Efficacy and Safety of Insulin Glargine in Patients With Acute Stroke and Hyperglycemia Receiving Intensive Care: Randomized Controlled Study

Efficacy and Safety of Insulin Glargine in Patients With Acute Stroke and Hyperglycemia Receiving Intensive Care: Randomized Controlled Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Original investigation Efficacy and Safety of Insulin Glargine in Patients With Acute Stroke and Hyperglycemia Receiving Intensive Care: Randomized Controlled Study Sung-Chun Tang, Shyang-Rong Shih, Shin-Yi Lin, Chih-Hao Chen, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-56284/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: This pilot study compared the basal–bolus regimens of long-acting insulin glargine (IG) and neutral protamine Hagedorn (NPH) insulin in efficacy and safety in acute stroke patients with hyperglycemia receiving intensive care (NCT02607943). Methods: This was a randomized, open-label, clinical trial. Stroke patients who were admitted to the intensive care unit within 72 h of onset and met the inclusion criteria were enrolled. They received either IG or NPH with added short-acting prandial regular insulin over a 72-h period. The primary endpoints were the percentage of glucose within the range of 80 to 180 mg/dL and the percentage of glucose reduction compared with pre-randomization glucose levels, assessed through continuous glucose monitoring (CGM). Results: A total of 50 patients were included, 26 and 24 were randomly assigned to the IG and NPH, respectively. The participant baseline characteristics were comparable between groups, except the IG had a significantly higher glucose level pre-randomization than the NPH (290.69 ± 82.31 versus 246.04 ± 41.76 mg/dL, P = .021). CGM data showed that the percentage of time with glucose levels between 80 and 180 mg/dL was 45.88 ± 27.04% in the IG and 53.56 ± 22.89% in the NPH ( P = .341) and the percentage of glucose reduction was 31.47 ± 17.52% in the IG and 27.28 ± 14.56% in the NPH ( P = .374). The percentage of time with hypoglycemia (< 60 mg/dl) was 0.14 ± 0.49% in the IG and 0.47 ± 1.74% in the NPH ( P = .361). Parameters representative of glucose variabilities, and poststroke outcomes were not significantly different between the groups. Conclusions: Our study results suggest that early initiation of an IG-based basal–bolus regimen is safe and equally effective as an NPH-based basal-bolus regimen for patients with acute stroke and hyperglycemia requiring intensive care. Trial registration: ClinicalTrials.gov, NCT02607943. Registered 18 Nov 2015, https://clinicaltrials.gov/ct2/show/NCT02607943 Endocrinology & Metabolism Cardiac & Cardiovascular Systems Stroke hyperglycemia insulin Glargin NPH intensive care Figures Figure 1 Background Stroke is the leading cause of mortality and permanent morbidity worldwide.[ 1 ] Several factors known to affect poststroke outcomes, including premorbid functional status, advanced age, stroke severity, stroke subtype, and whether acute reperfusion therapy was administered. However, most of these prognostic risk factors are unmodifiable and play a limited role in acute stroke management. Diabetes mellitus is a strong independent risk factor for the development of stroke.[ 2 ] Acute stroke may initiate several mechanisms that lead to acute hyperglycemia, such as increased innate immunity and stimulation of the hypothalamic–pituitary–adrenal axis.[ 3 ] Therefore, patients with acute stroke, especially those with a history of diabetes mellitus, frequently have hyperglycemia.[ 4 , 5 ] Notably, numerous studies have shown that persistent poststroke hyperglycemia is closely associated with stroke-in-evolution, symptomatic hemorrhagic transformation, hematoma expansion, and unfavorable functional outcomes.[ 6 – 9 ] The Guidelines for the Early Management of Patients with Acute Ischemic Stroke from the American Heart Association and the American Stroke Association suggest that the blood glucose level should be maintained between 140 and 180 mg/dL, in accordance with the current American Diabetes Association recommendation.[ 10 , 11 ] However, the optimal method to correct hyperglycemia during acute stroke remains unclear. Currently, multiple protocols of subcutaneous and intravenous insulin treatments are used to ameliorate hyperglycemia in patients with different diseases during hospitalization.[ 6 ] Continuous intravenous insulin infusion achieves rapid correction of hyperglycemia and is effective in maintaining glucose within a strict predetermined range.[ 12 ] However, a recent trial suggested that for patients with acute ischemic stroke and hyperglycemia, aggressive intravenous insulin infusion has a significantly higher chance of inducing hypoglycemia without absolute clinical benefits compared with subcutaneous insulin injection.[ 13 ] Neutral protamine Hagedorn (NPH) insulin is widely used for the treatment of hyperglycemia during hospitalization. The duration of its effects is approximately 12 h, and it exhibits a peak in its time-action profile at 5 to 7 h. These properties mean that NPH does not fully mimic the physiological secretion of basal insulin. By contrast, long-acting insulin analogs such as insulin glargine (IG) create a subcutaneous depot after injection, exhibit no pronounced peak after administration, and last for 24 h. They are currently preferred for glycemic control of diabetes.[ 14 ] Studies have demonstrated that IG is safe in various clinical situations, including for both non-critically and critically hospitalized patients.[ 15 – 19 ] However, evidence regarding the use of IG in patients with acute stroke and hyperglycemia is limited. The objective of this randomized controlled study was to determine the efficacy and safety of early initiation of subcutaneous once-daily IG compared with standard NPH regimens to achieve proper glycemic control in patients with acute stroke and hyperglycemia admitted to the intensive care unit (ICU). Patients And Methods This is a randomized, open-label, pilot clinical trial. Patients with acute stroke admitted to the stroke ICU of National Taiwan University Hospital within 72 h of onset (onset defined as the last known time at which the patient was well) were screened. The entry criteria for admittance to the stroke ICU included ischemic stroke with thrombolytic therapy or endovascular treatment, intracerebral hemorrhage with aggressive blood pressure control treatment, severe neurological deficits (e.g., a National Institute Health Stroke Scale score higher than 8), stroke-in-evolution, or other medical conditions requiring intensive care.[ 20 , 21 ] Patients who met the inclusion criteria (age ≥ 20 years, capillary blood glucose > 200 mg/dL after admission) were enrolled. Patients were excluded if they had any of the following conditions: autoimmune disease, human immunodeficiency virus infection, sepsis, pregnancy, treatment with corticosteroids or vasopressors, end-stage renal disease requiring dialysis, type I diabetes mellitus, or hypersensitivity to any insulin products. The diagnosis of stroke was confirmed through diffusion-weighted magnetic resonance imaging of the head or repeated computed tomography scanning (if the first scan did not clearly reveal the infarct region). Patients with ischemic stroke were further classified into 5 major subtypes according to the Trial of ORG 10172 in Acute Stroke Treatment criteria: large-artery atherosclerosis, small-vessel occlusion, cardioembolism, specific etiology, and undetermined etiology.[ 22 ] A detailed history of each patient’s clinical presentation, vascular risk factors, and comorbidity was obtained. Body mass index was calculated as weight divided by the square of height in meters. Stroke severity on admission was assessed using the National Institute Health Stroke Scale. Mortality and functional outcome 3 months poststroke were assessed using the modified Rankin scale. Acute stroke care for both groups followed the latest guidelines from the American Heart Association and the American Stroke Association. Randomization Patients were assigned to the IG group or the NPH group through computer-generated randomization. Allocation was concealed by the use of opaque, consecutively numbered envelopes. Treatment allocation was 1:1. Insulin Regimens All participants received only insulin for glycemic control during the intervention period, which was the first 72 h after study enrollment. Administration of oral hypoglycemic agents and noninsulin injections, regardless of whether they were used before stroke, was stopped. The insulin regimens in both groups are described as follows. A basal–bolus regimen of IG or NPH was used for glycemic control. All patients received regular insulin before meals as a correctional component. During the period when food was prohibited (nothing-by-mouth status), IG was administered because it does not demonstrate a pronounced peak. NPH was withheld to prevent hypoglycemia. The total daily insulin dose (TDD) was based on weight. For most patients, the TDD was 0.6 U/kg/day. For patients with anticipated insulin sensitivity, such as those aged over 80 years or those whose creatinine clearance rate was below 30 mL/min, the TDD was empirically reduced to 0.5 U/kg/day. The TDD of patients receiving insulin therapy before admission was based on their outpatient dose and modified by an endocrinologist. For the IG group, 50% of the TDD was basal insulin and the other 50% was evenly administered before each meal. For the NPH group, 25% of the TDD was basal insulin, and similarly, the remaining 75% was administered evenly before meals. After the regimens were administered, an endocrinologist carefully assessed glycemic levels and made daily adjustments to achieve glycemic levels between 80 and 180 mg/dL. Scheduled prandial or basal insulin administration was temporarily stopped during treatment of hypoglycemia (defined as blood glucose < 60 mg/dL), which was performed in accordance with a previously published guideline.[ 23 ] Blood Glucose Measurements Participants’ capillary blood glucose was measured before each meal and once during fasting, at the frequency of every 4 to 6 h, depending on their eating schedule. In addition, a Medtronic Enlite Glucose Sensor (Medtronic, Northridge, CA, USA) was used to monitor glycemia during the intervention period.[ 24 ] Interstitial glucose levels were recorded every 5 min with a detection range of 40 to 400 mg/dL. Glucose levels from capillary blood and continuous glucose monitoring (CGM) were compared and calibrated at randomization and 1, 3, and 4 h after randomization. The glycemic data from CGM were used in the analyses. Study Outcomes The primary efficacy outcomes were the percentage of glucose levels within the range of 80 to 180 mg/dL and the percentage of glucose reduction compared with prerandomization levels during the 72-h intervention period. The primary safety outcome was the percentage of time with hypoglycemia (glucose < 60 mg/dL). The secondary clinical outcomes were determined according to whether a favorable outcome was achieved (modified Rankin scale score ≤ 2), whether a poor outcome was achieved (modified Rankin scale score ≥ 4), mortality, and Barthel index scores at 3 months poststroke. The secondary laboratory outcomes were glycemic mean and variability, determined from CGM data. Glycemic variability was calculated through linear and nonlinear analyses using previously described methods. We computed two-time domain measures as standard deviations and the root mean square of successive beat-to-beat differences. The nonlinear analysis of sample entropy was also applied to the glucose data using methods described previously.[ 20 , 25 , 26 ] Statistical Analysis Sample size calculation was not directly applicable in this trial because the expected effect size of our primary outcome, namely the percentage of time before return to normoglycemia, was yet unknown. Instead, we followed a previously proposed method of enrolling at least 50 participants in a pilot study.