Abstract
Objectives: To determine the incidence and preoperative risk factors of post-excisional hypoglycemia in patients undergoing pheochromocytoma resection. Methods: Patients who underwent surgical resection of pheochromocytoma at a single institution were retrospectively enrolled in the present study. The primary end-point was the development of post-excisional hypoglycemia; that is, a serum glucose level <70 mg/dL. The serum levels of immunoreactive insulin and glucose levels during the preoperative oral glucose-tolerance test and surgery were analyzed to elucidate the mechanism of hypoglycemia.
Results: A total of 49 patients underwent surgical resection of pheochromocytoma, of which 21 patients (43%) developed post-excisional hypoglycemia. The incidence of hypoglycemia was not statistically different between patients with adrenal tumors and those with extra-adrenal tumors (18/41 [44%] vs 3/8 [38%], respectively, P = 0.73). There was no difference in the immunoreactive insulin/glucose ratio during the preoperative oral glucosetolerance test between patients with and those without post-excisional hypoglycemia. The intraoperative immunoreactive insulin/glucose ratio was significantly higher in patients with hypoglycemia than in those without hypoglycemia. A higher 24-h urinary epinephrine level, but not norepinephrine level, was a predictive factor for post-excisional hypoglycemia. Conclusions: Post-excisional hypoglycemia is a frequent complication of pheochromocytoma resection, irrespective of the tumor location, and might be common in patients with epinephrine-predominant tumors. All patients undergoing resection of adrenal and extra-adrenal pheochromocytoma require intensive monitoring of serum glucose levels during and after surgery.
Introduction
Pheochromocytoma is a rare, catecholamine-secreting neuroendocrine tumor originating from chromaffin cells in the adrenal medulla. The definitive therapy for pheochromocytoma is surgical resection; however, removal of the tumor often leads to hypotensive shock as a result of the sudden withdrawal of serum catecholamines. Post-excisional hypotensive shock has been well documented, and its management with catecholamine supplementation is well established.
Post-excisional hypoglycemia can develop postoperatively in patients who undergo pheochromocytoma resection, and typically presents with excessive drowsiness; thus, its early detection is difficult because of the prolonged effect of anesthesia. A proposed mechanism of post-excisional hypoglycemia is excessive rebound secretion of insulin as a result of pheochromocytoma resection, 1 which can be monitored by the ratio of serum IRI to serum glucose levels. 2 Although hypoglycemia can cause severe neurological complications if not detected promptly, only a few small retrospective studies have addressed its occurrence in patients with pheochromocytoma. 3, 4 The present study aimed to determine the incidence of post-excisional hypoglycemia in patients who underwent pheochromocytoma resection in order to evaluate its preoperative predictive factors and analyze the association between the perioperative IRI/glucose ratio and post-excisional hypoglycemia development.
Methods
The present single-center retrospective observational study was carried out at the Tokyo Medical and Dental University with the approval of the institutional review board (approval number: M2018-026). All participants were informed about the retrospective nature of this study during their regular follow-up visit, but written formal consent was not obtained. A total of 50 patients who underwent surgical resection of adrenal or extraadrenal pheochromocytoma between June 2010 and November 2017 were retrospectively enrolled.
Evaluation of glucose tolerance was included in the preoperative examination of pheochromocytoma. A total of 43 patients underwent an OGTT preoperatively. Based on the OGTT results, glucose tolerance was categorized according to the 2006 World Health Organization diagnostic criteria for diabetes as: (i) DM; (ii) prediabetes comprising impaired glucose tolerance and impaired fasting glucose; and (iii) normal glucose tolerance. 5 Six patients did not undergo OGTT and were categorized into the DM group owing to a definitive diagnosis of severe DM.
All operations were open procedures. All patients received continuous infusion of solutions containing 2.5-7.5% glucose postoperatively. If the presence of post-excisional hypoglycemia was confirmed, patients immediately received a bolus infusion of 50% glucose solution, followed by continuous glucose administration.
Considering the possible severe neurological consequences of unrecognized hypoglycemia, as a clinical practice, we frequently monitored the serum glucose and IRI levels during the perioperative period irrespective of the clinical symptoms. As IRI data for seven of 49 patients were missing, analysis of the serum glucose and IRI levels was carried out for the remaining 42 patients. The glucose and IRI data at the following time points were retrospectively analyzed: start of surgery; during tumor manipulation; and 5 min, 1 h, 2 h and 3 h after tumor resection.
Data on patient demographics, tumor characteristics, preoperative hormonal tests, operative details and postoperative outcomes were analyzed. The primary end-point was the development of postoperative hypoglycemia (serum glucose level <70 mg/dL) or imperative glucose administration as a result of neurogenic manifestations caused by a sudden drop in the serum glucose level. Fisher's exact test and the Wilcoxon test were used to compare categorical and continuous variables, respectively. Logistic regression analysis was used to identify predictive factors for the development of postexcisional hypoglycemia. A P-value <0.05 was considered statistically significant. All statistical analyses were performed using JMP 13 (SAS Institute, Cary, NC, USA).
