Stress-Induced Hyperglycemia After Hip Fracture and the Increased Risk of Acute Myocardial Infarction in Nondiabetic Patients

We performed a prospective observational study at the Tianjin Hospital. Consecutive hip fracture patients (n = 1,257) were selected for the analysis during a 5-year period from February 2007 to February 2012. The study protocol was approved by the Tianjin Hospital ethics committee, and informed consent of all patients was obtained. The inclusion criteria were 1) the injury time of hip fractures was <24 h before admission and fracture diagnosis by X-ray examinations in our emergency department, 2) patient participated in physical examinations each year and blood glucose was normal (<6.1 mmol/L) with ordinary values of glycosylated hemoglobin (HbA_1c), 3) a pair of lower limb venous vascular ultrasound examinations confirmed no deep venous thromboembolism (DVT), 4) osteoporosis was confirmed by bone density examination, and 5) orthopedic surgery was not completed within 1 week after admission to the hospital or no operation was performed (conservative treatment). The exclusion criteria were 1) the time of hip fracture injury was >24 h before admission; 2) diagnosed type 1 or type 2 diabetes; 3) need of emergency operation within 1 week after hip fracture; 4) the occurrence of DVT, pulmonary embolism, or thyroid disease; and 5) renal/liver failure.

Blood and urine routine, liver and kidney function, calcium, phosphorus, and serum cardiac enzyme concentrations, insulin level, and serum lipids were tested after admission. Electrocardiography (ECG), cardiorespiratory function test, ultrasonic cardiography, chest X-ray, lower limb venous vascular ultrasound, and bone mineral density measurements of the bilateral hip were conducted. Closed reduction, bone traction treatments, and prevention of DVT were administered to all patients with hip fractures on the day of admission (10) and they continued to take their cardiac medications. All patients who met the inclusion criteria were recorded with a standardized form throughout the study course. The fasting blood glucose (FBG) was examined at 6:00 a.m. every morning from the 1st to the 7th day after admission, and ECGs were measured at admission and from the 1st to the 7th day after admission at 10:00 a.m. every morning. If clinical symptoms indicated and/or electrocardiographic changes suggested a myocardial infarction, additional blood samples were drawn from the antecubital vein in order to examine creatine kinase (CK), CK-MB isoenzyme, and troponin-I values. AMI diagnosis met ST-segment elevation myocardial infarction (STEMI) or non–ST-segment elevation myocardial infarction (NSTEMI) criteria (11,12). AMI diagnosis criteria met at least two of following: 1) the CK-MB isoenzyme and/or troponin-I concentration elevated above the hospital laboratory's myocardial infarction threshold; 2) persistent ST-T segment changes, new Q waves, or left bundle branch block occurred; 3) serious precordial chest pain lasting for 30 min or more. Stress hyperglycemia diagnosis criteria were as follows: 1) patients did not have a previous diabetes history, 2) admission or in-hospital fasting plasma glucose levels of 7 mmol/L or more in two or more tests (13), and 3) normal HbA_1c values.

SPSS 17.0 (SPSS, Inc., Chicago, IL) software was applied by a professional statistician to complete the analyses. Continuous variables were expressed as mean with SD. Comparisons between continuous variables were performed using the Student t test or ANOVA. Categorical variables were expressed as frequency and percentage. Comparisons between categorical variables were compared using the χ² test or Fisher exact test. Multiple logistic regression analysis identified risk factors of AMI. P value ≤0.05 was considered statistically significant.

The period of follow-up interviews was 3 months after discharge, and mortality was recorded by the investigators via telephone calls and/or outpatient clinic visits.

Patients (n = 1,257) who met the inclusion criteria were enrolled in this clinical observation. Among the patients, the average age was 75.20 ± 7.71 years and 64.52% were women. The most prevalent comorbidity was hypertension (57.68%), followed by coronary artery disease (CAD) or family history of CAD (49.90%), dyslipidemia (elevation of LDL cholesterol [LDL-C], 49.27%; triglyceride, 39.14%; and low levels of HDL cholesterol [HDL-C], 21.40%), obesity (37.63%), and smoking (28.16%).

The frequency of stress hyperglycemia was 47.89% (602/1,257) and that of AMI was 9.31% (117/1,257). Table 1 shows the basic characteristics of the selected patients. There was a significant difference in admission glucose levels between the two groups. Figure 1 shows the correlation between time of fracture and FBG. In the stress hyperglycemia group, FBG values reached a maximum 2–3 days after hip fracture and then decreased gradually. Repeated ANOVAs showed that at each time point in the stress hyperglycemia group, the blood glucose values were significantly different (P < 0.05), whereas in the non-hyperglycemia patients, they did not change (P = 0.10) (Fig. 1). Table 2 shows characteristics of myocardial infarctions in the two groups. The incidence of AMI in the stress hyperglycemia group was significantly higher (12.46% [75/602]) than in the non-hyperglycemia group (6.41% [42/655], P < 0.05). The number of AMIs was correlated with the occurrence of hyperglycemia and was significantly higher ≤3 days after injury in the hyperglycemia group (P < 0.05), whereas the temporal distribution of AMI in the non-hyperglycemia group was not different between ≤3 and >3 days after injury (Table 2). In all patients with AMI, NSTEMI events occurred more often than STEMI (62.39% [73/117] vs. 37.61% [44/117]), but STEMI significantly prevailed in the stress hyperglycemia group (P < 0.05). In Table 3, risk factors for AMI and their significance are listed. A multiple logistic regression analysis using a forward stepwise (conditional) method revealed that stress hyperglycemia is an independent risk factor for the development of AMI (relative risk [RR] 2.130 [95% CI 1.431–3.172]). Patients with stress hyperglycemia after hip fracture were 2.130-fold more likely to develop an AMI than the non-hyperglycemia individuals.