[ 27 ] The analysis was performed as intention-to-treat to reflect clinical practice in stroke ICUs. Descriptive statistics of baseline characteristics of the study population are expressed as numbers (percentages) and means ± standard deviations. Because the primary efficacy and safety outcomes were nonnormally distributed quantitative variables, the Mann–Whitney U test was used to determine whether the between-group differences in mean percentage of time were significant. Between-group mean differences and 95% confidence intervals of the primary outcomes were also analyzed. The chi-square test or the Fisher’s exact test were applied for categorical secondary outcomes, whereas the Mann–Whitney U test was applied for the continuous variables. In addition, factors associated with a favorable outcome (modified Rankin scale score ≤ 2) were examined through univariate analysis. A logistic regression method was used to adjust for age and sex and univariate analysis of was conducted to identify factors that were significant predictors ( P < .05) of a favorable outcome. Statistical analyses were performed using IBM SPSS Statistics for Windows, version 26 (IBM Corp., Armonk, NY, USA). Significance was defined as P < .05. Ethics This study was approved by the Institutional Review Board and the Medical Ethics Committee of National Taiwan University Hospital (Clinicaltrials.gov number: NCT02607943). All participants provided informed consent or were recruited with consent provided by their first-degree relatives. The study was conducted in accordance with the revised version of the 2008 Declaration of Helsinki. Results Patient characteristics Between December 2015 and October 2019, 50 patients with stroke were randomized; 26 were assigned to the IG group and 24 were assigned to the NPH group. Two participants (one in each group) did not have CGM data because of unexpected technical issues. Of the participants, 37 (74%) were admitted with ischemic stroke, and the remainder were admitted with intracerebral hemorrhage. Two patients in the IG group were lost to follow-up at 3 months poststroke. A total of 14 patients (29.2%) had favorable outcomes, and 17 patients (35.4%, including 5 who died) had poor outcomes. The participant clinical characteristics are listed in Table 1 . Baseline profiles were comparable between the groups for age, sex, body mass index, prestroke functional status, stroke type, stroke severity on admission, stroke risk factors, percentage of participants receiving acute reperfusion therapy, and biochemical data on admission. However, creatinine levels were higher in the NPH group than in the IG group (1.21 ± 0.45 versus 0.97 ± 0.28, P = .027). In the NPH and IG groups, 8 and 10 patients had a nothing-by-mouth status when insulin regimens were initiated. Most of them started eating within several hours, but 3 patients in the IG group each fasted for 12, 19, and 41.5 h during the intervention period. Table 1 The baseline characteristics of AIS patients NPH Insulin (n = 24) Insulin Glargine (n = 26) P Age, year 62.7 ± 16.0 64.7 ± 14.6 0.649 Male (N) 16 (66.7) 15 (57.7) 0.571 BMI (kg/m 2 ) 26.3 ± 4.1 26.5 ± 5.2 0.889 Weight (kg) 70.3 ± 15.5 70.5 ± 16.5 0.970 History of stroke 9 (26.3) 4 (3.7) 0.109 Pre-mRS ≥ 2 5 (20.8) 4 (15.4) 0.721 NIHSS at admission 11.5 (6, 17) 13 (8, 21) 0.540 Atrial fibrillation 2 (8.3) 3 (11.5) 1.000 Diabetes mellitus 23 (95.8) 22 (84.6) 0.351 Hypertension 22 (91.7) 19 (84.6) 0.066 Hyperlipidemia 9 (37.5) 10 (38.5) 1.000 CAD 5 (20.8) 6 (23.1) 1.000 Infarction 18 (75.0) 19 (73.1) 0.969 Cardioembolism 6 (33.3) 6(31.6) LAA 7 (38.9) 7(36.8) Others 5 (27.8) 6(31.6) ICH 6 (25.0) 7 (26.9) 1.000 Smoking 7 (29.2) 5 (19.2) 0.514 IV rt-PA 5 (20.8) 7 (26.9) 0.745 EVT 6 (25.0) 5 (19.2) 0738 TG (mg/dl) 200.08 ± 119.88 190.0 ± 263.67 0.851 Total Cholesterol (mg/dl) 189.00 ± 52.43 175.88 ± 65.03 0.439 LDL (mg/dl) 108.25 ± 31.52 105.96 ± 45.13 0.837 Glucose at admission (mg/dl) 317.00 ± 116.85 270.88 ± 99.87 0.139 HbA1c (%) 9.84 ± 2.10 9.15 ± 1.94 0.235 Creatinine (mg/dl) 1.21 ± 0.45 0.97 ± 0.28 0.027* Hemoglobin (g/dl) 14.30 ± 2.22 14.30 ± 2.11 1.000 WBC (K/ul) 9.07 ± 2.85 10.17 ± 3.00 0.181 Platelet (k/ul) 238.58 ± 53.87 224.65 ± 61.51 0.418 PTT (second) 25.68 ± 2.29 25.61 ± 2.50 0.918 INR 0.97 ± 0.15 0.98 ± 0.06 0.936 Data was expressed as number (proportion) or mean ± standard deviation. * indicates statistical significance. Abbreviations: NPH, Neutral protamine hagedorn insulin; BMI, body mass index; mRS, modified Rankin Scale; NIHSS, National Institute of Health Stroke Scale; CAD, coronary artery disease; LAA, large artery atherosclerosis; Others include other determined and undetermined. ICH, intracerebral hemorrhage; IV: intravenous; EVT: endovascular thrombectomy; WBC, white blood cell; PTT, partial thromboplastin time; INR, international normalized ratio; TG, triglyceride; LDL, low-density lipoprotein; HbA1c, glycated hemoglobin; Effectiveness, Safety, And Variabilities As Table 2 shows, glycemic levels before randomization were significantly higher in the IG group than in the NPH group (290.69 ± 82.31 versus 246.04 ± 41.76 mg/dL, P = .021). The percentage of time with glucose levels between 80 and 180 mg/dL was 45.88 ± 27.04% in the IG and 53.56 ± 22.89% in the NPH ( P = .341) and the percentage of glucose reduction was 31.47 ± 17.52% in the IG and 27.28 ± 14.56% in the NPH ( P = .374). Table 2 Study outcome between treatment groups NPH Insulin (n = 24) Insulin Glargine (n = 26) Mean difference (95% CI) P value Primary outcome Pre- randomization (mg/dl) 246.04 ± 41.76 290.69 ± 82.31 44.65 (7.05 to 82.25) 0.021* Proportion of time in glucose 80–180 (mg/dl) 53.56 ± 22.89 45.88 ± 27.04 -7.67(-22.30 to 6.95) 0.341 Percentage of glucose reduction (mg/dL) a 27.28 ± 14.56 31.47 ± 17.52 4.19 (-5.21 to 13.60) 0.374 Secondary outcome (laboratory) b < 60 mg/dl (number of patients) 3 (12.5%) 2 (7.7%) NA 0.660 < 60 mg/dl (% of time) 0.47 ± 1.74 0.14 ± 0.49 -0.33 (-1.61 to 0.39) 0.361 Mean, mg/dl 175.82 ± 30.16 189.89 ± 32.86 14.07(-4.31 to 32.45) 0.130 SD 40.83 ± 11.57 41.11 ± 14.32 0.29 (-7.32 to 7.89) 0.958 RMSSD 2.99 ± 1.04 3.16 ± 1.06 0.177(-0.43 to 0.79) 0.561 Entropy 0.08 ± 0.04 0.07 ± 0.04 -0.147(-0.39 to 0.01) 0.234 Secondary outcome (clinical) c mRS ≤ 2, n(%) 8 (33.3) 6 (25.0) NA 0.752 mRS ≥ 4, n(%) 9 (37.5) 8 (33.3) NA 1.00 Mortality, n(%) 2 (8.3) 3 (12.5) NA 1.00 BI Scores, mean ± SD 52.29 ± 37.39 50.42 ± 34.89 -1.88 (-22.89-19.14) 0.858 Data was expressed as number (proportion) or mean ± standard deviation Abbreviations: NPH, Neutral protamine hagedorn insulin; SD, standard deviation; RMSSD, rootmeansquare of successive beat-to-beat differences; mRS, modified Rankin scale; BI, Barthel index; NA, not available a Glucose reduction in comparison to pre-randomized glucose level. b n = 24 in Glargine group because two subjects were lost of follow-up. c n = 23 and 25 in two groups, respectively, due to two subjects with unexpected technical issues of the continuous glucose monitor device. Hypoglycemia, glucose < 60 mg/dl. Table 3 Multivariable analysis for factors predicting AIS patients with good outcome Covariate ß estimate p odds ratio 95% CI Sex (male) -0.571 0.765 0.565 0.013–23.864 Age (per year) -0.216 0.046* 0.805 0.651–0.996 NIHSS at admission -0.412 0.040* 0.662 0.447–0.981 ICH 0.872 0.482 2.391 0.211–27.148 Weight (kg) -0.136 0.139 0.874 0.731–1.045 Hemoglobin (g/dl) 0.736 0.259 2.087 0.582–7.493 Insulin Glargine -1.252 0.361 0.286 0.020–4191 NIHSS, National Institute of Health Stroke Scale; ICH, intracerebral hemorrhage. * indicates statistical significance. For the safety outcome, 3 patients in the NPH group and 2 patients in the IG group had hypoglycemia. The percentage of time with hypoglycemia was very low and comparable between the groups (0.14% ± 0.49% in the IG group versus 0.47% ± 1.74% in the NPH group, P = .361). Most hypoglycemic events occurred during fasting (from after dinner on the first day to before breakfast on the second day). All patients were asymptomatic during the hypoglycemic period. Figure 1 presents line graphs of the 2 groups’ average and standard deviation of glucose levels at prerandomization and during the 72-h intervention period. The glucose variability are presented as standard deviations. The root mean square of successive beat-to-beat differences, and sample entropy did not differ significantly between the groups (Table 2 ). The capillary blood glucose of the 2 patients without CGM data, measured every 4 h during the intervention period, also did not differ significantly. All of the secondary clinical outcomes, namely favorable and poor outcomes, mortality, and Barthel index scores 3 months poststroke, were comparable between the groups (Table 2 and Supplementary Fig. 1). Factors Associated With A Favorable Outcome As Supplementary Table 1 shows, participants with favorable outcomes had a lower age, higher weight, lower score on the National Institute Health Stroke Scale on admission, greater likelihood of having the intracerebral hemorrhage stroke subtype, and higher levels of hemoglobin compared with those with poor outcomes. None of the glucose-related parameters, including insulin regimen, were associated with significant differences between favorable and poor outcomes. Multivariate analysis showed that only a younger age and lower National Institute Health Stroke Scale score on admission were significantly associated with favorable outcomes (odds ratio = 0.805 and 0.662, 95% confidence interval = 0.651–0.996 and 0.447–0.981, P = .046 and .040, respectively). Discussion This pilot study was designed to assess the safety and efficacy of using long-acting IG in the management of hyperglycemia in patients with acute stroke. To the best of our knowledge, this is the first randomized clinical trial to investigate the feasibility of early initiation of long-acting IG in patients with acute stroke receiving intensive care. Our results indicate that IG is equally as safe and effective as NPH for use to achieve glycemic control in patients with stroke in an ICU setting. Moreover, no significant between-group differences in outcome parameters were observed. Whether glucose should be controlled intensively and be consistently maintained at a low level in the acute phase of stroke to prevent hyperglycemia-related secondary brain injuries remains subject to debate. Several clinical trials have compared intensive intravenous insulin and standard care in patients with poststroke hyperglycemia.[ 28 – 30 ] Most trials have reported the efficacy of intensive intravenous insulin infusion in strict glycemic control but also increased risk of hypoglycemic complications. The overall benefit of intravenous insulin infusion for poststroke outcomes is unclear, primarily because of the small sample sizes of relevant studies.[ 31 ] The results of the Stroke Hyperglycemia Insulin Network Effort randomized clinical trial were recently published.[ 13 ] The purpose of the trial was to determine and compare the efficacy of intensive and standard treatment of hyperglycemia in patients with acute ischemic stroke. The study comprised 1151 participants randomly assigned to receive continuous intravenous insulin infusion through use of a computerized decision support tool to achieve blood glucose levels of 80 to 130 mg/dL or to receive subcutaneous insulin infusion on a sliding scale to achieve blood glucose levels of 80 to 179 mg/dL for up to 72 h. The results showed that the percentages of patients with favorable functional outcomes were comparable between the intensive and standard treatment groups (20.5% and 21.6%, respectively), but the incidence of early discontinuation of treatment due to hypoglycemia or other adverse effects was higher in the intensive group than in the standard group (11.2% versus 3.2%). These findings do not support the routine use of intensive glycemic control in patients with acute ischemic stroke and hyperglycemia. Notably, glycemic control in the standard treatment group of the Stroke Hyperglycemia Insulin Network Effort trial involved only a sliding scale of subcutaneous rapid-acting insulin administered every 6 h. Despite its convenience and simplicity, use of only sliding-scale insulin therapy in inpatient settings has been demonstrated to be worse for glycemic control compared with basal–bolus therapy and is strongly discouraged in the current American Diabetes Association guidelines.