RESEARCH ARTICLE

Range of glucose as a glycemic variability and 3–month outcome in diabetic patients with acute ischemic stroke Young Seo Kim1, Chulho Kim2*, Keun-Hwa Jung3, Hyung-Min Kwon4, Sung Hyuk Heo5, Beom Joon Kim6, Young Dae Kim7, Jeong-Min Kim8, Seung-Hoon Lee3

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1 Department of Neurology, Hanyang University School of Medicine, Seoul, Republic of Korea, 2 Department of Neurology, Chuncheon Sacred Heart Hospital, Chuncheon, Republic of Korea, 3 Department of Neurology, Seoul National University Hospital, Seoul, Republic of Korea, 4 Department of Neurology, Seoul National University Seoul Metropolitan Government Boramae Medical Center, Seoul, Republic of Korea, 5 Department of Neurology, Kyung Hee University School of Medicine, Seoul, Republic of Korea, 6 Department of Neurology and Cerebrovascular Center, Seoul National University Bundang Hospital, Seongnam, Republic of Korea, 7 Department of Neurology, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea, 8 Department of Neurology, Chung-Ang University Hospital, Seoul, Republic of Korea * [email protected]

OPEN ACCESS Citation: Kim YS, Kim C, Jung K-H, Kwon H-M, Heo SH, Kim BJ, et al. (2017) Range of glucose as a glycemic variability and 3–month outcome in diabetic patients with acute ischemic stroke. PLoS ONE 12(9): e0183894. https://doi.org/10.1371/ journal.pone.0183894 Editor: Xiaoying Wang, Massachusetts General Hospital, UNITED STATES Received: December 25, 2016 Accepted: August 14, 2017 Published: September 7, 2017 Copyright: © 2017 Kim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: The data set underlying this study is restricted from being made publicly available by the Chuncheon Sacred Heart Hospital Institutional Review Board and Ethics Committee. Interested and qualified researchers may send data requests to Kim Chulho at the following email address: [email protected]. Funding: The present study was supported by research grants from the Hallym University Specialization Fund (HRF-S-53) and from the Cerebrovascular Research Society Fund (2015-01).

Abstract Glycemic variability (GV) is reportedly a predictor for poor outcome in various clinical conditions. We aimed to assess whether GV during hospital admission is associated with poor outcomes in patients with acute ischemic stroke (AIS) and diabetes. We prospectively enrolled consecutive patients with AIS from the registry of 6 tertiary hospitals between January 2013 and December 2014. For the GV index, we used a glucose level range that was divided into 4 quartiles. Multivariable binary and ordinal logistic regression analyses were performed to determine the association between GV and the modified Rankin Scale score (3–6) at 3 months. We enrolled 1,504 patients with AIS and diabetes (mean age, 68.1 years; male, 57.2%), of which 35.1% had poor outcomes at 3 months. An increasing glucose range quartile was positively associated with initial neurologic severity and development of hypoglycemia during hospital admission. Multivariable analysis showed that the glucose level range quartile was associated with poor outcomes, even after adjusting for the number of glucose measurement and hypoglycemia (odds ratio [OR] Q2 vs. Q1: 1.50, 95% confidence interval [CI]: 1.02–2.18; OR Q3 vs. Q1: 2.01, 95% CI: 1.34–3.01; OR Q4 vs. Q1: 1.98, 95% CI: 1.22–3.23). These associations remained significant after dichotomization according to glycated hemoglobin levels at admission. An increasing glucose level range as a GV index during hospital admission was associated with poor functional outcomes at 3 months in patients with AIS and diabetes.

Introduction Diabetes is associated with increased risks and worse prognosis in cases with acute ischemic stroke (AIS) [1,2]. Patients with hyperglycemia at admission and during hospitalization, which

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The funders had no role in the study design, data collection and analysis, decision to publish, or preparation for the manuscript. Competing interests: The authors have declared that no competing interests exist.

is primarily noted among diabetic patients, are more likely to have worse clinical outcomes as compared to those with normoglycemia [3–5]. Hyperglycemia has a deleterious effect in cases of cerebral ischemia due to increased oxidative stress [6], inflammation [7], apoptosis [8], and inhibition of fibrinolysis [9]. However, the beneficial effects of intensive glucose lowering on the clinical outcomes after AIS remain unclear. In the Diabetes Control and Complications Trial, a reduction in the glycated hemoglobin (A1c) levels was associated with a decreased incidence and progression of microvascular complications in patients with diabetes [10]. However, the observation of a higher risk of retinopathy progression in the conventional treatment group than in the intensive treatment group with similar A1c levels suggests that glycemic variability (GV) could potentially be linked to the development of diabetic complications [11]. Increased fluctuation of blood glucose levels is reported to be associated with poor outcomes in critically ill patients [12,13]. Although several studies have suggested that the nervous system is vulnerable to glycemic excursion [14,15], the role of GV in the outcomes of patients with AIS remains unclear. Therefore, we hypothesized that high GV would be associated with poor functional outcomes in patients with AIS, irrespective of the presence of hyper- or hypoglycemia. In the present study, we aimed to evaluate the association between GV and functional prognosis in patients with diabetes after AIS.

