|ORIGINAL RESEARCH REPORT
|Year : 2021 | Volume
| Issue : 3 | Page : 142-147
An investigation of the relationship of the admission hyperglycemia to severity and 30-day outcome in acute ishemic and intracerebral hemorraghic stroke: A comparative cross sectional study
Osigwe Paul Agabi1, Oluwadamilola Omolara Ojo2, Mustapha Abudu Danesi2, Frank Ibe Ojini2, Njideka Ulumna Okubadejo2
1 Department of Medicine, Neurology Unit, Lagos University Teaching Hospital, Idi Araba, Lagos State, Nigeria
2 Department of Medicine, Neurology Unit, Lagos University Teaching Hospital; Department of Medicine, Faculty of Clinical Sciences, College of Medicine, University of Lagos, Idi Araba, Lagos State, Nigeria
|Date of Submission||29-Oct-2020|
|Date of Acceptance||10-Feb-2021|
|Date of Web Publication||23-Aug-2021|
Dr. Osigwe Paul Agabi
Department of Medicine, Neurology Unit, Lagos University Teaching Hospital, Idi Araba, Lagos State
Source of Support: None, Conflict of Interest: None
Background: Hyperglycemia is implicated as deleterious in acute stroke, although the impact may vary by stroke subtype. We sought to determine the frequency of admission hyperglycemia (subcategorized as diabetes related or reactive) and explore the relationship to stroke severity and functional motor outcome in acute ischemic stroke (AIS) and intracerebral hemorrhage (ICH) stroke subtypes. Methods: This cross-sectional study recruited 170 stroke patients (85 AIS, 85 ICH) presenting within 72 h of onset. Baseline characteristics including stroke severity (National Institutes of Health Stroke Scale score), random blood glucose (RBG), and glycated hemoglobin (HBA1C) were documented. The outcomes were 30-day case fatality rate (CFR) and functional motor outcome. Results: The frequency of admission hyperglycemia was 24.7% in AIS and 22.4% ICH, with 18.8%/5.9% of AIS and 9.4%/12.9% of ICH presumed diabetes related and reactive, respectively. Stroke severity and infarct size were positively correlated with admission RBG and HBA1C (P = 0.000) in AIS but not ICH. Presumed mechanism of hyperglycemia did not relate significantly with either infarct size or hematoma volume (P > 0.05). Thirty days CFR was higher in AIS with hyperglycemia (42.9%) compared to normoglycemia (12.5%) (P = 0.003), but did not vary significantly in ICH (42.1% with and 36.4% without hyperglycemia; P = 0.65). There was no significant relationship of hyperglycemia to functional outcome in either stroke subtype. Conclusions: The association of admission hyperglycemia to stroke severity and short-term case fatality is evident in AIS. In ICH, hyperglycemia was not associated with significantly greater stroke severity and death at 30 days, even though case fatality was higher in those with hyperglycemia.
Keywords: Case fatality, diabetes, hyperglycemia, intracerebral hemorrhage, ischemic, outcome, reactive, severity, stroke
|How to cite this article:|
Agabi OP, Ojo OO, Danesi MA, Ojini FI, Okubadejo NU. An investigation of the relationship of the admission hyperglycemia to severity and 30-day outcome in acute ishemic and intracerebral hemorraghic stroke: A comparative cross sectional study. J Clin Sci 2021;18:142-7
|How to cite this URL:|
Agabi OP, Ojo OO, Danesi MA, Ojini FI, Okubadejo NU. An investigation of the relationship of the admission hyperglycemia to severity and 30-day outcome in acute ishemic and intracerebral hemorraghic stroke: A comparative cross sectional study. J Clin Sci [serial online] 2021 [cited 2022 Aug 18];18:142-7. Available from: https://www.jcsjournal.org/text.asp?2021/18/3/142/324408
| Introduction|| |
Stroke is the leading cause of mortality and disability attributable to neurological diseases globally, including Africa. The determinants of outcome in hospitalized acute stroke cases include potentially modifiable pathobiological alterations which may be amenable to intervention. The impetus for recognizing these prognostic indicators is the unacceptably high stroke mortality and morbidity, particularly in resource-limited settings with limited capacity for more specific/targeted acute stroke therapies. In such settings, but also in the general care of acute stroke (including those receiving thrombolysis), current guidelines specify the importance of maintenance of a milieu that promotes neuronal cellular function and impedes deleterious effects on surviving neurons. Blood glucose elevation (either in preexisting diabetes or as an acute phase reaction) in the setting of acute stroke has been associated with more adverse outcomes such as functional and cognitive disability, prolonged hospitalization, higher complication rates, and an overall higher case fatality. The mechanism underlying the deleterious effect is most likely multifactorial. Elevated blood glucose has been implicated in the injurious metabolic changes (including lactic acidosis, lipid peroxidation, mitochondrial dysfunction, and cell death) occurring in cortical neurons following