| Stroke is the second leading cause of death globally and the first leading cause of death in China,the burden of which is steadily increasing worldwide.Intracerebral hemorrhage(ICH)accounts for 10-15% of all stroke cases in Western countries and up to 25% in China,which is associated with higher rates of death and disability than ischemic stroke.The evaluation and control of predictors for ICH clinical outcomes is of great importance.Disorders of glucose metabolism are prevalent in patients with ICH,such as elevated blood glucose and impaired glucose regulation(IGR)after onset.However,associations between those factors and ICH outcomes are still unclear,which make them unable to guide interventions for glucose management in ICH.Firstly,the prognostic value of elevated admission blood glucose(ABG)for ICH outcomes is still under debate and it is unclear whether elevated ABG portended a different prediction based on patients’ diabetic status.Some but not all studies have shown that elevated ABG is a predictor of poor outcomes in ICH,most of which are limited to small size,single-centre design,or no direct comparison between diabetics and non-diabetics.Evidences from large-scale multi-centre studies are quite limited,the study subjects of which are limited to specific population such as non-comatose or mild to moderate patients.The prognostic value of elevated ABG for clinical outcomes in diabetic and non-diabetic patients with ICH needs to be validated in a representative large cohort so as to investigate the target glucose levels for patients with and without diabetes.Secondly,the influence of IGR on ICH outcomes is still unknown.The prevalence of IGR is high(26.3%-32.8%)in patients with ICH.The association between IGR and clinical outcomes of ICH patients deserves investigation.However,most studies about IGR focus on the prevalence of IGR in patients with stroke and the prognosis value of IGR in outcomes of ischemic stroke.Evidence on IGR and ICH outcomes is scare,which needs to be investigated in clinical studies.Considering the poor prognosis of ICH,a tool to predict its mortality is useful in many ways such as determining prognosis,making treatment plan and improving patient-physician communication.However,the performance of existing ICH mortality prediction models is poor and complex for application.Smith et al developed and internally validated more general predictive models for in-hospital mortality from acute stroke of any type(ischemic stroke,ICH,subarachnoid hemorrhage,or uncertain type)using Get With the Guidelines-Stroke(GWTG-Stroke)database and implemented them into the GWTG-Stroke Patient Management Tool,of which,the prediction of ICH in-hospital mortality showed excellent discrimination and calibration.However,its usefulness in Chinese patients with acute stroke is still unknown.Accordingly,the purpose of the current study includes validating the prognostic value of elevated ABG for clinical outcomes in diabetic and non-diabetic patients with ICH,investigating the association between IGR and ICH outcomes,and evaluating the performance of the GWTG risk model for all stroke types in different stroke populations.Part one Association between admission blood glucose and prognosis of intracerebral hemorrhage with different glucose metabolismObjective: We aimed to validate prognostic value of elevated admission blood glucose(ABG)for clinical outcomes in diabetic and non-diabetic patients with intracerebral hemorrhage(ICH)in a representative large cohort.Methods:1 Study Population.The study was based on the China National Stroke Registry(CNSR),a nationwide,multicentre and prospective cohort study,the design,rationale,and baseline information of which has been described in detail elsewher.In brief,CNSR was the largest stroke registry of consecutive patients with acute cerebrovascular events between September 2007 and August 2008 in China.132 hospitals from different regions representing 27 provinces and 4 municipalities in mainland China were selected.The protocol and data collection was approved by the Institutional Review Board at Beijing Tiantan Hospital and all participating hospitals.Written informed consent was obtained from each participant or his/her designated relatives.To be eligible for the diagnosis of ICH in our study,subjects had to meet the following criteria: 1)hospitalized with a primary diagnosis of spontaneous ICH according to the World Health Organization criteria;2)ICH confirmed by brain CT.Patients were excluded with the following conditions: 1)no admission blood glucose data available;2)onset time over 24 hours;3)lost-to-follow up;4)primary intraventricular ICH,ICH caused by trauma,brain tumor,hemorrhage secondary to malignancy,subarachnoid hemorrhage,arteriovenous malformation and hemorrhagic transformation of cerebral infarct.2 Data Collection and Variable Definition.Demographic characteristics,clinical information,radiographic findings,treatment during hospitalization and ABG were collected from the database,as well as hemorrhage evaluation including stroke severity,hematoma volume and hematoma location.Stroke severity was measured using the initial National Institutes of Health Stroke Scale(NIHSS)score and Glasgow Coma Scale(GCS)score.According to previous studies,we used the first measured blood glucose as ABG.ABG was the first blood glucose measured at the initial emergency department or the blood glucose value from in-hospital immediate evaluation,which was generally done within 3 hours of admission.Patients with a history of diabetes or glucose-lowering treatment before ICH were classified as diabetics,according to previously