At the end of 3 months follow-up, there were no differences in mortality in patients with versus without stress-induced hyperglycemia (6.98% [42/602] vs. 4.43% [29/655], P = 0.051).

In our study, we found that the frequency of stress hyperglycemia was 47.89% and the incidence of AMI was 9.31% in patients after hip fractures. The incidence of AMI in the stress hyperglycemia group was 12.46%, whereas the overall AMI incidence in patients without hip fractures in China is 2.6% (14), indicating that the incidence of AMI in patients after hip fractures appears higher than overall AMI incidence in China.

Others have reported that the increased incidence of AMI after hip fracture was related to osteoporosis (4,14). Osteoporosis and cardiovascular diseases share common risk factors like poor general health status, lifestyle, nutrition, hormone secretion, vitamin D deficiency, systemic inflammation-related (e.g., C-reactive protein, interleukin-6, or tumor necrosis factor) diseases, and medications through different mechanisms both in bone and arteries (15–25).

Patients with osteoporotic fractures are likely to have coexisting blood vessel diseases, but in our study, we found that particularly stress hyperglycemia plays a vital role, because the incidence of AMI in the stress hyperglycemia group was 2.130 higher than in the non-hyperglycemia group. In patients with hip fractures, stress hyperglycemia was the sole significant independent risk factor for the development of AMI (95% CI 1.431–3.172).

Acute fractures induce stress hormone secretion of glucocorticoid, glucagon, adrenaline, thyroxin, somatotropin, and others, which is called the “stress response.” During the stress response, activation of serial hormones induces insulin resistance, resulting in hyperglycemia and the associated risk factors present then in patients with acute traumata (26). It is well known that stress hyperglycemia is associated with oxidative stress, inflammatory responses, damaging of coronary microcirculation, and markedly worsened signal transduction pathways of endogenous cardioprotective responses. Hyperglycemia can induce ADP-induced platelet aggregation and increase plasma catecholamine, which is associated with vulnerable plaque evolution, the promotion of microcircular dysfunctions, and thrombogenesis (27–37).

Our present work indicates that for patients without a history of diabetes, stress-induced hyperglycemia plays a key role in the risk of developing AMI. Our present analysis revealed that most (62.67% [47/75]) AMIs occurred within the first 3 days after hip fractures, which is in accordance with the literature (2). In the stress hyperglycemia group, blood glucose peaked at 2–3 days after hip fracture and then declined gradually, indicating a coincidence of AMI with the peak time of FBG. The cause of a more frequent STEMI occurrence in stress-induced hyperglycemia might be that raised glucose levels contribute to platelet activation and thereby enhanced platelet-mediated thrombogenesis (38), which develops into completely occlusive thrombi. In addition, our study showed stress hyperglycemia ranges of 6.1–9.7 mmol/L after hip fractures for the first time, and we recommend that stress-induced hyperglycemias after hip fracture should be identified early.

A limitation of our study was that we did not investigate an effect of inflammatory factors and/or stress hormones on FBG levels, which lead to increased AMI risk. In addition, we did not compare the results of this study with patients suffering from diabetes, and we did not find differences between the stress hyperglycemia and no hyperglycemia groups regarding comorbid disorders and/or drug administrations, e.g., statin against hypertension. Therefore we cannot completely rule out that other factors also contributed to the incidence of myocardial infarctions. Moreover, patients were not accurately diagnosed for diabetes in the longer term, and because blood glucose levels largely fluctuate, we did not specifically treat the hyperglycemias. Up until now, there has been no clear agreement on whether it is necessary to control glucose levels in these patients. In addition, we only show the significance of hyperglycemia on the incidence of AMI during admission; we did not show clinical outcome data at follow-up. However, this study underlines the importance of understanding the indication for adopting appropriate methods to identify stress-induced hyperglycemia in correlation with AMI after hip fracture.

We recommend that in patients, even without previous diabetes, FBGs and ECGs should be monitored for at least the first 7 days after hip fractures. This might be helpful for the endocrinologist, cardiologist, and orthopedic surgeon to timely detect AMIs.

We conclude that stress-induced hyperglycemia increased the risk of AMI in patients with hip fractures. Stress-induced hyperglycemias after hip fracture should be identified early.

No potential conflicts of interest relevant to this article were reported.

Y.C. designed the study, collected the data, and wrote the first draft of the manuscript. X.Y., K.M., and Z.Z. designed the study and reviewed and analyzed the data. B.M. and X.L. conducted the study. B.Q. researched data and analyzed samples. S.C., P.C., and Y.Y. researched data, analyzed samples, and conceived and edited the manuscript. B.Q. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

The authors thank Dr. Guosheng Xing (Tianjin Hospital, Tianjin, China) who managed the data collection. The authors also thank the people with hip fractures who participated in this study.