ischemic stroke and in exacerbating brain edema and perihematomal cell death following intracerebral hemorrhage (ICH).,, Admission hyperglycemia (either in the setting of comorbid diabetes mellitus (DM) or as a reactive phenomenon) is prevalent in acute ischemic stroke (AIS) and ICH. The precise prevalence reported has varied depending on the various factors such as the definitive cutoff for hyperglycemia, sub-population of interest (nondiabetic compared to diabetic), duration of monitoring (hyper-acute within a few hours versus early poststroke such as within 72 h), and intensity of the reference monitoring (single value compared to continuous averaged readings). Whereas the association between admission hyperglycemia and worse short-term neurological outcome in AIS is fairly consistent, available literature presents a more variable association as a prognostic indicator in ICH. Furthermore, some studies have suggested a variable impact of hyperglycemia on stroke outcome in persons with preexisting diabetes in contrast to those in which hyperglycemia seemingly occurs as an acute phase poststroke stress response., The objectives of the present study were to compare the frequency of admission hyperglycemia (reactive or due to preexisting diabetes) and explore the relationship to stroke severity determined by the National Institutes of Health Stroke Scale (NIHSS) score and short-term outcome (functional motor and case fatality) in AIS and ICH.
| Methods|| |
This was a cross-sectional comparative study conducted at the Lagos University Teaching Hospital (LUTH), Lagos State, Nigeria. The approval of the study protocol was obtained from the LUTH Health Research Ethics Committee. All strokes were managed by a multidisciplinary stroke team in a general neurology ward or intensive care unit using a treatment protocol adapted from the existing international guidelines. No AIS case received thrombolytic therapy. All adult patients (≥18 years) presenting over a 12-month period (November 2014 to October 2015) to the emergency department within 72 h of a first ever neuroimaging confirmed stroke and for whom informed consent was obtained (from patient or proxy) were recruited into the study. The minimum sample size of 155 was calculated with the Kish and Leslie formula and rounded up to 170 (to account for 10% possibility of attrition), with participants recruited in a 1:1 ratio of AIS and ICH (85 participants per group). The time of stroke onset was defined as the last time the patient was known to be well (without any neurological deficit). Repeat clinically evident stroke and subarachnoid hemorrhage were excluded. On the basis of a predetermined sample size and case ratio, 85 AIS and 85 ICH were enrolled. During the study period, a total of 230 patients presenting with the features consistent with acute stroke were screened for enrolment. Of these, 60 were excluded on account of presentation after 72 h of stroke onset (43), unavailability of brain imaging (11), or transfer to outside facility soon after admission (6). Demographic and stroke-related clinical data and neurological findings including stroke severity assessed using the NIHSS were documented on admission.,
Noncontrast brain computerized tomography (CT) was utilized to confirm stroke subtype. All CT scans were assessed by a researcher (clinical neurologist) with experience in interpretation of brain CT scans and a consultant radiologist with expertise in neuroradiology. As utilized in previous stroke studies, all lesion volumes (cm3/ml; infarcts and hemorrhages) were calculated using the A X B X C/2 method, where A was the greatest lesion diameter by CT, B was the diameter 90° to A, and C was the approximate number of CT slices with lesion multiplied by the slice thickness.,,
Random blood glucose (RBG) (mg/dL) and glycated hemoglobin (HBA1C) (%) were estimated on venous samples drawn at admission. Admission hyperglycemia was defined as a RBG ≥7.8 mmol/l (≥140 mg/dL). Reactive hyperglycemia was admission hyperglycemia in a patient without evidence of prior diabetes in line with the American Diabetes Association and the American Association of Clinical Endocrinologists consensus guidelines. Preexisting DM was diagnosed based on HBA1C ≥6.5 with or without a documented history of DM. Nondiabetics with admission hyperglycemia and normal HBA1C were presumed to have reactive hyperglycemia. Although stress-related hyperglycemia can also occur in diabetes, there is no established consensus on its definition. As such, in patients with DM (new or established) with elevated admission blood glucose, the patient was categorized under diabetes-related hyperglycemia. All cases were followed up for 30 days (or until demise if earlier). The primary outcomes of interest were case fatality and functional outcome (in survivors) at 30 days poststroke onset. Functional outcome was assessed using the Modified Rankin Scale and dichotomized as good (0–2) and poor (3–5).