Materials and methods Study design and participants We enrolled patients with AIS from 6 tertiary teaching hospitals who were admitted within 7 days of symptom onset, from January 2013 to December 2014. Of 4,376 patients with AIS, we excluded 2,729 who were not diagnosed with diabetes, as glucose measurements during admission alone were not sufficient to indicate glycemic excursion in the usual clinical settings. Moreover, we excluded patients who underwent glucose measurement less than 5 times during admission (n = 132) and those with missing laboratory data (n = 11) (Fig 1). Written Informed consent was obtained from all the patients or the authorized next of kin, and the institutional review board (IRB) and ethics committee of each participating hospital (IRBs in Hanyang University Hospital, Chuncheon Sacred Heart Hospital, Seoul National University Hospital, Seoul National University Seoul Metropolitan Government Boramae Medical Center, Kyung Hee University Hospital and Seoul National University Bundang Hospital) approved this study.

Data collection All the participating centers contributed to the prospective registry of the Clinical Research Center for Stroke; the detailed methods of data collection have been described previously [16]. In brief, this registry includes information on patient demographics and clinical variables and outcomes, in-hospital treatment including thrombolysis, and premorbid conditions including risk factors. Stroke was classified as transient ischemic attack (TIA), large artery atherosclerosis (LAA), small vessel occlusion (SVO), cardioembolic (CE) stroke, stroke of undetermined etiology (SUE), or stroke of other determined etiology (SOE) according to Trial of ORG 10172 in Acute Stroke Trial [17]. The stroke severity at admission was evaluated using the National Institute Health Stroke Scale (NIHSS) score [18]. Hypertension was diagnosed in patients who were taking antihypertensive medications or in patients with an average sitting blood pressure of 140 mmHg (systolic) or 90 mmHg (diastolic). Diabetes was diagnosed in patients who were receiving medical treatment for diabetes, in those with a fasting serum glucose level of  126 mg/dL, or those with a non-fasting serum glucose level of  200 mg/dL, with corresponding symptoms of diabetes, and in those with an admission A1c 6.5%. Hyperlipidemia was diagnosed in patients with a total cholesterol level of  240 mg/dL, or in patients who

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Glycemic variability and outcome after acute ischemic stroke

Fig 1. Study participants. https://doi.org/10.1371/journal.pone.0183894.g001

were treated with lipid lowering agents. Current smoking status was considered in patients who smoked 1 or more cigarettes per day within the last 6 months.

Blood glucose measurement All the admitted patients underwent immediate blood glucose measurement to rule out focal neurologic deficits. After the initial assessment, the blood sugar levels were determined 4 times daily (fasting state [7 AM], post-prandial [9 AM], before dinner [4 PM], and at night [10 PM]) by the finger prick method. Cases of hyperglycemia were managed according to the established guidelines, which state that the blood glucose level should be maintained within 140–180 mg/ dL. If insulin was injected to maintain the optimal blood glucose level, additional blood tests were permitted to determine whether sufficient blood glucose lowering was achieved or whether the insulin injection induced hypoglycemia. However, blood sugar tests were not performed for all patients after the acute period until an appropriate blood glucose level was achieved. After the acute period of stroke, a blood glucose test was performed if the patients exhibited a detrimental neurologic status or symptomatic hypo- and hyperglycemia. In other

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cases, the glucose levels were managed as per the current guideline to prevent the development of long-term complications of diabetes [19].

Glycemic variability index Capillary glucose levels were obtained sequentially from admission to discharge by using an electronic medical recording system. The mean and median values of glucose during admission were calculated. Hypoglycemia was defined as capillary blood glucose 3 were removed from the model to minimize the multicollinearity. Statistical significance was set at P 235 mg/ dL, N = 372)

Age, years

68.1±10.7

68.6±11.1

67.8±10.4

68.3±10.8

67.8±10.6

0.375

Male, %

860 (57.2)

205 (53.5)

232 (61.4)

220 (59.3)

203 (54.6)

0.089 0.270

Risk factors, % Previous stroke

393 (26.1)

91 (23.8)

96 (25.4)

95 (25.6)

111 (29.8)

1,114 (78.1)

315 (82.2)

301 (79.6)

277 (74.7)

281 (75.5)

0.039

Hyperlipidemia

648 (43.1)

187 (48.8)

171 (45.2)

159 (42.9)

131 (35.2)

0.002

Current smoking

376 (25.0)

92 (24.0)

90 (23.8)

107 (28.8)

87 (23.4)

0.271

Atrial fibrillation

210 (14.0)

53 (13.8)

55 (14.6)

41 (11.1)

61 (16.4)

0.206

Hypertension

TIA and TOAST subtype, %

0.199

TIA

56 (3.7)

21 (5.5)

13 (3.4)

13 (3.5)

9 (2.4)

LAA

534 (35.5)

133 (34.7)

119 (31.5)

143 (38.5)

139 (37.4)

SVO

428 (28.5)

101 (26.4)

124 (32.8)

110 (29.6)

93 (25.0)

CE

69 (18.5)

269 (17.9)

66 (17.2)

71 (18.8)

63 (17.0)

SOE

24 (1.6)

5 (1.3)

7 (1.9)

5 (1.3)

7 (1.9)

SUE

193 (12.8)

57 (14.9)

44 (11.6)

37 (10.0)

55 (14.8)

3 (1, 6)

2 (1, 4)

3 (1, 6)

3 (1, 6)

4 (2, 8)

Range of glucose as a glycemic variability and 3-month outcome in diabetic patients with acute ischemic stroke.

Glycemic variability (GV) is reportedly a predictor for poor outcome in various clinical conditions. We aimed to assess whether GV during hospital adm...
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