[ 23 ] Sliding-scale insulin therapy is reactive, does not enable adjustments to be made according to the carbohydrate content of meals, and most importantly, does not mimic the physiological delivery of insulin. By contrast, basal–bolus insulin therapy more closely mimics physiological insulin secretion. Administering daily long-acting insulin on top of prandial rapid-acting insulin reduces not only mean daily glucose levels but also glycemic fluctuation. An insulin regimen comprising basal and correction components is the preferred treatment for noncritically ill hospitalized patients with nothing-by-mouth status.[ 32 , 33 ] For patients with a stable oral intake, a correction component should be added.[ 23 ] However, basal–bolus regimens with long-acting IG have not been tested in patients with acute stroke in intensive care. Several studies have compared IG- and NPH-based regimens in hospitalized patients. Most of them have reported comparable glycemic control between the 2 types of insulin.[ 34 – 36 ] However, one investigation demonstrated a higher incidence of hypoglycemic events in the NPH group,[ 34 ] and another reported that the daily insulin requirement was lower in the NPH group.[ 35 ] In our study, the primary and secondary endpoints were mostly comparable between the groups. The proportion of patients with hypoglycemia was very low and also comparable between the groups. Notably, most episodes of hypoglycemia occurred during fasting (from after dinner on the first day to before breakfast on the second day). In addition, one patient in the IG group extended nothing-by-mouth status after the intervention and experienced hypoglycemia. However, none of the patients with hypoglycemia developed clinical signs or complications. Physicians should be more aware of patients’ glycemic levels during long fasting periods and promptly treat hypoglycemia should it occur. Although the percentage of time for glucose between 80 and 180 mg/dL was lower in the IG group than in the NPH group, the percentage of glucose reduction compared with prerandomization levels was higher in the IG group than in the NPH group. This suggests that the insulin regimens may be equally effective and that the mentioned differences could be attributable to the different baseline glucose levels and relatively short intervention period. In addition, 90% of the participants had prestroke diabetes, and the average glycated hemoglobin and admission blood glucose levels were higher than 9% and 250 mg/dL, respectively. The starting dose we selected may have been too conservative for these patients. The TDD of the 2 groups was comparable throughout the intervention period (Supplementary Table 2), but the total daily basal insulin dose was significantly higher in the IG group (27.5 ± 11.3 U/kg in the NPH group versus 57.2 ± 19.4 U/kg in the IG group, P < .001). The data correlated well with our study design; 50% and 25% of the TDD was basal insulin in the IG group and the NPH group, respectively. This study has several strengths. It is the first to compare guideline-recommended basal–bolus insulin regimens for the treatment of acute stroke of moderate to high severity requiring critical care. The participants in our study received the optimal treatment for hyperglycemia rather than intensive insulin infusion or regular sliding-scale insulin therapy. In addition, to determine glycemic variability, we performed CGM subcutaneously, ensuring continual delivery of glycemic data (every 5 min) during the intervention period. Thus, the effectiveness and safety of both insulin regimens were comprehensively evaluated. This study also has some limitations. First, the small sample size and proportion of patients with the heterogeneous stroke subtype may have limited the power of detection of between-group statistical differences in the endpoints. Second, the intervention period (< 72 h) may have been too short to observe the benefits of glycemic control in stroke outcomes. Nevertheless, the successful application of IG-based basal–bolus regimens can serve as a reference for future studies with larger sample sizes and more specific groups of patients with acute stroke, which would broaden the generalizability of our findings. Conclusion This study demonstrates that IG-based basal–bolus regimens are safe and feasible for patients with acute stroke and hyperglycemia requiring intensive care. Early administration of basal–bolus insulin regimens in the glycemic management of hospitalized patients with stroke, rather than dependence on sliding-scale insulin, should be promoted. Abbreviations IG: insulin glargine NPH: neutral protamine Hagedorn CGM: continuous glucose monitoring ICU: intensive care unit TDD: total daily insulin dose Declarations Ethics approval and consent to participate: The study was approved by the Research Ethics Committee of National Taiwan University Hospital (NTUH-REC No. 201504075MIN). All participants provided informed consent or were recruited with consent provided by their first-degree relatives. Consent for publication : consent for publication is given where applicable. Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Competing Interest: All authors had no conflicts of interests to disclose. Funding : The study was funded by the grant of MOST 104-2314-B-002 -220 Authors’ contributions: SCT, SRS, WSY, JSJ: Conception and design of the study. SCT, CHC, SJY, LKT: Patients recruitment, and clinical management. SCT, SRS, SYL, CHC: Data acquisition and statistical analysis. SCT, SYL, CHC: Drafting of the manuscript. WSY, JSJ: Critical revision of the manuscript. Acknowledgements: We thank all the stroke team members in the National Taiwan University Hospital on their efforts of taking care of these stroke patients. 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Ruiz de Adana MS, Colomo N, Maldonado-Araque C, Fontalba MI, Linares F, García-Torres F, Fernández R, Bautista C, Olveira G, de la Cruz JL et al : Randomized clinical trial of the efficacy and safety of insulin glargine vs. NPH insulin as basal insulin for the treatment of glucocorticoid induced hyperglycemia using continuous glucose monitoring in hospitalized patients with type 2 diabetes and respiratory disease . Diabetes research and clinical practice 2015, 110 (2):158-165. Danne T, Philotheou A, Goldman D, Guo X, Ping L, Cali A, Johnston P: A randomized trial comparing the rate of hypoglycemia--assessed using continuous glucose monitoring--in 125 preschool children with type 1 diabetes treated with insulin glargine or NPH insulin (the PRESCHOOL study) . Pediatric diabetes 2013, 14 (8):593-601. Korytkowski MT, Salata RJ, Koerbel GL, Selzer F, Karslioglu E, Idriss AM, Lee KK, Moser AJ, Toledo FG: Insulin therapy and glycemic control in hospitalized patients with diabetes during enteral nutrition therapy: a randomized controlled clinical trial . Diabetes care 2009, 32 (4):594-596. Oghazian MB, Javadi MR, Radfar M, Torkamandi H, Sadeghi M, Hayatshahi A, Gholami K: Effectiveness of regular versus glargine insulin in stable critical care patients receiving parenteral nutrition: a randomized controlled trial . Pharmacotherapy 2015, 35 (2):148-157. Nader ND, Hamishehkar H, Naghizadeh A, Shadvar K, Iranpour A, Sanaie S, Chang F, Mahmoodpoor A: Effect of Adding Insulin Glargine on Glycemic Control in Critically Ill Patients Admitted to Intensive Care Units: A Prospective Randomized Controlled Study . Diabetes, metabolic syndrome and obesity : targets and therapy 2020, 13 :671-678. Tang SC, Jen HI, Lin YH, Hung CS, Jou WJ, Huang PW, Shieh JS, Ho YL, Lai DM, Wu AY et al : Complexity of heart rate variability predicts outcome in intensive care unit admitted patients with acute stroke Journal of neurology, neurosurgery, and psychiatry 2015, 86 (1):95-100. Lin SY, Tang SC, Tsai LK, Yeh SJ, Shen LJ, Wu FL, Jeng JS: Incidence and Risk Factors for Acute Kidney Injury Following Mannitol Infusion in Patients With Acute Stroke: A Retrospective Cohort Study . Medicine (Baltimore) 2015, 94 (47):e2032. Adams HP, Jr., Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE, 3rd: Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment . Stroke 1993, 24 (1):35-41. Diabetes Care in the Hospital: Standards of Medical Care in Diabetes-2020 . Diabetes care 2020, 43 (Suppl 1):S193-s202. Mayeda L, Katz R, Ahmad I, Bansal N, Batacchi Z, Hirsch IB, Robinson N, Trence DL, Zelnick L, de Boer IH: Glucose time in range and peripheral neuropathy in type 2 diabetes mellitus and chronic kidney disease . BMJ Open Diabetes Res Care 2020, 8 (1). Chen CH, Huang PW, Tang SC, Shieh JS, Lai DM, Wu AY, Jeng JS: Complexity of Heart Rate Variability Can Predict Stroke-In-Evolution in Acute Ischemic Stroke Patients . Scientific reports 2015, 5 :17552. Tang SC, Huang PW, Hung CS, Shan SM, Lin YH, Shieh JS, Lai DM, Wu AY, Jeng JS: Identification of Atrial Fibrillation by Quantitative Analyses of Fingertip Photoplethysmogram . Scientific reports 2017, 7 :45644. Sim J, Lewis M: The size of a pilot study for a clinical trial should be calculated in relation to considerations of precision and efficiency . J Clin Epidemiol 2012, 65 (3):301-308. Bruno A, Kent TA, Coull BM, Shankar RR, Saha C, Becker KJ, Kissela BM, Williams LS: Treatment of hyperglycemia in ischemic stroke (THIS): a randomized pilot trial . Stroke 2008, 39 (2):384-389. Kreisel SH, Berschin UM, Hammes HP, Leweling H, Bertsch T, Hennerici MG, Schwarz S: Pragmatic management of hyperglycaemia in acute ischaemic stroke: safety and feasibility of intensive intravenous insulin treatment . Cerebrovascular diseases (Basel, Switzerland) 2009, 27 (2):167-175. McCormick M, Hadley D, McLean JR, Macfarlane JA, Condon B, Muir KW: Randomized, controlled trial of insulin for acute poststroke hyperglycemia . Annals of neurology 2010, 67 (5):570-578. Cerecedo-Lopez CD, Cantu-Aldana A, Patel NJ, Aziz-Sultan MA, Frerichs KU, Du R: Insulin in the Management of Acute Ischemic Stroke: A Systematic Review and Meta-Analysis . World neurosurgery 2020, 136 :e514-e534. Umpierrez GE, Hellman R, Korytkowski MT, Kosiborod M, Maynard GA, Montori VM, Seley JJ, Van den Berghe G: Management of hyperglycemia in hospitalized patients in non-critical care setting: an endocrine society clinical practice guideline . The Journal of clinical endocrinology and metabolism 2012, 97 (1):16-38. Umpierrez GE, Smiley D, Hermayer K, Khan A, Olson DE, Newton C, Jacobs S, Rizzo M, Peng L, Reyes D et al : Randomized study comparing a Basal-bolus with a basal plus correction insulin regimen for the hospital management of medical and surgical patients with type 2 diabetes: basal plus trial . Diabetes care 2013, 36 (8):2169-2174. Bellido V, Suarez L, Rodriguez MG, Sanchez C, Dieguez M, Riestra M, Casal F, Delgado E, Menendez E, Umpierrez GE: Comparison of Basal-Bolus and Premixed Insulin Regimens in Hospitalized Patients With Type 2 Diabetes . Diabetes care 2015, 38 (12):2211-2216. Dhital SM, Shenker Y, Meredith M, Davis DB: A retrospective study comparing neutral protamine hagedorn insulin with glargine as basal therapy in prednisone-associated diabetes mellitus in hospitalized patients . Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists 2012, 18 (5):712-719. Umpierrez GE, Smiley D, Zisman A, Prieto LM, Palacio A, Ceron M, Puig A, Mejia R: Randomized study of basal-bolus insulin therapy in the inpatient management of patients with type 2 diabetes (RABBIT 2 trial) . Diabetes care 2007, 30 (9):2181-2186. Supplementary Files insulintablesupplement.pdf Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-56284","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Original investigation","associatedPublications":[],"authors":[{"id":1841293,"identity":"9f7a9ed7-a355-4776-9d36-581633778913","order_by":0,"name":"Sung-Chun Tang","email":"","orcid":"https://orcid.org/0000-0003-3731-5973","institution":"National Taiwan University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Sung-Chun","middleName":"","lastName":"Tang","suffix":""},{"id":1841294,"identity":"84f15fe1-fa27-47be-9985-117c659fed42","order_by":1,"name":"Shyang-Rong Shih","email":"","orcid":"","institution":"National Taiwan University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Shyang-Rong","middleName":"","lastName":"Shih","suffix":""},{"id":1841295,"identity":"7ff5f956-dff7-49e5-944c-d38a03c95727","order_by":2,"name":"Shin-Yi Lin","email":"","orcid":"","institution":"National Taiwan University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Shin-Yi","middleName":"","lastName":"Lin","suffix":""},{"id":1841296,"identity":"82dfef61-bac5-4606-b8a1-c834d09c8aa1","order_by":3,"name":"Chih-Hao Chen","email":"","orcid":"","institution":"National Taiwan University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Chih-Hao","middleName":"","lastName":"Chen","suffix":""},{"id":1841297,"identity":"4981037a-a736-4432-813a-fdd72e05c7e6","order_by":4,"name":"Shin-Joe Yeh","email":"","orcid":"","institution":"National Taiwan University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Shin-Joe","middleName":"","lastName":"Yeh","suffix":""},{"id":1841298,"identity":"8b2bf758-01a2-4936-9936-62498a7b86ea","order_by":5,"name":"Li-Kai Tsai","email":"","orcid":"","institution":"National Taiwan University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Li-Kai","middleName":"","lastName":"Tsai","suffix":""},{"id":1841299,"identity":"bf80cb86-d94a-42a1-a244-a8e6f81d74fe","order_by":6,"name":"Wei-Shiung Yang","email":"","orcid":"","institution":"National Taiwan University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Wei-Shiung","middleName":"","lastName":"Yang","suffix":""},{"id":1841300,"identity":"ae38ccbe-1aa5-45bd-bfe4-8c65deed0f40","order_by":7,"name":"Jiann-Shing Jeng","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAx0lEQVRIiWNgGAWjYBACxgaGBCBlA+HxkKAlDaIaSEgQa9lhErQw9x94+Ljg1/k8e4kExgdv2xjqDA4QctiMhGTjmX23i3kkEpgN57YxSBChhSFNmrfndmKPRAKbNC9QixlBLf0H0n/z9pwDaWH/TZyWhoQ0Zp4fB8C2MBOnBegXad6G5MSeMw+bJeeck5DcT0iLYf+ZxM88f+wS29uTD354U2bDL9lASEsDTwIDYxvEjQxExaQ8AzvQIX8IKxwFo2AUjIIRDABYpj9pZ512cgAAAABJRU5ErkJggg==","orcid":"","institution":"National Taiwan University Hospital","correspondingAuthor":true,"prefix":"","firstName":"Jiann-Shing","middleName":"","lastName":"Jeng","suffix":""}],"badges":[],"createdAt":"2020-08-09 10:29:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-56284/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-56284/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":2204069,"identity":"71afcf09-7a87-4008-b921-53c09be23912","added_by":"auto","created_at":"2020-09-02 16:26:26","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":41888,"visible":true,"origin":"","legend":"The line graphs of the average and standard deviation of glucose levels at prerandomization and during the 72-h intervention period in insulin glargine and NPH insulin groups.","description":"","filename":"OnlineFIGURE120200705.Png","url":"https://assets-eu.researchsquare.com/files/rs-56284/v1/OnlineFIGURE120200705.Png"},{"id":13586936,"identity":"836933b0-3993-4d27-b20f-25d29d4a8946","added_by":"auto","created_at":"2021-09-17 04:49:06","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1537575,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-56284/v1/7f4d0f97-0d41-4927-b455-8d541d31ae54.pdf"},{"id":2204071,"identity":"fb88b055-7a20-4fa5-8537-b3ba19be3f80","added_by":"auto","created_at":"2020-09-02 16:26:27","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":63827,"visible":true,"origin":"","legend":"","description":"","filename":"insulintablesupplement.pdf","url":"https://assets-eu.researchsquare.com/files/rs-56284/v1/insulintablesupplement.pdf"}],"financialInterests":"","formattedTitle":"Efficacy and Safety of Insulin Glargine in Patients With Acute Stroke and Hyperglycemia Receiving Intensive Care: Randomized Controlled Study","fulltext":[{"header":"Background","content":" \u003cp\u003eStroke is the leading cause of mortality and permanent morbidity worldwide.[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] Several factors known to affect poststroke outcomes, including premorbid functional status, advanced age, stroke severity, stroke subtype, and whether acute reperfusion therapy was administered. However, most of these prognostic risk factors are unmodifiable and play a limited role in acute stroke management. Diabetes mellitus is a strong independent risk factor for the development of stroke.[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] Acute stroke may initiate several mechanisms that lead to acute hyperglycemia, such as increased innate immunity and stimulation of the hypothalamic\u0026ndash;pituitary\u0026ndash;adrenal axis.[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] Therefore, patients with acute stroke, especially those with a history of diabetes mellitus, frequently have hyperglycemia.[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] Notably, numerous studies have shown that persistent poststroke hyperglycemia is closely associated with stroke-in-evolution, symptomatic hemorrhagic transformation, hematoma expansion, and unfavorable functional outcomes.[\u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eThe Guidelines for the Early Management of Patients with Acute Ischemic Stroke from the American Heart Association and the American Stroke Association suggest that the blood glucose level should be maintained between 140 and 180\u0026nbsp;mg/dL, in accordance with the current American Diabetes Association recommendation.[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] However, the optimal method to correct hyperglycemia during acute stroke remains unclear. Currently, multiple protocols of subcutaneous and intravenous insulin treatments are used to ameliorate hyperglycemia in patients with different diseases during hospitalization.[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] Continuous intravenous insulin infusion achieves rapid correction of hyperglycemia and is effective in maintaining glucose within a strict predetermined range.[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] However, a recent trial suggested that for patients with acute ischemic stroke and hyperglycemia, aggressive intravenous insulin infusion has a significantly higher chance of inducing hypoglycemia without absolute clinical benefits compared with subcutaneous insulin injection.[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eNeutral protamine Hagedorn (NPH) insulin is widely used for the treatment of hyperglycemia during hospitalization. The duration of its effects is approximately 12\u0026nbsp;h, and it exhibits a peak in its time-action profile at 5 to 7\u0026nbsp;h. These properties mean that NPH does not fully mimic the physiological secretion of basal insulin. By contrast, long-acting insulin analogs such as insulin glargine (IG) create a subcutaneous depot after injection, exhibit no pronounced peak after administration, and last for 24\u0026nbsp;h. They are currently preferred for glycemic control of diabetes.[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] Studies have demonstrated that IG is safe in various clinical situations, including for both non-critically and critically hospitalized patients.[\u003cspan additionalcitationids=\"CR16 CR17 CR18\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] However, evidence regarding the use of IG in patients with acute stroke and hyperglycemia is limited. The objective of this randomized controlled study was to determine the efficacy and safety of early initiation of subcutaneous once-daily IG compared with standard NPH regimens to achieve proper glycemic control in patients with acute stroke and hyperglycemia admitted to the intensive care unit (ICU).\u003c/p\u003e "},{"header":"Patients And Methods","content":"\u003cp\u003eThis is a randomized, open-label, pilot clinical trial. Patients with acute stroke admitted to the stroke ICU of National Taiwan University Hospital within 72\u0026nbsp;h of onset (onset defined as the last known time at which the patient was well) were screened. The entry criteria for admittance to the stroke ICU included ischemic stroke with thrombolytic therapy or endovascular treatment, intracerebral hemorrhage with aggressive blood pressure control treatment, severe neurological deficits (e.g., a National Institute Health Stroke Scale score higher than 8), stroke-in-evolution, or other medical conditions requiring intensive care.[\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e] Patients who met the inclusion criteria (age\u0026thinsp;\u0026ge;\u0026thinsp;20 years, capillary blood glucose\u0026thinsp;\u0026gt;\u0026thinsp;200\u0026nbsp;mg/dL after admission) were enrolled. Patients were excluded if they had any of the following conditions: autoimmune disease, human immunodeficiency virus infection, sepsis, pregnancy, treatment with corticosteroids or vasopressors, end-stage renal disease requiring dialysis, type I diabetes mellitus, or hypersensitivity to any insulin products.\u003c/p\u003e\n\u003cp\u003eThe diagnosis of stroke was confirmed through diffusion-weighted magnetic resonance imaging of the head or repeated computed tomography scanning (if the first scan did not clearly reveal the infarct region). Patients with ischemic stroke were further classified into 5 major subtypes according to the Trial of ORG 10172 in Acute Stroke Treatment criteria: large-artery atherosclerosis, small-vessel occlusion, cardioembolism, specific etiology, and undetermined etiology.[\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/p\u003e\n\u003cp\u003eA detailed history of each patient\u0026rsquo;s clinical presentation, vascular risk factors, and comorbidity was obtained. Body mass index was calculated as weight divided by the square of height in meters. Stroke severity on admission was assessed using the National Institute Health Stroke Scale. Mortality and functional outcome 3 months poststroke were assessed using the modified Rankin scale. Acute stroke care for both groups followed the latest guidelines from the American Heart Association and the American Stroke Association.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eRandomization\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003ePatients were assigned to the IG group or the NPH group through computer-generated randomization. Allocation was concealed by the use of opaque, consecutively numbered envelopes. Treatment allocation was 1:1.\u003c/p\u003e \u003cp\u003e\u003cstrong\u003eInsulin Regimens\u003c/strong\u003e\u003c/p\u003e \u003cp\u003eAll participants received only insulin for glycemic control during the intervention period, which was the first 72\u0026nbsp;h after study enrollment. Administration of oral hypoglycemic agents and noninsulin injections, regardless of whether they were used before stroke, was stopped. The insulin regimens in both groups are described as follows. A basal\u0026ndash;bolus regimen of IG or NPH was used for glycemic control. All patients received regular insulin before meals as a correctional component. During the period when food was prohibited (nothing-by-mouth status), IG was administered because it does not demonstrate a pronounced peak. NPH was withheld to prevent hypoglycemia.\u003c/p\u003e \u003cp\u003eThe total daily insulin dose (TDD) was based on weight. For most patients, the TDD was 0.6 U/kg/day. For patients with anticipated insulin sensitivity, such as those aged over 80\u0026nbsp;years or those whose creatinine clearance rate was below 30\u0026nbsp;mL/min, the TDD was empirically reduced to 0.5 U/kg/day. The TDD of patients receiving insulin therapy before admission was based on their outpatient dose and modified by an endocrinologist. For the IG group, 50% of the TDD was basal insulin and the other 50% was evenly administered before each meal. For the NPH group, 25% of the TDD was basal insulin, and similarly, the remaining 75% was administered evenly before meals. After the regimens were administered, an endocrinologist carefully assessed glycemic levels and made daily adjustments to achieve glycemic levels between 80 and 180\u0026nbsp;mg/dL. Scheduled prandial or basal insulin administration was temporarily stopped during treatment of hypoglycemia (defined as blood glucose\u0026thinsp;\u0026lt;\u0026thinsp;60\u0026nbsp;mg/dL), which was performed in accordance with a previously published guideline.