Statistical analysis was performed using the IBM Statistical Package for the Social Sciences (SPSS®) software version 20 (IBM, Armonk, NY, USA). Descriptive statistics are provided for the clinical characteristics of AIS and ICH cases, with comparison of intergroup differences performed using appropriate statistics for comparing the means for normally distributed continuous variables (analysis of variance) and nonnormally distributed data (presented as medians; non parametric Mann–Whitney U test). Categorical variables were compared using the Pearson Chi-squared test, whereas bivariate correlation analysis was conducted using the Pearson correlation test. In all the analyses, level of significance was set at a P < 0.05.
| Results|| |
Baseline data, stroke severity, and 30-day outcome
This study enrolled 170 acute stroke cases (85 AIS and 85 ICH), of which 111 (65.3%) were male. [Table 1] provides a description of the demographic and clinical characteristics in AIS and ICH. The mean age at stroke onset was significantly lower in ICH than in AIS (P = 0.008); the 30-day case fatality rate (CFR) and functional outcome were significantly higher and poorer respectively in ICH compared with AIS (P = 0.01 for both comparisons).
|Table 1: Comparison of demographic and clinical profile in acute ischemic and intracerebral haemorrhage|
Click here to view
Admission hyperglycemia: Frequency, attribution, relationship to stroke severity, and outcome
Admission hyperglycemia was present in 23.5% (40/170) of all stroke, and the frequency did not differ significantly based on stroke subtype (P = 0.72; AIS– 21 i.e., 24.7%; ICH– 19 i.e., 22.4%) [Table 2]. Of those with hyperglycemia, 24 (60.0%; representing 14.1% of all stroke) were attributed to diabetes, whereas 16 (40.0% of hyperglycemia and 9.4% of all stroke) were presumed reactive. The distributions of AIS and ICH patients based on presumed mechanism of hyperglycemia did not differ significantly, as shown in [Table 2].
|Table 2: Clinical and radiological characteristics and outcome of stroke cases in relation to admission blood glucose characterization|
Click here to view
Stroke severity (determined by the NIHSS score) was significantly positively correlated with both admission RBG (r = 0.30; P = 0.000) and HBA1C (r = 0.24; P = 0.002) in all strokes combined. This significant association remained in the subcategory with AIS (RBG r = 0.47; P = 0.000 and HBA1C r = 0.45; P = 0.000) but not ICH [Figure 1].
|Figure 1: Correlation of stroke severity using NIHSS and glucose profile in AIS and ICH. (a) Correlation of stroke severity (NIHSS) and Random blood glucose in AIS (r=0.47, P=0.000), (b) Correlation of stroke severity (NIHSS) and HbA1c in AIS (r=0.45, P=0.000), (c) Correlation of stroke severity (NIHSS) and Random blood glucose in ICH (R=0.19, P=0.08), (d) Correlation of stroke severity (NIHSS) and HbA1c in ICH (R=0.11, P=0.33)|
Click here to view
The median (interquartile range) NIHSS score was 13.0 (9) in normoglycemic versus 16.5 (12) in hyperglycemic stroke. Neither HBA1C (r = 0.039; P = 0.94) nor RBG (r = −0.050; P = 0.65) correlated with hematoma volume. In contrast, both measures were significantly positively correlated with infarct size (HBA1C: R = 0.53; P = 0.000 and RBG: R = 0.54; P = 0.000).