published articles.3 Outcome Measures.The clinical outcomes was poor outcome defined as death or dependency(modified Rankin scale [mRS] score of 3 to 6)and death(mRS score of 6)at 3 months,which was assessed by trained study investigators.The telephone follow-up was conducted centrally for all enrolled patients with a standardized interview protocol.4 Statistical Analysis.Baseline demographic and clinical characteristics were expressed as mean(standard deviation)or median(interquartile range)for continuous variables and as number(%)for categorical variables.The chi-square test for categorical variables and Mann–Whitney test for continuous variables were used as needed.Associations of ABG,both as continuous and categorical(quartile)variables,and risk of poor outcome and death were evaluated by separate univariable and multivariable logistic regression.Odds ratios(ORs)with 95% confidence intervals(CI)were calculated.All significant(P<0.05)baseline variables in the univariable analysis were included in the multivariable analysis.We further evaluated the associations between ABG and risk of poor outcome and death using a multivariable logistic regression model with restricted cubic splines for ABG adjusting for all confounding factors.The 5 knots for spline were placed at the 5th,25 th,50th,75 th,95th percentiles of ABG.These analyses were performed in the entire cohort and repeated in patients with and without DM.A 2-sided P value <0.05 was set as the level for statistical significance.All analyses were performed with SAS software version 9.4(SAS Institute Inc,Cary,NC,USA).Results: 2951 ICH patients were enrolled,including 267(9.0%)diabetics.In the entire cohort,there was a trend to increased risk of poor outcome with increasing ABG levels(adjusted OR 1.09;95% CI,1.04-1.15;P<0.001).The risk of poor outcome was significantly greatest for the highest quartile(≥7.53 mmol/L)of ABG(adjusted OR 1.54;95% CI,1.17-2.03;P=0.002,P for trend 0.004).We got similar association in non-diabetics but not in diabetics.Elevated ABG confers a higher risk of poor outcome in non-diabetics than diabetics with similar glucose level.Part two Association between impaired glucose regulation and prognosis of Chinese patients with intracerebral hemorrhageObjective: This study aimed at observing the influence of impaired glucose regulation(IGR)on 1-year outcomes in patients with intracerebral hemorrhage(ICH).Methods:1 Study Population.The study population was derived from the study of Abnormal gluCose Regulation in patients with acute strOke acro SS China(ACROSS-China).In brief,ACROSS-China was a nationwide,multicenter and prospective cohort study,aimed at investigating the prevalence and influence of abnormal glucose regulation among patients hospitalized with acute stroke.Patients with ischemic stroke,ICH,or subarachnoid hemorrhage(SAH)within 14 days after onset were recruited consecutively from 35 participating hospitals across China from August 2008 to October 2009.A standard Oral glucose tolerance test(OGTT)was performed in all the participants without previously known DM at the day 14±3 after stroke onset or before discharge according to the World Health Organization(WHO)criteria.The protocol and data collection were approved by the Ethics Committees at Beijing Tiantan Hospital and all participating hospitals.Written informed consent was obtained from each participant or his/her designated relatives.Acute stroke was diagnosed according to WHO criteria combined with brain CT or MRI confirmation.For the current study,patients with ischemic stroke and SAH were excluded.We also excluded patients with previously known diabetes,no OGTT performed,newly diagnosed diabetes(NDM)based on OGTT results and patients lost to follow-up.2 Data Collection and Variable Definition.Demographic characteristics,clinical information,status on admission including stroke severity and blood pressure values,hematoma locations,laboratory values on admission,treatment during hospitalization and OGTT results were collected from the database.Stroke severity was measured using the initial NIHSS score and GCS score.The definition of NGR,IGR and NDM were based on the OGTT results.According to the WHO criteria,IGR was defined as having isolated IFG(FPG≥6.1 mmol/L and < 7.0 mmol/L,meanwhile,2-h plasma glucose [2-h PG] < 7.8 mmol/L),or isolated IGT(FPG < 6.1 mmol/L,meanwhile,2-h PG ≥7.8 mmol/L and < 11.1 mmol/L),or complex IGT(FPG ≥ 6.1 mmol/L and < 7.0 mmol/L,meanwhile,2-h PG ≥7.8 mmol/L and <11.1 mmol/L).NGR was defined as FPG <6.1 mmol/L and 2-h PG <7.8 mmol/L.NDM was defined as FPG ≥7.0 mmol/L and/or 2-h PG ≥11.1 mmol/L.Patients with self-reported physician diagnosis of DM or hypoglycemic treatment before ICH were classified as those with previously known DM.3 Outcome Measures.The outcomes were all-cause death(modified Rankin scale [mRS] score of 6),dependency(mRS score of 2 to 5)and poor outcome defined as mRS score of 2 to 6 at 1 year.The 1-year follow-up of participants were conducted by trained research personnel at Beijing Tiantan Hospital.The mRS score at 1 year after onset of ICH were recorded through telephone interview.A death certificate from the local citizen registry or the attended hospital was used to confirm the case fatality.4 Statistical Analysis.Baseline demographic and clinical characteristics were expressed as mean(standard deviation)or median(interquartile range)for continuous variables and as percentages for categorical variables.The chi-square test for categorical variables and Mann–Whitney test for continuous variables were used as needed.Cox proportion hazard model for death and logistic regression