[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/p\u003e \u003cp\u003e\u003cstrong\u003eBlood Glucose Measurements\u003c/strong\u003e\u003c/p\u003e \u003cp\u003eParticipants\u0026rsquo; capillary blood glucose was measured before each meal and once during fasting, at the frequency of every 4 to 6\u0026nbsp;h, depending on their eating schedule. In addition, a Medtronic Enlite Glucose Sensor (Medtronic, Northridge, CA, USA) was used to monitor glycemia during the intervention period.[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] Interstitial glucose levels were recorded every 5\u0026nbsp;min with a detection range of 40 to 400\u0026nbsp;mg/dL. Glucose levels from capillary blood and continuous glucose monitoring (CGM) were compared and calibrated at randomization and 1, 3, and 4\u0026nbsp;h after randomization. The glycemic data from CGM were used in the analyses.\u003c/p\u003e \u003cp\u003e\u003cstrong\u003eStudy Outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary efficacy outcomes were the percentage of glucose levels within the range of 80 to 180\u0026nbsp;mg/dL and the percentage of glucose reduction compared with prerandomization levels during the 72-h intervention period. The primary safety outcome was the percentage of time with hypoglycemia (glucose\u0026thinsp;\u0026lt;\u0026thinsp;60\u0026nbsp;mg/dL). The secondary clinical outcomes were determined according to whether a favorable outcome was achieved (modified Rankin scale score\u0026thinsp;\u0026le;\u0026thinsp;2), whether a poor outcome was achieved (modified Rankin scale score\u0026thinsp;\u0026ge;\u0026thinsp;4), mortality, and Barthel index scores at 3 months poststroke. The secondary laboratory outcomes were glycemic mean and variability, determined from CGM data. Glycemic variability was calculated through linear and nonlinear analyses using previously described methods. We computed two-time domain measures as standard deviations and the root mean square of successive beat-to-beat differences. The nonlinear analysis of sample entropy was also applied to the glucose data using methods described previously.[\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/p\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSample size calculation was not directly applicable in this trial because the expected effect size of our primary outcome, namely the percentage of time before return to normoglycemia, was yet unknown. Instead, we followed a previously proposed method of enrolling at least 50 participants in a pilot study.[\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e] The analysis was performed as intention-to-treat to reflect clinical practice in stroke ICUs. Descriptive statistics of baseline characteristics of the study population are expressed as numbers (percentages) and means\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviations.\u003c/p\u003e\n\u003cp\u003eBecause the primary efficacy and safety outcomes were nonnormally distributed quantitative variables, the Mann\u0026ndash;Whitney U test was used to determine whether the between-group differences in mean percentage of time were significant. Between-group mean differences and 95% confidence intervals of the primary outcomes were also analyzed. The chi-square test or the Fisher\u0026rsquo;s exact test were applied for categorical secondary outcomes, whereas the Mann\u0026ndash;Whitney U test was applied for the continuous variables. In addition, factors associated with a favorable outcome (modified Rankin scale score\u0026thinsp;\u0026le;\u0026thinsp;2) were examined through univariate analysis. A logistic regression method was used to adjust for age and sex and univariate analysis of was conducted to identify factors that were significant predictors (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;.05) of a favorable outcome. Statistical analyses were performed using IBM SPSS Statistics for Windows, version 26 (IBM Corp., Armonk, NY, USA). Significance was defined as \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;.05.\u003c/p\u003e\n\u003c/div\u003e\u003cp\u003e\u003cstrong\u003eEthics\u003c/strong\u003e\u003c/p\u003e \u003cp\u003eThis study was approved by the Institutional Review Board and the Medical Ethics Committee of National Taiwan University Hospital (Clinicaltrials.gov number: NCT02607943). All participants provided informed consent or were recruited with consent provided by their first-degree relatives. The study was conducted in accordance with the revised version of the 2008 Declaration of Helsinki.\u003c/p\u003e "},{"header":"Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n\u003cp\u003e\u003cstrong\u003ePatient characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBetween December 2015 and October 2019, 50 patients with stroke were randomized; 26 were assigned to the IG group and 24 were assigned to the NPH group. Two participants (one in each group) did not have CGM data because of unexpected technical issues. Of the participants, 37 (74%) were admitted with ischemic stroke, and the remainder were admitted with intracerebral hemorrhage. Two patients in the IG group were lost to follow-up at 3 months poststroke. A total of 14 patients (29.2%) had favorable outcomes, and 17 patients (35.4%, including 5 who died) had poor outcomes.\u003c/p\u003e\n\u003cp\u003eThe participant clinical characteristics are listed in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. Baseline profiles were comparable between the groups for age, sex, body mass index, prestroke functional status, stroke type, stroke severity on admission, stroke risk factors, percentage of participants receiving acute reperfusion therapy, and biochemical data on admission. However, creatinine levels were higher in the NPH group than in the IG group (1.21\u0026thinsp;\u0026plusmn;\u0026thinsp;0.45 versus 0.97\u0026thinsp;\u0026plusmn;\u0026thinsp;0.28, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.027). In the NPH and IG groups, 8 and 10 patients had a nothing-by-mouth status when insulin regimens were initiated. Most of them started eating within several hours, but 3 patients in the IG group each fasted for 12, 19, and 41.5\u0026nbsp;h during the intervention period.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eThe baseline characteristics of AIS patients\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eNPH Insulin\u003c/p\u003e\n\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;24)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eInsulin Glargine (n\u0026thinsp;=\u0026thinsp;26)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAge, year\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e62.7\u0026thinsp;\u0026plusmn;\u0026thinsp;16.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e64.7\u0026thinsp;\u0026plusmn;\u0026thinsp;14.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.649\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMale (N)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16 (66.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15 (57.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.571\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e26.3\u0026thinsp;\u0026plusmn;\u0026thinsp;4.1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e26.5\u0026thinsp;\u0026plusmn;\u0026thinsp;5.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.889\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eWeight (kg)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e70.3\u0026thinsp;\u0026plusmn;\u0026thinsp;15.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e70.5\u0026thinsp;\u0026plusmn;\u0026thinsp;16.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.970\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHistory of stroke\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9 (26.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4 (3.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.109\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePre-mRS\u0026thinsp;\u0026ge;\u0026thinsp;2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (20.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4 (15.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.721\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNIHSS at admission\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11.5 (6, 17)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13 (8, 21)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.540\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAtrial fibrillation\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (8.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (11.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.000\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDiabetes mellitus\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e23 (95.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e22 (84.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.351\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHypertension\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e22 (91.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e19 (84.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.066\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHyperlipidemia\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9 (37.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10 (38.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.000\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCAD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (20.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 (23.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.000\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eInfarction\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18 (75.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e19 (73.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"4\" align=\"left\"\u003e\n\u003cp\u003e0.969\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCardioembolism\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 (33.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6(31.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLAA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 (38.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7(36.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOthers\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (27.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6(31.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eICH\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 (25.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 (26.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.000\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSmoking\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 (29.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (19.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.514\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIV rt-PA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (20.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 (26.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.745\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEVT\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 (25.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (19.