Admission hyperglycemia and short-term (30-day) case fatality rate
As shown in [Table 2], CFR was higher in those with (compared to without) hyperglycemia in all strokes considered. Of the 40 stroke cases with admission hyperglycemia, 30-day CFR was 42.5% (17 cases). In the subgroup of 21 AIS with hyperglycemia, CFR was 9/21 (42.9%), compared to a CFR of 8/19 (42.1%) in ICH with hyperglycemia (P > 0.05). Mortality was significantly higher in AIS with hyperglycemia compared to AIS without hyperglycemia (42.9% versus 12.5%; P = 0.003) but not in ICH with hyperglycemia compared to without hyperglycemia (42.1% vs. 36.4%; P = 0.65) [Figure 2].
|Figure 2: Case fatality rates based on subgroup analysis of AIS and ICH cases. Bar chart showing case fatality rates (%) categorized by stroke subtype, presence or absence of hyperglycemia, and presumed mechanism of hyperglycemia (reactive or diabetes related). DM = Diabetes mellitus, HG = Hyperglycemia, NG = Normoglycemia, AIS = Acute ischemic stroke, ICH = Intracerebral hematoma|
Click here to view
Admission hyperglycemia and short-term functional outcome
Seventy-five (62.0%) of the stroke survivors had a favorable outcome. The proportion of AIS and ICH cases with favorable and unfavorable outcome did not differ significantly (P = 0.07) [Table 2]. There was no relationship between the presence of hyperglycemia and functional motor outcome irrespective of stroke subtype (P > 0.05).
| Discussion|| |
This study investigated the relative frequency of admission hyperglycemia (overall and based on presumed mechanism, i.e., reactive versus diabetes related) and explored the relationship to severity and short-term outcome (30-day CFR and functional outcome) in acute ischemic compared to intracerebral hemorrhagic strokes. Our main findings support the opinion that hyperglycemia contributes significantly to stroke severity (in AIS) and impacts negatively on outcome (in both AIS and ICH). First, admission hyperglycemia was similarly prevalent in AIS (24.7%) and ICH (22.4%), affecting about a quarter of persons with stroke in this cohort. In addition, we noted a trend toward different predominant mechanisms, with higher proportions of DM-related and reactive hyperglycaemia observed in AIS and ICH, respectively. Furthermore, we observed that whereas the mean hematoma volume in ICH was similar irrespective of the presence of admission hyperglycemia, the infarct size in AIS was significantly higher (more than two-fold) in the presence of hyperglycemia (in contrast to normoglycemia). However, the presumed mechanism of hyperglycemia was not significantly related to either infarct size or hematoma volume in this study. The CFR was significantly higher in stroke with hyperglycemia (relative to normoglycemia), and the trend was highest in the diabetes-related sub-categorizations (diabetes-related overall, ICH and AIS with diabetes-related hyperglycemia).
Previous studies have provided inconsistent data regarding the association between admission hyperglycemia and stroke severity and outcome in acute ICH in particular, but have been concordant with respect to AIS.,,,, In the post hoc analysis of 60 patients in the Antihypertensive Treatment of Acute Cerebral Hemorrhage I study, rising blood glucose within the first 72 h was associated with a 2.5-fold increased risk of 90-day death or disability on univariate analysis. This was, however, not significant when adjusted for stronger predictors of ICH severity such as the Glasgow Coma Scale score, ICH volume, and presence of intraventricular extension. In the large cohort of 2653 patients studied to determine the prognostic significance of hyperglycemia in acute ICH (INTERACT 2), hyperglycemia and DM were associated with greater stroke severity and were the independent predictors of poor outcome. Capes et al. conducted a meta-analysis of 26 studies and reported that the risk of 30-day mortality in ICH with admission hyperglycemia was not elevated in diabetic and nondiabetic patients. This contrasts with our finding that the highest mortality overall was in ICH with DM-related admission hyperglycemia (62.5%), although it coincides with our conclusion of lower mortality in ICH with reactive hyperglycemia (27.3%) compared to ICH overall (37.6%). We are however cautious in over-emphasizing these rates based on the small numbers within each sub-category and describe the findings as trends that warrant further study.