model for dependency and poor outcome were performed both in univariable and multivariable analyses to show the association between IGR and outcomes.Hazard ratios(HRs)and odds ratios(ORs)with 95%CI were calculated.Age,gender and all significant baseline variables in the univariable analysis were included in the multivariable analysis.A 2-sided P value <0.05 was set as the level for statistical significance.All analyses were performed with SAS software version 9.4(SAS Institute Inc,Cary,NC,USA).Results: A total of 288 non-diabetic ICH patients were included in this analysis,among which 150(52.1%)were IGR.IGR was associated with 1-year dependency(adjusted OR 2.18,95% confidence interval [CI],1.19-3.99;P=0.01)and poor outcome(adjusted OR 2.17;95% CI,1.24-3.80;P=0.007)of patients with ICH.However,IGR showed no significant association with 1-year death(adjusted HR 1.49,95% CI,0.60-3.67;P=0.39).Part three External validation and extension application of GWTG risk model for all stroke typesObjective: We aimed to externally validate the GWTG risk model for all stroke types to predict in-hospital stroke mortality in Chinese patients and moreover to explore its prognostic value in predicting 3-month mortality after stroke.Methods:1 Study population.The data set was derived from the China National Stroke Registry-II(CNSR-II),which was a nationwide prospective cohort study of consecutive patients with acute stroke within 7 days after the onset of symptoms from June 2012 to January 2013 in China.A total of 219 hospitals from different regions in mainland China were selected.Detailed demographic and clinical data were collected by trained research coordinators with standardized data collection tool.The protocol and data collection was approved by the Institutional Review Board at Beijing Tiantan Hospital and all participating hospitals.Written informed consents were obtained from all participants or their designated relatives.The diagnosis and classification of acute stroke was made according to WHO criteria combined with brain CT or MRI confirmation.For the current study,we included acute stroke of any type(IS,ICH,SAH,and uncertain type).2 Variable Definition and data collection.Variables for GWTG risk model included age,gender,initial NIHSS Score,mode of arrival(ambulance from scene,private transport,and did not present via emergency department),medical history(history of atrial fibrillation,previous stroke/transient ischemic attack(TIA),coronary artery disease,peripheral vascular disease and dyslipidemia),time of arrival(7am-5pm Monday to Friday as daytime regular hours)and stroke type.Data were derived from the CNSR II database according to the definitions in the original article.Patients were excluded if any of the variables above were not available.3 Outcome Measures.The main outcomes of interest were in-hospital and 3-month death.A death certificate from the local citizen registry or the attended hospital was used to confirm the in-hospital case fatality.Death at 3 months was assessed by trained study investigators through telephone interview at 3 months,which was centralized with a standardized interview protocol.4 Statistical Analyses.Baseline characteristics were expressed as mean(standard deviation)or median(interquartile range)for continuous variables and as percentages for categorical variables.Student t test or Kruskal-Wallis test for continuous variables and χ2 test for categorical variables were used as needed.The calculation of the mortality and risk score category were performed in a manner identical to that reported in the original article.The discrimination of the model(c-statistic)was assessed by the area under the receiver-operator curves(AUCs)and 95% confidence intervals(CIs).Calibration was assessed by Pearson correlation coefficient.The observed and predicted mortality rates were plotted with 10 deciles of predicted risk.The discrimination and calibration of the model for each individual stroke type were also assessed.A 2-sided P value <0.05 was set as the level for statistical significance.All analyses were performed with SAS software version 9.4(SAS Institute Inc,Cary,NC,USA).Results: Date from 21684 stroke patients with complete data for in-hospital mortality prediction and 20348 stroke patients with complete data for 3-month mortality prediction in the CNSR-II were abstracted.The in-hospital and 3-month mortality were 1.4% and 5.6%,respectively.The C statistics in the CNSR-II were 0.86(95% CI,0.84-0.88)and 0.83(95% CI,0.81-0.84)for in-hospital and 3-month mortality,respectively.Calibration plot presented high correlation between the observed and predicted mortality rates(Pearson correlation coefficient,0.996 for in-hospital and 0.998 for 3-month mortality;both P<0.001).The model performed nearly as well in each stroke type as in the overall model including all types.In solely ICH,the C statistics were 0.80 and 0.83 for in-hospital and 3-month mortality,respectively.Pearson correlation coefficient,0.987 for in-hospital and 0.995 for 3-month mortality;both P<0.001.Conclusions:1.Elevated ABG is an independent predictor of 3-month poor outcome in ICH patients,the prognostic value of which is greater in non-diabetics than diabetics with similar glucose level.2.IGR is independently associated with 1-year poor outcome of ICH in Chinese patients,with more important influence on dependency than death.3.The GWTG risk model for all stroke types is a valid clinical tool to predict in-hospital and 3-month mortality in Chinese patients with ICH,which could be applied to acute stroke of any type as well. |
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