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0738\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTG (mg/dl)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e200.08\u0026thinsp;\u0026plusmn;\u0026thinsp;119.88\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e190.0\u0026thinsp;\u0026plusmn;\u0026thinsp;263.67\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.851\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTotal Cholesterol (mg/dl)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e189.00\u0026thinsp;\u0026plusmn;\u0026thinsp;52.43\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e175.88\u0026thinsp;\u0026plusmn;\u0026thinsp;65.03\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.439\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLDL (mg/dl)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e108.25\u0026thinsp;\u0026plusmn;\u0026thinsp;31.52\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e105.96\u0026thinsp;\u0026plusmn;\u0026thinsp;45.13\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.837\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGlucose at admission (mg/dl)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e317.00\u0026thinsp;\u0026plusmn;\u0026thinsp;116.85\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e270.88\u0026thinsp;\u0026plusmn;\u0026thinsp;99.87\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.139\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHbA1c (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9.84\u0026thinsp;\u0026plusmn;\u0026thinsp;2.10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9.15\u0026thinsp;\u0026plusmn;\u0026thinsp;1.94\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.235\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCreatinine (mg/dl)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.21\u0026thinsp;\u0026plusmn;\u0026thinsp;0.45\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.97\u0026thinsp;\u0026plusmn;\u0026thinsp;0.28\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.027*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHemoglobin (g/dl)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14.30\u0026thinsp;\u0026plusmn;\u0026thinsp;2.22\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14.30\u0026thinsp;\u0026plusmn;\u0026thinsp;2.11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.000\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eWBC (K/ul)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9.07\u0026thinsp;\u0026plusmn;\u0026thinsp;2.85\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10.17\u0026thinsp;\u0026plusmn;\u0026thinsp;3.00\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.181\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePlatelet (k/ul)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e238.58\u0026thinsp;\u0026plusmn;\u0026thinsp;53.87\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e224.65\u0026thinsp;\u0026plusmn;\u0026thinsp;61.51\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.418\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePTT (second)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e25.68\u0026thinsp;\u0026plusmn;\u0026thinsp;2.29\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e25.61\u0026thinsp;\u0026plusmn;\u0026thinsp;2.50\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.918\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eINR\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.97\u0026thinsp;\u0026plusmn;\u0026thinsp;0.15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.98\u0026thinsp;\u0026plusmn;\u0026thinsp;0.06\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.936\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"4\"\u003eData was expressed as number (proportion) or mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation.\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"4\"\u003e* indicates statistical significance.\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"4\"\u003eAbbreviations: NPH, Neutral protamine hagedorn insulin; BMI, body mass index; mRS, modified Rankin Scale; NIHSS, National Institute of Health Stroke Scale; CAD, coronary artery disease; LAA, large artery atherosclerosis; Others include other determined and undetermined. ICH, intracerebral hemorrhage; IV: intravenous; EVT: endovascular thrombectomy; WBC, white blood cell; PTT, partial thromboplastin time; INR, international normalized ratio; TG, triglyceride; LDL, low-density lipoprotein; HbA1c, glycated hemoglobin;\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003c/div\u003e\u003cp\u003e\u003cstrong\u003eEffectiveness, Safety, And Variabilities\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eAs Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e shows, glycemic levels before randomization were significantly higher in the IG group than in the NPH group (290.69\u0026thinsp;\u0026plusmn;\u0026thinsp;82.31 versus 246.04\u0026thinsp;\u0026plusmn;\u0026thinsp;41.76\u0026nbsp;mg/dL, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.021). The percentage of time with glucose levels between 80 and 180\u0026nbsp;mg/dL was 45.88\u0026thinsp;\u0026plusmn;\u0026thinsp;27.04% in the IG and 53.56\u0026thinsp;\u0026plusmn;\u0026thinsp;22.89% in the NPH (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.341) and the percentage of glucose reduction was 31.47\u0026thinsp;\u0026plusmn;\u0026thinsp;17.52% in the IG and 27.28\u0026thinsp;\u0026plusmn;\u0026thinsp;14.56% in the NPH (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.374).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eStudy outcome between treatment groups\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eNPH Insulin (n\u0026thinsp;=\u0026thinsp;24)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eInsulin Glargine (n\u0026thinsp;=\u0026thinsp;26)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eMean difference (95% CI)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePrimary outcome\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePre- randomization (mg/dl)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e246.04\u0026thinsp;\u0026plusmn;\u0026thinsp;41.76\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e290.69\u0026thinsp;\u0026plusmn;\u0026thinsp;82.31\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e44.65 (7.05 to 82.25)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.021*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eProportion of time in glucose 80\u0026ndash;180 (mg/dl)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e53.56\u0026thinsp;\u0026plusmn;\u0026thinsp;22.89\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e45.88\u0026thinsp;\u0026plusmn;\u0026thinsp;27.04\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-7.67(-22.30 to 6.95)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.341\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePercentage of glucose reduction (mg/dL)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e27.28\u0026thinsp;\u0026plusmn;\u0026thinsp;14.56\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e31.47\u0026thinsp;\u0026plusmn;\u0026thinsp;17.52\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.19 (-5.21 to 13.60)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.374\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSecondary outcome (laboratory)\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;60\u0026nbsp;mg/dl (number of patients)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (12.5%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (7.7%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.660\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;60\u0026nbsp;mg/dl (% of time)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.47\u0026thinsp;\u0026plusmn;\u0026thinsp;1.74\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.14\u0026thinsp;\u0026plusmn;\u0026thinsp;0.49\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.33 (-1.61 to 0.39)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.361\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMean, mg/dl\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e175.82\u0026thinsp;\u0026plusmn;\u0026thinsp;30.16\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e189.89\u0026thinsp;\u0026plusmn;\u0026thinsp;32.86\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14.07(-4.31 to 32.45)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.130\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e40.83\u0026thinsp;\u0026plusmn;\u0026thinsp;11.57\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e41.11\u0026thinsp;\u0026plusmn;\u0026thinsp;14.32\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.29 (-7.32 to 7.89)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.958\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRMSSD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.99\u0026thinsp;\u0026plusmn;\u0026thinsp;1.04\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.16\u0026thinsp;\u0026plusmn;\u0026thinsp;1.06\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.177(-0.43 to 0.79)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.561\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEntropy\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.08\u0026thinsp;\u0026plusmn;\u0026thinsp;0.04\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.07\u0026thinsp;\u0026plusmn;\u0026thinsp;0.04\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.147(-0.39 to 0.01)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.234\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSecondary outcome (clinical) \u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emRS\u0026thinsp;\u0026le;\u0026thinsp;2, n(%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8 (33.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 (25.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.752\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emRS\u0026thinsp;\u0026ge;\u0026thinsp;4, n(%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9 (37.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8 (33.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.00\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMortality, n(%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (8.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (12.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.00\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBI Scores, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e52.29\u0026thinsp;\u0026plusmn;\u0026thinsp;37.39\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e50.42\u0026thinsp;\u0026plusmn;\u0026thinsp;34.89\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-1.88 (-22.89-19.14)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.858\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003eData was expressed as number (proportion) or mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003eAbbreviations: NPH, Neutral protamine hagedorn insulin; SD, standard deviation; RMSSD, rootmeansquare of successive beat-to-beat differences; mRS, modified Rankin scale; BI, Barthel index; NA, not available\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003e\u003csup\u003ea\u003c/sup\u003e Glucose reduction in comparison to pre-randomized glucose level.\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003e\u003csup\u003eb\u003c/sup\u003e n\u0026thinsp;=\u0026thinsp;24 in Glargine group because two subjects were lost of follow-up.\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003e\u003csup\u003ec\u003c/sup\u003e n\u0026thinsp;=\u0026thinsp;23 and 25 in two groups, respectively, due to two subjects with unexpected technical issues of the continuous glucose monitor device.\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003eHypoglycemia, glucose\u0026thinsp;\u0026lt;\u0026thinsp;60\u0026nbsp;mg/dl.