of pheochromocytoma surgery that require minimal tumor manipulation to avoid excessive catecholamines release. On one hand increased levels of catecholamines result in the increase of blood pressure, on the other early adrenal vein ligation decreases their releasing into systemic circulation leading to sudden hypotension. Therefore, the anesthetist must be alerted and fully cooperate with the surgeon.
A large number of patients require vasopressor agents in the early period after tumor removal. The explanation of this phenomenon is on one hand high concentration of antihypertensive drugs, relatively low volume of circulating blood due to chronic vasospasm caused by catecholamines and their sudden decrease after surgery (13,48,52,53). Moreover, an association between down-regulation of alpha- and beta-adrenergic receptors caused by catecholamines and postoperative hypotension was observed (54,55). The rate of persistent postoperative hypotension varies between 30% and 60% and so far few studies focused on its risk factors (53,56-59). It has been shown that tumor size and preoperative levels of catecholamines (which correlate with tumor size) were associated with postoperative hemodynamic instability (53). According to Kiernan et al. the need for vasopressors was significantly higher after open procedures in univariate analysis (52). It was not confirmed in a multivariate model when the size of the tumor was additionally taken into consideration. Obviously open procedure is more often used in larger tumors, which are more hormonally active. Therefore, it is difficult to clearly answer the question whether it is really the type of surgery or the size of the tumor which in fact results in increased risk of hypotension after open procedure. On the contrary the study of Parnaby et al. comparing postoperative outcomes after laparoscopic adrenalectomy for pheochromocytoma vs. other tumors did not show any differences between groups (47). Although it may suggest that prolonged hypotension may occur irrespective of hormonal status of the tumor, the study groups were small which does not allow explicit conclusions. In summary, the postoperative hypotension occurs relatively often after pheochromocytoma removal and may require postoperative use of vasopressors. It is strongly associated with tumor size and overproduction of catecholamines.
In conclusion, hemodynamic instability is one of the most commonly diagnosed adverse events in patients undergoing laparoscopic adrenalectomy for pheochromocytoma. Although it occurs mostly during surgery, a significant proportion of patients require vasopressor agents also in the postoperative period. There are several risk factors associated with increased incidence of hemodynamic instability. They are directly related to the tumor size and its hormonal activity. Appropriate preoperative assessment and treatment with antihypertensive drugs significantly reduces the incidence of hemodynamic changes during and after surgery, thus minimizing serious complications and mortality. Moreover, operative factors seem to play crucial role. Meticulous dissection and gentle and minimal tumor manipulation and early adrenal vein ligation lower their incidence. Laparoscopy in the case of pheochromocytoma is safe and feasible. It is not associated with higher risk of hemodynamic instability. Such approach does not carry additional risk also in larger tumors. To minimize morbidity and mortality a close cooperation between the surgeon and anesthetist is mandatory in every patient with suspected or confirmed pheochromocytoma.
Conflicts of Interest: The authors have no conflicts of interest to declare.
- DeLellis RA, International Agency for Research on Cancer, World Health Organization. Pathology and Genetics of Tumours of Endocrine Organs. 3rd Edition. Lyon: IARC Press, 2004.
- Welbourn RB. The History of Endocrine Surgery. New York: Greenwood Publishing Group, 1990.
- Kvale WF, Manger WM, Priestley JT, et al. Pheochromocytoma. Circulation 1956;14:622-30. [Crossref] [PubMed]
- Gagner M, Breton G, Pharand D, et al. Is laparoscopic adrenalectomy indicated for pheochromocytomas? Surgery 1996;120:1076-9; discussion 1079-80. [Crossref] [PubMed]
- Smith CD, Weber CJ, Amerson JR. Laparoscopic adrenalectomy: new gold standard. World J Surg 1999;23:389-96. [Crossref] [PubMed]
- Stefanidis D, Goldfarb M, Kercher KW, et al. SAGES guidelines for minimally invasive treatment of adrenal pathology. Surg Endosc 2013;27:3960-80. [Crossref] [PubMed]
- Ulchaker JC, Goldfarb DA, Bravo EL, et al. Successful outcomes in pheochromocytoma surgery in the modern era. J Urol 1999;161:764-7. [Crossref] [PubMed]
- van Heerden JA, Sheps SG, Hamberger B, et al. Pheochromocytoma: current status and changing trends. Surgery 1982;91:367-73. [PubMed]
- Pędziwiatr M, Natkaniec M, Kisialeuski M, et al. Adrenal incidentalomas: should we operate on small tumors in the era of laparoscopy? Int J Endocrinol 2014;2014:658483.