With respect to AIS, there is perhaps more harmony in the conclusions that have been derived from the majority of studies. Consistent with the findings in our study, Capes et al. reported a pooled two-fold increased risk of short-term mortality after ischemic stroke from three of the studies that reported data for diabetic and reactive hyperglycemia combined. Similar trends have been reported by Wahab et al. and Kiers et al., In contrast, Stead et al., studied 447 patients with AIS and reported that stress hyperglycemia (rather than preexisting DM-related hyperglycemia) was associated with greater stroke severity and higher mortality at 90 days.
On this basis, the core concept that these studies on AIS and ICH support is the trend toward a potentially deleterious effect of hyperglycaemia on stroke severity and outcome that is largely supported by literature which emphasizes the effect of hyperglycemia-induced brain damage in both human and animal studies.
Indeed, this study observed a strong association between hyperglycemia and larger infarct sizes with a nonsignificant trend toward larger infarcts in those with preexisting hyperglycemia. The implication is that greater emphasis needs to be paid to control of hyperglycemia in persons with diabetes prestroke, and in the unfortunate event of a stroke, guideline recommendations regarding interventions for hyperglycemia should be implemented early to derive the benefits supported by existing metanalysis., Functional recovery was not significantly impacted by hyperglycemia in our study, although we observed a trend of nearly double the proportion of strokes with poor functional outcome in the hyperglycemic versus normoglycemic strokes overall. We postulate that one of the contributory factors is the gain from early physical therapy intervention which is known to provide better poststroke functional recovery in both human and mice models of stroke.
Our study has certain limitations that restrict the generalizability of our findings. We acknowledge the limitation inherent in utilizing a single blood glucose measurement obtained at admission rather than a serial estimation of blood sugar and utilization of the pooled means of such estimations. This approach would provide a more robust assessment of the dynamics of hyperglycemia in the acute setting. The sample size was modest (though calculated as the minimum sample size), and consequently, the sub-group analyses would not be sufficiently powered to expose any strong associations or lend itself well to incorporating multivariable regression analyses.
| Conclusion|| |
We conclude from our findings that admission hyperglycemia (including reactive and DM-related mechanisms) has an undesirable association with stroke severity (measured by the NIHSS) and case fatality in AIS. In ICH, the connotation is less clear, but the trend indicates a less profound connection to short-term case fatality relative to AIS, and the probability of a more deleterious association of previously existing hyperglycemia (diabetes-related) compared to reactive hyperglycemia in ICH. The latter warrants further interrogation using more robust methodologies.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Feigin VL, Nicohls E, Alam T, Bannick MS, Beghi E, Blake N, et al
. Global, regional, and national burden of neurological disorders, 1990-2016: A systematic analysis for the global burden of disease study 2016. Lancet Neurol 2019;18:459-80.
William JP, Alejandro AR, Teri A, Opeolu MA, Nicholas CB, Kyra B, et al
. Guidelines 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. Stroke 2019;50:344-418.
Capes SE, Hunt D, Malmberg K, Pathak P, Gerstein HC. Stress hyperglycemia and prognosis of stroke in non-diabetic and diabetic patients: A systematic overview. Stroke 2001;32:2426-32.
Anderson RE, Tan WK, Martin HS, Meyer FB. Effects of glucose and PaO2 modulation on cortical intracellular acidosis, NADH redox state, and infarction in the ischemic penumbra. Stroke 1999;30:160-70.
Suh SW, Shin BS, Ma H, Van Hoecke M, Brennan AM, Yenari MA, et al
. Glucose and NADPH oxidase drive neuronal superoxide formation in stroke. Ann Neurol 2008;64:654-63.
Kimura K, Iguchi Y, Inoue T, Shibazaki K, Matsumoto N, Kobayashi K, et al
. Hyperglycemia independently increases the risk of early death in acute spontaneous intracerebral hemorrhage. J Neurol Sci 2007;255:90-4.
