1. Abstract 1.1. Objectives: Corticosteroid are commonly used for the management of vasogenic edema and increased intracranial pressure in patients with brain tumors. The purpose of this study was to investigate postoperative and persistent hyperglycemia in patients with brain tumors treated with corticosteroid. 1.2. Methods: A total of 32 brain tumor patients met the inclusion criteria: 1) dexamethasone was administered for at least 3 to 10 days after surgery 2) fasting plasma glucose(FPG) before surgery, during hospitalization and during follow-up period up to 6 months were obtained; 3) Patients with hyperglycemia were consulted with endocrinologists. Persistent hyperglycemia was defined as FPG ≥126 mg/dL without administration of corticosteroid at 3 or 6 months postoperatively. 1.3. Results: Twenty-five patients had no diabetes mellitus (DM) before operation and 7 were already diagnosed with DM. Peak value of FPG (170.4±46.9 mg/dL) was noted in day 1 postoperatively and gradually decreased in non-diabetes group. Persistent hyperglycemia occurred in 11 (44%) of 25 non-DM patients who were not given with any steroid at the outpatient clinic. Body mass index and the level of glutamic oxaloacetate transaminase(GOT) were higher in patients with persistent hyperglycemia. FPG (158.71±32.77 mg/dL) is higher on day 4 postoperatively in patients with persistent hyperglycemia than those (123.83±17.85 mg/ dL) without persistent hyperglycemia even though operation time, total dosage of steroid and duration of steroid administration were not different. 1.4. Conclusions: Persistent hyperglycemia is not uncommon in non-DM patients with brain tumors treated with corticosteroid perioperatively. We suggest that patients with high FPG on operation day and day 4 postoperatively have a risk of persistent hyperglycemia.
Keywords: Hyperglycemia; Dexamethasone; Brain neoplasm
2. Introduction Vasogenic edema is one of the most common and critical complication in brain tumor patients [1]. Corticosteroids are commonly used to treat vasogenic edema despite they might cause complications [2]. Among many complications of corticosteroids, hyperglycemia is crucial in that it may cause multiple organ failures [3]. It’s been already published that hyperglycemia may even serve as a poor prognostic marker for brain tumors like glioblastoma [4]. Steroid-induced hyperglycemia occurs easily and may develop late postoperatively [5-7]. The duration of steroid therapy increases the frequency of side effects, and prolonged treatment (>3 weeks) is associated with greater toxicity [8]. Hypergycemia has been reported in up to 72% of patients with primary brain tumors receiving dexamethasone [9]. The hyperglycemia from corticosteroid therapy usually occurs in the first 6 weeks of therapy and is believed to be secondary to insulin resistance and increased hepatic gluconeogenesis [10].
3. Materials and Methods 3.1. Patient population This study was approved by the Institutional Review Board of a participating center. We retrospectively reviewed 103 cases underwent the first craniotomy for the resection of brain tumors by a single surgeon (SHY) from 2006 to 2014. Of these patients, 32 met retrospective selection criteria: 1) brain tumor patients were administered with dexamethasone to relieve peritumoral edema; 2) dexamethasone was administered perioperatively for at least 3 days or longer; 3) the values of FPG before surgery, during hospitalization and during follow-up period up to 6 months were measured using a glucose oxidase method (Beckman instruments, Chaska, MN); 4) Patients with hyperglycemia were consulted with endocrinologists. The exclusion criteria included: 1) dexamethasone was administered for less than 3 days; 2) chronic renal failure, liver cirrhosis, pancreatitis, inflammatory disease and autoimmune disease; 3) other medical illness treated with corticosteroid; 4) lack of FPG data during hospitalization and during follow-up period up. Our dexamethasone protocol is as follows. 5 or 10 mg dexamethasone per day was administered preoperatively. 10 or 20mg dexamethasone per day was administered on day 1 postoperatively and tapered. When the patients require dexamethasone, dexamethasone was continued during hospitalization. Steroids were used up to 10 days after surgery. Immediate hyperglycemia during corticosteroid use was controlled with regular insulin schedule which was modified according to capillary glucose level every 4 hours. Then patients were consulted with an endocrinology specialist (JSY). The diagnosis of steroid-induced hyperglycemia followed the current criteria established by the American Association of Diabetes: blood glucose level of ≥126 mg/dL. Persistent hyperglycemia was considered if patients had FPG of 126 mg/dL or higher at 3 to 6 months after surgery. 3.2. Statistical Analysis Subjects were divided into 2 groups according to FPG above or below 126 mg/dL at follow-up 6 months. Chi-square analysis was performed for categorical variables and Mann-Whitney analysis was performed for continuous variables. In addition, Kruskal-Wallis analysis was conducted for continuous variables with the above two groups and those diagnosed with diabetes before surgery.