- McDermott S, McCarthy CJ, Blake MA. Images of pheochromocytoma in adrenal glands. Gland Surg 2015;4:350-8. [PubMed]
- Witteles RM, Kaplan EL, Roizen MF. Sensitivity of diagnostic and localization tests for pheochromocytoma in clinical practice. Arch Intern Med 2000;160:2521-4. [Crossref] [PubMed]
- Lenders JW, Pacak K, Walther MM, et al. Biochemical diagnosis of pheochromocytoma: which test is best? JAMA 2002;287:1427-34. [Crossref] [PubMed]
- Bruynzeel H, Feelders RA, Groenland TH, et al. Risk Factors for Hemodynamic Instability during Surgery for Pheochromocytoma. J Clin Endocrinol Metab 2010;95:678-85. [Crossref] [PubMed]
- Myklejord DJ. Undiagnosed pheochromocytoma: the anesthesiologist nightmare. Clin Med Res 2004;2:59-62. [Crossref] [PubMed]
- Roizen MF, Horrigan RW, Koike M, et al. A prospective randomized trial of four anesthetic techniques for resection of pheochromocytoma. Anesthesiology 1982;57:A43. [Crossref]
- Ramakrishna H. Pheochromocytoma resection: Current concepts in anesthetic management. J Anaesthesiol Clin Pharmacol 2015;31:317-23. [Crossref] [PubMed]
- Lentschener C, Gaujoux S, Tesniere A, et al. Point of controversy: perioperative care of patients undergoing pheochromocytoma removal-time for a reappraisal? Eur J Endocrinol 2011;165:365-73. [Crossref] [PubMed]
- Pacak K. Preoperative management of the pheochromocytoma patient. J Clin Endocrinol Metab 2007;92:4069-79. [Crossref] [PubMed]
- Goldstein RE, O'Neill JA Jr, Holcomb GW 3rd, et al. Clinical experience over 48 years with pheochromocytoma. Ann Surg 1999;229:755-64; discussion 764-6. [Crossref] [PubMed]
- Malchoff CD, MacGillivray D, Shichman S. Pheochromocytoma treatment. In: Mansoor GA. editor. Secondary Hypertension. Totowa, NJ: Humana Press, 2004:235-49.
- Steinsapir J, Carr AA, Prisant LM, et al. Metyrosine and pheochromocytoma. Arch Intern Med 1997;157:901-6. [Crossref] [PubMed]
- Perry RR, Keiser HR, Norton JA, et al. Surgical management of pheochromocytoma with the use of metyrosine. Ann Surg 1990;212:621-8. [Crossref] [PubMed]
- Brogden RN, Heel RC, Speight TM, et al. alpha-Methyl-p-tyrosine: a review of its pharmacology and clinical use. Drugs 1981;21:81-9. [Crossref] [PubMed]
- Kuchel O, Buu NT, Edwards DJ. Alternative catecholamine pathways after tyrosine hydroxylase inhibition in malignant pheochromocytoma. J Lab Clin Med 1990;115:449-53. [PubMed]
- Boutros AR, Bravo EL, Zanettin G, et al. Perioperative management of 63 patients with pheochromocytoma. Cleve Clin J Med 1990;57:613-7. [Crossref] [PubMed]
- Desmonts JM, Marty J. Anaesthetic management of patients with phaeochromocytoma. Br J Anaesth 1984;56:781-9. [Crossref] [PubMed]
- Thompson JE, Arrowood JG. Pheochromocytoma; surgical and anesthetic management. Anesthesiology 1954;15:658-65. [Crossref] [PubMed]
- Gosse P, Tauzin-Fin P, Sesay MB, et al. Preparation for surgery of phaeochromocytoma by blockade of alpha-adrenergic receptors with urapidil: what dose? J Hum Hypertens 2009;23:605-9. [Crossref] [PubMed]
- Lebuffe G, Dosseh ED, Tek G, et al. The effect of calcium channel blockers on outcome following the surgical treatment of phaeochromocytomas and paragangliomas. Anaesthesia 2005;60:439-44. [Crossref] [PubMed]
- Lentschener C, Gaujoux S, Thillois JM, et al. Increased arterial pressure is not predictive of haemodynamic instability in patients undergoing adrenalectomy for phaeochromocytoma. Acta Anaesthesiol Scand 2009;53:522-7. [Crossref] [PubMed]
- Ahmed J, Khan S, Gatt M, et al. Compliance with enhanced recovery programmes in elective colorectal surgery. Br J Surg 2010;97:754-8. [Crossref] [PubMed]
- Prys-Roberts C, Farndon JR. Efficacy and safety of doxazosin for perioperative management of patients with pheochromocytoma. World J Surg 2002;26:1037-42. [Crossref] [PubMed]
- Ross EJ, Prichard BN, Kaufman L, et al. Preoperative and operative management of patients with phaeochromocytoma. Br Med J 1967;1:191-8. [Crossref] [PubMed]
- Oliva R, Angelos P, Kaplan E, et al. Pheochromocytoma in pregnancy: a case series and review. Hypertension 2010;55:600-6. [Crossref] [PubMed]