\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab3\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eMultivariable analysis for factors predicting AIS patients with good outcome\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eCovariate\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u0026szlig; estimate\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ep\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eodds ratio\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e95% CI\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSex (male)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e-0.571\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.765\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.565\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.013\u0026ndash;23.864\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAge (per year)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e-0.216\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.046*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.805\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.651\u0026ndash;0.996\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNIHSS at admission\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e-0.412\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.040*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.662\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.447\u0026ndash;0.981\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eICH\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.872\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.482\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e2.391\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.211\u0026ndash;27.148\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eWeight (kg)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e-0.136\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.139\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.874\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.731\u0026ndash;1.045\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHemoglobin (g/dl)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.736\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.259\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e2.087\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.582\u0026ndash;7.493\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eInsulin Glargine\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e-1.252\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.361\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.286\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.020\u0026ndash;4191\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003eNIHSS, National Institute of Health Stroke Scale; ICH, intracerebral hemorrhage.\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003e* indicates statistical significance.\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003cp\u003eFor the safety outcome, 3 patients in the NPH group and 2 patients in the IG group had hypoglycemia. The percentage of time with hypoglycemia was very low and comparable between the groups (0.14% \u0026plusmn; 0.49% in the IG group versus 0.47% \u0026plusmn; 1.74% in the NPH group, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.361). Most hypoglycemic events occurred during fasting (from after dinner on the first day to before breakfast on the second day). All patients were asymptomatic during the hypoglycemic period.\u003c/p\u003e\n\u003cp\u003eFigure \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e presents line graphs of the 2 groups\u0026rsquo; average and standard deviation of glucose levels at prerandomization and during the 72-h intervention period. The glucose variability are presented as standard deviations. The root mean square of successive beat-to-beat differences, and sample entropy did not differ significantly between the groups (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). The capillary blood glucose of the 2 patients without CGM data, measured every 4\u0026nbsp;h during the intervention period, also did not differ significantly. All of the secondary clinical outcomes, namely favorable and poor outcomes, mortality, and Barthel index scores 3 months poststroke, were comparable between the groups (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e and Supplementary Fig.\u0026nbsp;1).\u0026nbsp;\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eFactors Associated With A Favorable Outcome\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eAs Supplementary Table\u0026nbsp;1 shows, participants with favorable outcomes had a lower age, higher weight, lower score on the National Institute Health Stroke Scale on admission, greater likelihood of having the intracerebral hemorrhage stroke subtype, and higher levels of hemoglobin compared with those with poor outcomes. None of the glucose-related parameters, including insulin regimen, were associated with significant differences between favorable and poor outcomes. Multivariate analysis showed that only a younger age and lower National Institute Health Stroke Scale score on admission were significantly associated with favorable outcomes (odds ratio\u0026thinsp;=\u0026thinsp;0.805 and 0.662, 95% confidence interval\u0026thinsp;=\u0026thinsp;0.651\u0026ndash;0.996 and 0.447\u0026ndash;0.981, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.046 and .040, respectively).\u003c/p\u003e"},{"header":"Discussion","content":" \u003cp\u003eThis pilot study was designed to assess the safety and efficacy of using long-acting IG in the management of hyperglycemia in patients with acute stroke. To the best of our knowledge, this is the first randomized clinical trial to investigate the feasibility of early initiation of long-acting IG in patients with acute stroke receiving intensive care. Our results indicate that IG is equally as safe and effective as NPH for use to achieve glycemic control in patients with stroke in an ICU setting. Moreover, no significant between-group differences in outcome parameters were observed.\u003c/p\u003e \u003cp\u003eWhether glucose should be controlled intensively and be consistently maintained at a low level in the acute phase of stroke to prevent hyperglycemia-related secondary brain injuries remains subject to debate. Several clinical trials have compared intensive intravenous insulin and standard care in patients with poststroke hyperglycemia.[\u003cspan additionalcitationids=\"CR29\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e] Most trials have reported the efficacy of intensive intravenous insulin infusion in strict glycemic control but also increased risk of hypoglycemic complications. The overall benefit of intravenous insulin infusion for poststroke outcomes is unclear, primarily because of the small sample sizes of relevant studies.[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eThe results of the Stroke Hyperglycemia Insulin Network Effort randomized clinical trial were recently published.[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] The purpose of the trial was to determine and compare the efficacy of intensive and standard treatment of hyperglycemia in patients with acute ischemic stroke. The study comprised 1151 participants randomly assigned to receive continuous intravenous insulin infusion through use of a computerized decision support tool to achieve blood glucose levels of 80 to 130\u0026nbsp;mg/dL or to receive subcutaneous insulin infusion on a sliding scale to achieve blood glucose levels of 80 to 179\u0026nbsp;mg/dL for up to 72\u0026nbsp;h. The results showed that the percentages of patients with favorable functional outcomes were comparable between the intensive and standard treatment groups (20.5% and 21.6%, respectively), but the incidence of early discontinuation of treatment due to hypoglycemia or other adverse effects was higher in the intensive group than in the standard group (11.2% versus 3.2%). These findings do not support the routine use of intensive glycemic control in patients with acute ischemic stroke and hyperglycemia.\u003c/p\u003e \u003cp\u003eNotably, glycemic control in the standard treatment group of the Stroke Hyperglycemia Insulin Network Effort trial involved only a sliding scale of subcutaneous rapid-acting insulin administered every 6\u0026nbsp;h. Despite its convenience and simplicity, use of only sliding-scale insulin therapy in inpatient settings has been demonstrated to be worse for glycemic control compared with basal\u0026ndash;bolus therapy and is strongly discouraged in the current American Diabetes Association guidelines.[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] Sliding-scale insulin therapy is reactive, does not enable adjustments to be made according to the carbohydrate content of meals, and most importantly, does not mimic the physiological delivery of insulin. By contrast, basal\u0026ndash;bolus insulin therapy more closely mimics physiological insulin secretion. Administering daily long-acting insulin on top of prandial rapid-acting insulin reduces not only mean daily glucose levels but also glycemic fluctuation. An insulin regimen comprising basal and correction components is the preferred treatment for noncritically ill hospitalized patients with nothing-by-mouth status.[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e] For patients with a stable oral intake, a correction component should be added.[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] However, basal\u0026ndash;bolus regimens with long-acting IG have not been tested in patients with acute stroke in intensive care.\u003c/p\u003e \u003cp\u003eSeveral studies have compared IG- and NPH-based regimens in hospitalized patients. Most of them have reported comparable glycemic control between the 2 types of insulin.[\u003cspan additionalcitationids=\"CR35\" citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e] However, one investigation demonstrated a higher incidence of hypoglycemic events in the NPH group,[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e] and another reported that the daily insulin requirement was lower in the NPH group.[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e] In our study, the primary and secondary endpoints were mostly comparable between the groups. The proportion of patients with hypoglycemia was very low and also comparable between the groups. Notably, most episodes of hypoglycemia occurred during fasting (from after dinner on the first day to before breakfast on the second day). In addition, one patient in the IG group extended nothing-by-mouth status after the intervention and experienced hypoglycemia. However, none of the patients with hypoglycemia developed clinical signs or complications. Physicians should be more aware of patients\u0026rsquo; glycemic levels during long fasting periods and promptly treat hypoglycemia should it occur.\u003c/p\u003e \u003cp\u003eAlthough the percentage of time for glucose between 80 and 180\u0026nbsp;mg/dL was lower in the IG group than in the NPH group, the percentage of glucose reduction compared with prerandomization levels was higher in the IG group than in the NPH group. This suggests that the insulin regimens may be equally effective and that the mentioned differences could be attributable to the different baseline glucose levels and relatively short intervention period. In addition, 90% of the participants had prestroke diabetes, and the average glycated hemoglobin and admission blood glucose levels were higher than 9% and 250\u0026nbsp;mg/dL, respectively. The starting dose we selected may have been too conservative for these patients. The TDD of the 2 groups was comparable throughout the intervention period (Supplementary Table\u0026nbsp;2), but the total daily basal insulin dose was significantly higher in the IG group (27.5\u0026thinsp;\u0026plusmn;\u0026thinsp;11.3 U/kg in the NPH group versus 57.2\u0026thinsp;\u0026plusmn;\u0026thinsp;19.4 U/kg in the IG group, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;.001). The data correlated well with our study design; 50% and 25% of the TDD was basal insulin in the IG group and the NPH group, respectively.\u003c/p\u003e \u003cp\u003eThis study has several strengths. It is the first to compare guideline-recommended basal\u0026ndash;bolus insulin regimens for the treatment of acute stroke of moderate to high severity requiring critical care. The participants in our study received the optimal treatment for hyperglycemia rather than intensive insulin infusion or regular sliding-scale insulin therapy. In addition, to determine glycemic variability, we performed CGM subcutaneously, ensuring continual delivery of glycemic data (every 5\u0026nbsp;min) during the intervention period. Thus, the effectiveness and safety of both insulin regimens were comprehensively evaluated.\u003c/p\u003e \u003cp\u003eThis study also has some limitations. First, the small sample size and proportion of patients with the heterogeneous stroke subtype may have limited the power of detection of between-group statistical differences in the endpoints. Second, the intervention period (\u0026lt;\u0026thinsp;72\u0026nbsp;h) may have been too short to observe the benefits of glycemic control in stroke outcomes. Nevertheless, the successful application of IG-based basal\u0026ndash;bolus regimens can serve as a reference for future studies with larger sample sizes and more specific groups of patients with acute stroke, which would broaden the generalizability of our findings.