4. Results Characteristics of 32 patients are summarized in Table 1. Baseline variables were compared between patients diagnosed preoperatively with diabetes mellitus and non-diabetes mellitus. BMI was higher in diabetes group than in non-diabetes group. The mean duration of steroid administration was 7.2 days. Other characteristics were not different. We serially assessed FPG preoperatively, perioperatively and postoperatively. Preoperative FPG were 101.1±13.5 and 133.6±52.0 mg/dL in non-diabetes and diabetes patients, respectively. Peak value of FPG was noted in day 1 postoperatively and gradually decreased in non-diabetes group. FPG in diabetes group were higher in day 3, 8 and 10 postoperatively than those in non-diabetes group even though operation time, total dosage of steroid and duration of steroid administration were similar between groups. Next, we assessed FPG at 3 through 6 months after surgery in non-diabetes patients. Persistent hyperglycemia (≥126 mg/dL) occurred after more than 3 months in 11 (44%) of 25 patients who were not given with any steroid (Table 2). BMI and the level of Glutmic oxalacetic transaminase (GOT) were higher in patients with persistent hyperglycemia, but it was not statistically different. Preoperative FPG were 102.36±12.56 and 100.14±14.54 mg/dL in patients with and without persistent hyperglycemia, respectively. FPG on operation day was 150.55±38.05 mg/dL in patients with persistent hyperglycemia, compared with 123.23±32.17 mg/dL in patients without persistent hyperglycemia (p-value, 0.082). FPG (158.71±32.77 mg/dL) is higher on day 4 postoperatively in patients with persistent hyperglycemia than those (123.83±17.85 mg/ dL) in patients without persistent hyperglycemia (p-value, 0.038) even though operation time, total dosage of steroid and duration of steroid administration were not different (Figure 1). In the case of patients diagnosed with diabetes before surgery, FPG at 3 months after surgery found to be 126 mg/dL or more in all but one patient despite they were managed with anti-diabetic agents.
5. Discussion This study investigated the association between steroid administration for brain tumor surgery and postoperative hyperglycemia. It was found that the diagnosis of diabetes mellitus was associated with high FPG postoperatively. We found that 44% nondiabetic patients treated with brain tumor surgery and steroid therapy had FPG ≥126 mg/dL after three months of surgery. FPG on day 4 postoperatively could predict the occurrence of persistent hyperglycemia (3 through 6 months postoperatively) in non-diabetic patients who were administered with dexamethasone for mean 7.6 days. On day 4 postoperatively, FPG was 158.0±32.77 mg/ dL in nondiabetic patients with persistent hyperglycemia, which was significantly higher than 123.83±17.85 mg/dL in nondiabetic patients without persistent hyperglycemia. Steroid administration increases insulin resistance with the subsequent state of hyperinsulinism. In healthy subjects, this mechanism is compensated by an increase in pancreatic insulin secretion, causing serum glucose levels to remain within normal range [11]. However, in susceptible populations, such as normoglycemic individuals with reduced insulin sensitivity and a low rate of production of the same prior to steroid use, this offsetting effect is lost, resulting in hyperglycemia [12]. Treatment of brain tumor (surgery, chemotherapy, or radiotherapy) is most frequently associated with disorders of the endocrine system [13]. Patients treated for brain tumor experience a lack of physical activities over the entire course of their treatment, which leads to physical deconditioning [14, 15]. Our data suggest that BMI could be associated with persistent hyperglycemia. The risk factors of developing diabetes following steroid administration are the dose of steroid, [16] duration of treatment, [17] a continuous steroid scheme, [18] older age, [19] and body mass index [11]. In our series, operation time, total dosage and duration of steroid administration were not associated with persistent hyperglycemia. Most patients with brain tumors begin to improve symptomatically within hours of dexamethasone administration, achieving maximum benefit within 24-73 hours [20]. A high rate of side effects is associated with prolonged dexamethasone use, as is a risk of suppression of the hypothalamic-pituitary-adrenocortical axis. All patients who are started on steroid treatment should have a baseline glucose, as well as education on daily self-monitoring of glucose. In hospitalized patients, monitoring should start with capillary glucose determination from the start of steroid treatment. Since almost 94% of cases of hyperglycemia develop within 1 to 2 days of initiation of steroid therapy in the hospital setting, other authors reported that in nondiabetic patients who maintain glucose levels < 140 mg/dL without insulin requirements of 24-48 hours, glycemic monitoring can be discontinued [6]. However, we found that obese patients with high FPG on operation day and day 4 postoperatively have a risk of persistent hyperglycemia. We recommend that clinicians pay attention to steroid-induced and persistent hyperglycemia even in nondiabetic patients with brain tumors. The proper management is needed because hyperglycemia caused by steroid has a significant effect on prognosis [21].
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Seung Ho Yang. Persistent Hyperglycemia in Brain Tumor Patients Treated with Dexamethasone Peri-Operatively and Post-Operatively. Annals of Clinical and Medical Case Reports 2021