- Joris JL, Hamoir EE, Hartstein GM, et al. Hemodynamic changes and catecholamine release during laparoscopic adrenalectomy for pheochromocytoma. Anesth Analg 1999;88:16-21. [PubMed]
- Okoh AK, Berber E. Laparoscopic and robotic adrenal surgery: transperitoneal approach. Gland Surg 2015;4:435-41. [PubMed]
- Pędziwiatr M, Wierdak M, Ostachowski M, et al. Single center outcomes of laparoscopic transperitoneal lateral adrenalectomy--Lessons learned after 500 cases: A retrospective cohort study. Int J Surg 2015;20:88-94. [Crossref] [PubMed]
- Assalia A, Gagner M. Laparoscopic adrenalectomy. Br J Surg 2004;91:1259-74. [Crossref] [PubMed]
- Gumbs AA, Gagner M. Laparoscopic adrenalectomy. Best Pract Res Clin Endocrinol Metab 2006;20:483-99. [Crossref] [PubMed]
- Natkaniec M, Pędziwiatr M, Wierdak M, et al. Laparoscopic Transperitoneal Lateral Adrenalectomy for Large Adrenal Tumors. Urol Int 2016;97:165-72. [Crossref] [PubMed]
- Pahwa M. Robot assisted adrenalectomy: a handy tool or glorified obsession? Gland Surg 2015;4:279-82. [PubMed]
- Ball MW, Allaf ME. Robotic adrenalectomy: the jury is still out. Gland Surg 2015;4:277-8. [PubMed]
- Nigri G, Rosman AS, Petrucciani N, et al. Meta-analysis of trials comparing laparoscopic transperitoneal and retroperitoneal adrenalectomy. Surgery 2013;153:111-9. [Crossref] [PubMed]
- Brandao LF, Autorino R, Laydner H, et al. Robotic versus laparoscopic adrenalectomy: a systematic review and meta-analysis. Eur Urol 2014;65:1154-61. [Crossref] [PubMed]
- Pędziwiatr M, Wierdak M, Natkaniec M, et al. Laparoscopic transperitoneal lateral adrenalectomy for malignant and potentially malignant adrenal tumours. BMC Surg 2015;15:101. [Crossref] [PubMed]
- Natkaniec M, Pędziwiatr M, Wierdak M, et al. Laparoscopic adrenalectomy for pheochromocytoma is more difficult compared to other adrenal tumors. Wideochir Inne Tech Maloinwazyjne 2015;10:466-71. [Crossref] [PubMed]
- Parnaby CN, Serpell MG, Connell JM, et al. Perioperative haemodynamic changes in patients undergoing laparoscopic adrenalectomy for phaeochromocytomas and other adrenal tumours. Surgeon 2010;8:9-14. [Crossref] [PubMed]
- Kinney MA, Warner ME, vanHeerden JA, et al. Perianesthetic risks and outcomes of pheochromocytoma and paraganglioma resection. Anesth Analg 2000;91:1118-23. [PubMed]
- Tauzin-Fin P, Sesay M, Gosse P, et al. Effects of perioperative alpha1 block on haemodynamic control during laparoscopic surgery for phaeochromocytoma. Br J Anaesth 2004;92:512-7. [Crossref] [PubMed]
- Möbius E, Nies C, Rothmund M. Surgical treatment of pheochromocytomas: laparoscopic or conventional? Surg Endosc 1999;13:35-9. [Crossref] [PubMed]
- Vargas HI, Kavoussi LR, Bartlett DL, et al. Laparoscopic adrenalectomy: a new standard of care. Urology 1997;49:673-8. [Crossref] [PubMed]
- Kiernan CM, Du L, Chen X, et al. Predictors of hemodynamic instability during surgery for pheochromocytoma. Ann Surg Oncol 2014;21:3865-71. [Crossref] [PubMed]
- Namekawa T, Utsumi T, Kawamura K, et al. Clinical predictors of prolonged postresection hypotension after laparoscopic adrenalectomy for pheochromocytoma. Surgery 2016;159:763-70. [Crossref] [PubMed]
- Malhotra SK, Ramprabu K, Dutta A, et al. An unusual cause of respiratory distress and hypotension following removal of a pheochromocytoma. Can J Anaesth 2002;49:1099-100. [Crossref] [PubMed]
- Streeten DH, Anderson GH Jr. Mechanisms of orthostatic hypotension and tachycardia in patients with pheochromocytoma. Am J Hypertens 1996;9:760-9. [Crossref] [PubMed]
- Gagner M, Lacroix A, Bolté E. Laparoscopic adrenalectomy in Cushing's syndrome and pheochromocytoma. N Engl J Med 1992;327:1033. [Crossref] [PubMed]
- Kercher KW, Park A, Matthews BD, et al. Laparoscopic adrenalectomy for pheochromocytoma. Surg Endosc 2002;16:100-2. [Crossref] [PubMed]
- Sprung J, O'Hara JF Jr, Gill IS, et al. Anesthetic aspects of laparoscopic and open adrenalectomy for pheochromocytoma. Urology 2000;55:339-43. [Crossref] [PubMed]
- Kasahara T, Nishiyama T, Takahashi K. Laparoscopic adrenalectomy for pheochromocytoma: evaluation of experience and strategy at a single institute. BJU Int 2009;103:218-22. [Crossref] [PubMed]