Results
Of the 50 patients enrolled in the present study, one patient was excluded because his post-excisional serum glucose levels were not consistently monitored. The final study cohort comprised 49 patients. The patient and tumor characteristics, and results of preoperative hormonal tests are summarized in Table 1 . The mean age at the time of surgery was 48 years (range 16-77 years), and 28 (57%) patients were women. A total of 28 (57%) patients had symptoms attributable to excessive serum catecholamines, and 11 (22%) were diagnosed with DM. A total of 41 (84%) patients had adrenal pheochromocytomas, seven (14%) had retroperitoneal extraadrenal tumors and one (2%) had a bladder tumor. An alphaadrenergic antagonist was given preoperatively in 47 (96%) patients, and all patients were given doxazosin (median dose 12 mg/day). A total of 10 (20%) patients were categorized into the DM group, 21 (43%) into the prediabetes group and 18 (37%) into the normal glucose tolerance group.
Intraoperative sequential monitoring of serum glucose levels showed that the median serum glucose level increased up to 193 mg/dL (range 95-409 mg/dL) during tumor manipulation, and subsequently reduced to 106 mg/dL (range 38-208 mg/dL) 2 h after tumor resection. A total of 21 (43%) patients experienced post-excisional hypoglycemia, and six (12%) patients developed severe hypoglycemia with nadir serum glucose level <50 mg/dL. Hypoglycemia was diagnosed at 60 min after resection in two patients, at 90 min in four patients, at 120 min in five patients, at 180 min in four patients, at 240 min in five patients and at 360 min in one patient. The median time from tumor resection to hypoglycemia development was 150 min (range 60-360 min).
Despite glucose infusion therapy after the diagnosis of post-excisional hypoglycemia, nine (43%) of the 21 patients with an initial episode of hypoglycemia developed a second episode at 4-14 h after tumor resection, and required repeated glucose bolus infusion (2 episodes in 7 patients, 3 episodes in 1 patient and 4 episodes in 1 patient). In two patients, potassium supplementation was required to treat hypokalemia. All patients eventually recovered from hypoglycemia after repeated glucose infusion, and none of them developed persistent neurological complications.
There was no difference in the categorical results of preoperative OGTT and insulinogenic index between patients with and those without post-excisional hypoglycemia. Patients in both groups showed a persistent increase in the IRI/glucose ratio from 30 to 120 min (Fig. 1) , but no statistical difference in the IRI/glucose ratio at each time point.
All patients showed a transient increase in the IRI/glucose ratio after tumor resection, irrespective of hypoglycemia development (Fig. 2) . Although patients with and those without hypoglycemia showed no significant difference in the IRI/glucose ratio at the start of surgery and during tumor manipulation, the IRI/glucose ratio remained statistically higher in the former than in the latter from 5 min to 3 h after tumor resection.
The symptoms, DM history, tumor size, presence of cystic component, tumor location, operation time and blood loss were not significantly different between patients who developed and those who did not develop post-excisional hypoglycemia (Table 1) . Among the 41 patients with adrenal pheochromocytoma, 18 (44%) developed hypoglycemia, and three (38%) of the eight patients who had extra-adrenal tumors (7 in the retroperitoneum and 1 in the bladder) developed hypoglycemia. The incidence of post-excisional hypoglycemia was not significantly different between patients with adrenal pheochromocytoma and those with extra-adrenal tumors (P = 0.73). Patients who developed hypoglycemia had significantly higher preoperative 24-h urinary metanephrine, epinephrine and serum epinephrine levels (P < 0.01 for all) than those who did not develop hypoglycemia. Logistic regression analysis showed that the preoperative 24-h urinary epinephrine level, not the norepinephrine level, of >10-fold the NUL was the only predictive factor for the development of post-excisional hypoglycemia (OR 19.8, P < 0.01). A previous history of DM and prediabetes or DM pattern in OGTT was not a predictive factor of post-excisional hypoglycemia (Table 2) .
Discussion
Post-excisional hypoglycemia is a unique complication of catecholamine-secreting tumors, including pheochromocytoma. Although most patients recover quickly with intravenous glucose therapy, careful monitoring is mandatory, because hypoglycemia could be prolonged 6 or recurrent 7 and cause severe neurological complications. 8 A study of the perioperative complications of pheochromocytoma resection reported that 15% of the patients developed post-excisional hypoglycemia and required intensive glucose therapy; 9 other studies reported a similar incidence of post-excisional hypoglycemia (13.3% with hypoglycemia defined as serum glucose levels <50 mg/ dL 3 and 4.2% with hypoglycemia defined as serum glucose levels <55 mg/dL 4 ) as the present study, suggesting that postexcisional hypoglycemia is a common complication after surgery for pheochromocytoma. These consistent results highlight the importance of careful monitoring of serum glucose levels during and after pheochromocytoma resection.