\u003c/p\u003e "},{"header":"Conclusion","content":" \u003cp\u003eThis study demonstrates that IG-based basal\u0026ndash;bolus regimens are safe and feasible for patients with acute stroke and hyperglycemia requiring intensive care. Early administration of basal\u0026ndash;bolus insulin regimens in the glycemic management of hospitalized patients with stroke, rather than dependence on sliding-scale insulin, should be promoted.\u003c/p\u003e "},{"header":"Abbreviations","content":"\u003cp\u003e\u003cstrong\u003eIG: \u003c/strong\u003einsulin glargine\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNPH:\u003c/strong\u003e neutral protamine Hagedorn\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCGM:\u003c/strong\u003e continuous glucose monitoring\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eICU: \u003c/strong\u003eintensive care unit\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTDD:\u003c/strong\u003e total daily insulin dose\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e The study was approved by the Research Ethics Committee of National Taiwan University Hospital (NTUH-REC No. 201504075MIN). All participants provided informed consent or were recruited with consent provided by their first-degree relatives.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003cstrong\u003e: \u003c/strong\u003econsent for publication is given where applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u003c/strong\u003e The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interest:\u003c/strong\u003e All authors had no conflicts of interests to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e: The study was funded by the grant of MOST 104-2314-B-002 -220\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions:\u003c/strong\u003e SCT, SRS, WSY, JSJ: Conception and design of the study. SCT, CHC, SJY, LKT: Patients recruitment, and clinical management. SCT, SRS, SYL, CHC: Data acquisition and statistical analysis. SCT, SYL, CHC: Drafting of the manuscript. WSY, JSJ: Critical revision of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u003c/strong\u003e We thank all the stroke team members in the National Taiwan University Hospital on their efforts of taking care of these stroke patients.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eFeigin VL, Nguyen G, Cercy K, Johnson CO, Alam T, Parmar PG, Abajobir AA, Abate KH, Abd-Allah F, Abejie AN\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eGlobal, Regional, and Country-Specific Lifetime Risks of Stroke, 1990 and 2016\u003c/strong\u003e. \u003cem\u003eThe New England journal of medicine \u003c/em\u003e2018, \u003cstrong\u003e379\u003c/strong\u003e(25):2429-2437.\u003c/li\u003e\n\u003cli\u003eHsieh FI, Lien LM, Chen ST, Bai CH, Sun MC, Tseng HP, Chen YW, Chen CH, Jeng JS, Tsai SY\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eGet With the Guidelines-Stroke performance indicators: surveillance of stroke care in the Taiwan Stroke Registry: Get With the Guidelines-Stroke in Taiwan\u003c/strong\u003e. \u003cem\u003eCirculation \u003c/em\u003e2010, \u003cstrong\u003e122\u003c/strong\u003e(11):1116-1123.\u003c/li\u003e\n\u003cli\u003eKruyt ND, Biessels GJ, Devries JH, Roos YB: \u003cstrong\u003eHyperglycemia in acute ischemic stroke: pathophysiology and clinical management\u003c/strong\u003e. \u003cem\u003eNature reviews Neurology \u003c/em\u003e2010, \u003cstrong\u003e6\u003c/strong\u003e(3):145-155.\u003c/li\u003e\n\u003cli\u003eCapes SE, Hunt D, Malmberg K, Pathak P, Gerstein HC: \u003cstrong\u003eStress hyperglycemia and prognosis of stroke in nondiabetic and diabetic patients: a systematic overview\u003c/strong\u003e. \u003cem\u003eStroke \u003c/em\u003e2001, \u003cstrong\u003e32\u003c/strong\u003e(10):2426-2432.\u003c/li\u003e\n\u003cli\u003eDesilles JP, Meseguer E, Labreuche J, Lapergue B, Sirimarco G, Gonzalez-Valcarcel J, Lavall\u0026eacute;e P, Cabrejo L, Guidoux C, Klein I\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eDiabetes mellitus, admission glucose, and outcomes after stroke thrombolysis: a registry and systematic review\u003c/strong\u003e. \u003cem\u003eStroke \u003c/em\u003e2013, \u003cstrong\u003e44\u003c/strong\u003e(7):1915-1923.\u003c/li\u003e\n\u003cli\u003ePalaiodimou L, Lioutas VA, Lambadiari V, Paraskevas GP, Voumvourakis K, Tsivgoulis G: \u003cstrong\u003eGlycemia management in acute ischemic stroke: current concepts and novel therapeutic targets\u003c/strong\u003e. \u003cem\u003ePostgraduate medicine \u003c/em\u003e2019, \u003cstrong\u003e131\u003c/strong\u003e(7):423-437.\u003c/li\u003e\n\u003cli\u003eWilliams LS, Rotich J, Qi R, Fineberg N, Espay A, Bruno A, Fineberg SE, Tierney WR: \u003cstrong\u003eEffects of admission hyperglycemia on mortality and costs in acute ischemic stroke\u003c/strong\u003e. \u003cem\u003eNeurology \u003c/em\u003e2002, \u003cstrong\u003e59\u003c/strong\u003e(1):67-71.\u003c/li\u003e\n\u003cli\u003eShimoyama T, Kimura K, Uemura J, Saji N, Shibazaki K: \u003cstrong\u003eElevated glucose level adversely affects infarct volume growth and neurological deterioration in non-diabetic stroke patients, but not diabetic stroke patients\u003c/strong\u003e. \u003cem\u003eEuropean journal of neurology \u003c/em\u003e2014, \u003cstrong\u003e21\u003c/strong\u003e(3):402-410.\u003c/li\u003e\n\u003cli\u003eChen W, Wang X, Liu F, Ma L, Chen J, You C: \u003cstrong\u003eAssociation of blood glucose with 30-day mortality in patients with intracerebral hemorrhage undergoing neurosurgical treatment\u003c/strong\u003e. \u003cem\u003eBritish journal of neurosurgery \u003c/em\u003e2020:1-6.\u003c/li\u003e\n\u003cli\u003ePowers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, Biller J, Brown M, Demaerschalk BM, Hoh B\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eGuidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association\u003c/strong\u003e. \u003cem\u003eStroke \u003c/em\u003e2019, \u003cstrong\u003e50\u003c/strong\u003e(12):e344-e418.\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003e15. 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Management of Acute Ischemic Stroke: A Systematic Review and Meta-Analysis\u003c/strong\u003e. \u003cem\u003eWorld neurosurgery \u003c/em\u003e2020, \u003cstrong\u003e136\u003c/strong\u003e:e514-e534.\u003c/li\u003e\n\u003cli\u003eUmpierrez GE, Hellman R, Korytkowski MT, Kosiborod M, Maynard GA, Montori VM, Seley JJ, Van den Berghe G: \u003cstrong\u003eManagement of hyperglycemia in hospitalized patients in non-critical care setting: an endocrine society clinical practice guideline\u003c/strong\u003e. \u003cem\u003eThe Journal of clinical endocrinology and metabolism \u003c/em\u003e2012, \u003cstrong\u003e97\u003c/strong\u003e(1):16-38.\u003c/li\u003e\n\u003cli\u003eUmpierrez GE, Smiley D, Hermayer K, Khan A, Olson DE, Newton C, Jacobs S, Rizzo M, Peng L, Reyes D\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eRandomized study comparing a Basal-bolus with a basal plus correction insulin regimen for the hospital management of medical and surgical patients with type 2 diabetes: basal plus trial\u003c/strong\u003e. \u003cem\u003eDiabetes care \u003c/em\u003e2013, \u003cstrong\u003e36\u003c/strong\u003e(8):2169-2174.\u003c/li\u003e\n\u003cli\u003eBellido V, Suarez L, Rodriguez MG, Sanchez C, Dieguez M, Riestra M, Casal F, Delgado E, Menendez E, Umpierrez GE: \u003cstrong\u003eComparison of Basal-Bolus and Premixed Insulin Regimens in Hospitalized Patients With Type 2 Diabetes\u003c/strong\u003e. \u003cem\u003eDiabetes care \u003c/em\u003e2015, \u003cstrong\u003e38\u003c/strong\u003e(12):2211-2216.\u003c/li\u003e\n\u003cli\u003eDhital SM, Shenker Y, Meredith M, Davis DB: \u003cstrong\u003eA retrospective study comparing neutral protamine hagedorn insulin with glargine as basal therapy in prednisone-associated diabetes mellitus in hospitalized patients\u003c/strong\u003e. \u003cem\u003eEndocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists \u003c/em\u003e2012, \u003cstrong\u003e18\u003c/strong\u003e(5):712-719.\u003c/li\u003e\n\u003cli\u003eUmpierrez GE, Smiley D, Zisman A, Prieto LM, Palacio A, Ceron M, Puig A, Mejia R: \u003cstrong\u003eRandomized study of basal-bolus insulin therapy in the inpatient management of patients with type 2 diabetes (RABBIT 2 trial)\u003c/strong\u003e. \u003cem\u003eDiabetes care \u003c/em\u003e2007, \u003cstrong\u003e30\u003c/strong\u003e(9):2181-2186.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Stroke, hyperglycemia, insulin Glargin, NPH, intensive care","lastPublishedDoi":"10.21203/rs.3.rs-56284/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-56284/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003cem\u003e \u003c/em\u003e\u003c/strong\u003eThis pilot study compared the basal–bolus regimens of long-acting insulin glargine (IG) and neutral protamine Hagedorn (NPH) insulin in efficacy and safety in acute stroke patients with hyperglycemia receiving intensive care (NCT02607943).\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eThis was a randomized, open-label, clinical trial. Stroke patients who were admitted to the intensive care unit within 72 h of onset and met the inclusion criteria were enrolled. They received either IG or NPH with added short-acting prandial regular insulin over a 72-h period. The primary endpoints were the percentage of glucose within the range of 80 to 180 mg/dL and the percentage of glucose reduction compared with pre-randomization glucose levels, assessed through continuous glucose monitoring (CGM).\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e A total of 50 patients were included, 26 and 24 were randomly assigned to the IG and NPH, respectively. The participant baseline characteristics were comparable between groups, except the IG had a significantly higher glucose level pre-randomization than the NPH (290.69 ± 82.31 versus 246.04 ± 41.76 mg/dL, \u003cem\u003eP\u003c/em\u003e = .021). CGM data showed that the percentage of time with glucose levels between 80 and 180 mg/dL was 45.88 ± 27.04% in the IG and 53.56 ± 22.89% in the NPH (\u003cem\u003eP\u003c/em\u003e = .341) and the percentage of glucose reduction was 31.47 ± 17.52% in the IG and 27.28 ± 14.56% in the NPH (\u003cem\u003eP\u003c/em\u003e = .374). The percentage of time with hypoglycemia (\u0026lt; 60 mg/dl) was 0.14 ± 0.49% in the IG and 0.47 ± 1.74% in the NPH (\u003cem\u003eP\u003c/em\u003e = .361). Parameters representative of glucose variabilities, and poststroke outcomes were not significantly different between the groups.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eOur study results suggest that early initiation of an IG-based basal–bolus regimen is safe and equally effective as an NPH-based basal-bolus regimen for patients with acute stroke and hyperglycemia requiring intensive care.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eTrial registration:\u003c/strong\u003e ClinicalTrials.gov, NCT02607943. Registered 18 Nov 2015, https://clinicaltrials.gov/ct2/show/NCT02607943\u003c/p\u003e","manuscriptTitle":"Efficacy and Safety of Insulin Glargine in Patients With Acute Stroke and Hyperglycemia Receiving Intensive Care: Randomized Controlled Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2020-09-02 16:26:13","doi":"10.21203/rs.3.rs-56284/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"759f854b-18c0-4411-98c4-93c10d3b9bb8","owner":[],"postedDate":"September 2nd, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":414217,"name":"Endocrinology \u0026 Metabolism"},{"id":414218,"name":"Cardiac \u0026 Cardiovascular Systems"}],"tags":[],"updatedAt":"2020-09-06T16:59:50+00:00","versionOfRecord":[],"versionCreatedAt":"2020-09-02 16:26:13","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-56284","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-56284","identity":"rs-56284","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}