Scott JF, Robinson GM, French JM, O'Connell JE, Alberti KG, Gray CS. Prevalence of admission hyperglycaemia across clinical sub-types of stroke. Lancet 1999;353:376-7.
Counsell C, Dennis M. Systematic review of prognostic models in patients with acute stroke. Cerebrovasc Dis 2001;12:159-70.
Snarska KK, Bachórzewska-Gajewska H, Kapica-Topczewska K, Drozdowski W, Chorąży M, Kułakowska A, et al
. Hyperglycemia and diabetes have different impacts on outcome of ischemic and hemorrhagic stroke. Arch Med Sci 2017;13:100-8.
Muir KW, Weir CJ, Murray GD, Povey C, Lees KR. Comparison of neurological scales and scoring systems for acute stroke prognosis. Stroke 1996;27:1817-20.
Hage V. The NIH stroke scale: A window into neurological status. Nurs Spectr 2011;24:44-9.
Vogt G, Laage R, Shuaib A, Schneider A. VISTA Collaboration. Initial lesion volume is an independent predictor of clinical stroke outcome at day 90: An analysis of the Virtual International Stroke Trials Archive (VISTA) database. Stroke 2012;43:1266-72.
Pullicino P, Snyder W, Munschauer F, Pordell R, Greiner F. Interrater agreement of computed tomography infarct measurement. J Neuroimag 1996;6:16-9.
Kothari RU, Brott T, Broderick JP, Barsan WG, Sauerbeck LR, Zuccarello M, et al
. The ABCs of measuring intracerebral hemorrhage volumes. Stroke 1996;27:1304-5.
Farrokhi F, Smiley D, Umpierrez GE. Glycemic control in non-diabetic critically ill patients. Best Pract Res Clin Endocrinol Metab 2011;25:813-24.
Gillett MJ. International Expert Committee Report on the Role of the A1c assay in the diagnosis of diabetes: Diabetes Care 2009; 32 (7): 1327-1334. Clin Biochem Rev 2009;30:197-200.
Haacke C, Althaus A, Spottke A, Siebert U, Back T, Dodel R. Long-term outcome after stroke: Evaluating health-related quality of life using utility measurements. Stroke 2006;37:193-8.
Stead LG, Gilmore RM, Bellolio MF, Mishra S, Bhagra A, Vaidyanathan L, et al
. Hyperglycemia as an independent predictor of worse outcome in non-diabetic patients presenting with acute ischemic stroke. Neurocrit Care 2009;10:181-6.
Wahab K, Okubadejo N, Ojini F, Danesi M. Effect of admission hyperglycemia on short-term outcome in adult Nigerians with a first acute ischemic stroke. Afr J Neurol Sci 2007;26:48-54.
Kiers L, Davis SM, Larkins R, Hopper J, Tress B, Rossiter SC, et al
. Stroke topography and outcome in relation to hyperglycaemia and diabetes. J Neurol Neurosurg Psychiatry 1992;55:263-70.
Qureshi AI, Palesch YY, Martin R, Novitzke J, Cruz-Flores S, Ehtisham A, et al
. Association of serum glucose concentrations during acute hospitalization with hematoma expansion, perihematomal edema, and three month outcome among patients with intracerebral hemorrhage. Neurocrit Care 2011;15:428-35.
Saxena A, Anderson CS, Wang X, Sato S, Arima H, Chan E, et al
. Prognostic significance of hyperglycemia in acute intracerebral hemorrhage: The INTERACT2 study. Stroke 2016;47:682-8.
Hemphill JC 3rd
, Greenberg SM, Anderson CS, Becker K, Bendok BR, Cushman M, et al
. Guidelines for the management of spontaneous intracerebral hemorrhage: A guideline for healthcare professionals from the American heart association/American stroke association. Stroke 2015;46:2032-60.
Paolucci S, Antonucci G, Grasso MG, Morelli D, Troisi E, Coiro P, et al
. Early versus delayed inpatient stroke rehabilitation: A matched comparison conducted in Italy. Arch Phys Med Rehabil 2000;81:695-700.
[Figure 1], [Figure 2]
[Table 1], [Table 2]