Various metabolic factors could contribute to the development of hypoglycemia after pheochromocytoma resection. Catecholamines inhibit pancreatic insulin secretion through the alpha-2 adrenergic receptor. 10 Endogenous insulin secretion is suppressed by high levels of circulating catecholamines in patients with pheochromocytoma, and excessive rebound secretion of insulin after the removal of the tumor contributes to hypoglycemia. 1 In the present cohort, a higher IRI/glucose ratio was observed after pheochromocytoma resection in patients who developed hypoglycemia than in those without hypoglycemia. However, even patients without post-excisional hypoglycemia showed a mild increase in the IRI/glucose ratio. Akiba et al. carried out sequential monitoring of the serum IRI/ glucose ratio in 10 patients with pheochromocytoma, and confirmed a transient increase in both patients who developed hypoglycemia and in five of eight patients without hypoglycemia. 3 Thus, post-excisional rebound hypersecretion of insulin might be common in patients with pheochromocytoma, regardless of hypoglycemia, and other factors might accelerate the development of hypoglycemia.
Catecholamines could contribute to the development of post-excisional hypoglycemia by depleting the hepatic glycogen store and consequently impairing the compensatory ability of catecholamines to alleviate hypoglycemia. Additionally, catecholamines enhance peripheral insulin resistance through beta-adrenergic receptors. 11, 12 Sudden withdrawal of catecholamine enhances peripheral insulin sensitivity with increased glucose use by skeletal muscle, which contributes to the development of post-excisional hypoglycemia.
The present study showed that the preoperative urinary epinephrine level, but not the urinary norepinephrine level, is a predictor for post-excisional hypoglycemia. Consistently, previous studies showed that epinephrine-predominant tumors can predict hypoglycemia. 3, 4 As sudden withdrawal of betaadrenergic stimulation and alpha-stimulation together contributes to post-excisional hypoglycemia development, the preoperative level of epinephrine, which has both alpha-and beta-agonist capacities, could be more predictive of post-excisional hypoglycemia than norepinephrine, which has only alpha-agonist capacity. We also found that the urinary epinephrine level was a better predictor of hypoglycemia than the urinary metanephrine level, whereas the urinary metanephrine level is superior for the detection of pheochromocytoma, suggesting that the catecholamine activity is associated with the risk of hypoglycemia.
Patients with pheochromocytoma are at a high risk of DM (incidence of 35.6%). 13 However, it is uncertain whether a preoperative diagnosis of DM could be a clinical risk factor for the development of post-excisional hypoglycemia. In the present study, neither a previous history of DM nor the presence of DM/prediabetes in preoperative OGTT was predictive of post-excisional hypoglycemia. Furthermore, the IRI/glucose ratio during OGTT was not statistically different at each time point between patients with and without post-excisional hypoglycemia. Diabetes patients with low insulinogenic capacity might have a low risk of hypoglycemia, because excessive insulin secretion is not common in such patients. 14 As the preoperative OGTT cannot distinguish between patients whose insulin secretion is inhibited by a hypercatecholamine status and those with a low pancreatic insulinogenic capacity, it could be difficult to predict post-excisional hypoglycemia only by preoperative OGTT results. Although post-excisional hypoglycemia occurs in patients with adrenal pheochromocytoma, previous studies did not investigate its incidence in patients with extra-adrenal pheochromocytoma. In the present cohort, three (43%) of the seven patients with non-adrenal tumor developed hypoglycemia, and its incidence was comparable with those in patients with adrenal tumors (40%). Intriguingly, all three patients with extra-adrenal pheochromocytoma who developed hypoglycemia showed high urinary epinephrine levels. As epinephrine is converted from the precursor norepinephrine by PNMT, which is almost exclusively expressed in the adrenal medulla, extra-adrenal pheochromocytomas can cause an increase in the norepinephrine, but not epinephrine, levels. In contrast, the present results suggested that epinephrine hypersecretion and post-excisional hypoglycemia could occur in patients with extra-adrenal tumors. Ectopic expression of PNMT in extra-adrenal tumors might cause epinephrine hypersecretion. 15 In addition, a recent study reported that PNMT expression was not significantly different between extra-adrenal and adrenal pheochromocytomas. 16 Thus, we should not exclude the possibility of epinephrine hypersecretion and post-excisional hypoglycemia in patients with extraadrenal tumors.
In the present study, all observed hypoglycemic episodes occurred within 6 h of tumor resection. More than half the patients with initial episodes experienced second episodes in the next 24 h. For patients who do not develop hypoglycemia within 6 h of tumor resection, the frequency of serum glucose monitoring can be reduced. In contrast, for patients who experience an initial episode of hypoglycemia, active monitoring up to 24 h is required.
The present study had a few limitations. First, because of the rarity of the disease, a small number of patients were included, which could lead to a bias. Second, because of the retrospective nature of the study, complete IRI/glucose monitoring data for some patients were not collected.
In conclusion, post-excisional hypoglycemia is a frequent complication of pheochromocytoma resection, irrespective of the tumor location, and frequently occurs in patients with high preoperative urinary epinephrine levels. Although rebound secretion of insulin after tumor resection might be the main cause of post-excisional hypoglycemia, other mechanisms including beta-adrenergic stimulation could further accelerate this complication. Serum glucose levels of all patients who undergo resection of adrenal and extra-adrenal pheochromocytomas should be intensively monitored during and after surgery.

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