- Email: [email protected]
Prognostic value of peripheral leukocyte counts and plasma glucose in intracerebral haemorrhage
Journal of Clinical Neuroscience xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical commentary
Prognostic value of peripheral leukocyte counts and plasma glucose in intracerebral haemorrhage S. Kayhanian a,1, C.K. Weerasuriya b,1, U. Rai c, A.M.H. Young d,⇑ a
School of Clinical Medicine, University of Cambridge, Cambridge, UK Department of Medicine, Addenbrooke’s Hospital, Cambridge, UK c Department of Stroke Medicine, Queen Elizabeth Hospital, King’s Lynn, UK d Department of Clinical Neurosciences, Addenbrooke’s Hospital, University of Cambridge, Cambridge, UK b
a r t i c l e
i n f o
Article history: Received 30 December 2016 Accepted 6 March 2017 Available online xxxx Keywords: Stroke Haemorrhage Glucose Leukocyte Outcome
a b s t r a c t Introduction: The value of routine blood markers as prognostic indicators is increasingly established in acute ischaemic stroke. The relationship is less well defined in haemorrhagic stroke. In this study, we examined routine admission blood markers and applied a logistic regression model to predict outcome in haemorrhagic stroke. Method: A retrospective study was performed between September 2009–2011 in a general admission stroke unit in the UK. 1400 patients were admitted with stroke during this period, of which 117 were haemorrhagic. Admission systolic and diastolic blood pressure, venous blood samples and pre- and post-morbid (i.e. at discharge or death) modified Rankin scores were also recorded. Patients were controlled for age, sex, smoking status, hypertension status and co-morbidities (using Charleson Comorbidity Index scores). Logistic regression models were generated using SPSS. Results: 113 patients were analysed (58 male/55 female). Lower admission blood glucose (p = 0.009), lower total leukocyte count (p = 0.001) and lower neutrophil count (p = 0.021) were found to be significantly associated with survival vs. death. 90 patients with complete glucose, leukocyte count, sex (forced) and pre-morbid Rankin score (forced) data were entered into a logistic regression model. This predicted correct group membership (survived/deceased) in 72.2% of cases (83.9% survivors/52.9% deceased correctly predicted). In females with normal leukocyte count and glucose, survival was predicted with 68% accuracy. Conclusion: These results suggest that a logistic regression model using low admission glucose and low total leukocyte count may be markers of better prognosis in acute haemorrhagic stroke with a differential effect between sexes. Ó 2017 Published by Elsevier Ltd.
1. Introduction Acute non-traumatic intracerebral haemorrhage (ICH) is a major public health problem with an incidence that has remained unchanged over the past thirty years [1]. It currently accounts for only about one-fifth of the 16.8 million strokes that occur annually but is known to have a higher mortality than other stroke subtypes and, unlike ischaemic stroke, mortality from this disease has not improved over the past decade [2–4]. It also accounts for a disproportionately greater number of the ‘‘productive life years lost” due ⇑ Corresponding author at: Department of Academic Neurosurgery, Department of Clinical Neurosciences, Addenbrooke’s Hospital, University of Cambridge, Cambridge, UK. E-mail address: [email protected] (A.M.H. Young). 1 Both authors contributed equally.
to strokes since it tends to affect people at earlier ages compared with acute ischaemic stroke [2]. The treatment options for ICH range from supportive care to more aggressive interventions such as decompressive surgery. These interventions may carry a significantly higher risk to the patient yet it is not currently possible to clearly identify which patients should be treated most intensively. A reliable and accurate prognostic biomarker in ICH would be valuable for a number of reasons. Firstly, it would allow patients to be stratified according to their expected clinical outcomes. This would be enormously useful in informing clinical decision-making as well as by aiding in the selection of patients for trials of new treatments. A routine marker that gives an early impression of prognosis would also be useful to clinicians when counselling patients and their families. Moreover, since the pathophysiology of neuronal damage in ICH is poorly understood, new biomarkers
http://dx.doi.org/10.1016/j.jocn.2017.03.032 0967-5868/Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Kayhanian S et al. Prognostic value of peripheral leukocyte counts and plasma glucose in intracerebral haemorrhage. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.03.032
2
S. Kayhanian et al. / Journal of Clinical Neuroscience xxx (2017) xxx–xxx
may direct and inform studies to understand the disease mechanisms of this devastating condition. Various biomarkers for brain injury have been extensively studied in recent decades, with recognition that these could revolutionise the delivery of care post-injury [5]. However, relatively few studies have focused on biomarkers for non-traumatic brain injuries. In this retrospective study, we aimed to identify markers that could be suitable in offering predictive value for mortality during hospital-stay. We only examined clinical parameters that would be routinely available for every patient who is admitted to hospital. 2. Methods 2.1. Patient selection We retrospectively reviewed of all cases of stroke admitted to Queen Elizabeth Hospital, King’s Lynn between 2009 and 2011, and selected all radiologically confirmed cases of haemorrhagic stroke (intracerebral haemorrhage) for further analysis. Cases of acute ischaemic stroke, sub-arachnoid and sub-dural haemorrhage were excluded. Routine data on demographics and co-morbidities were obtained. Additionally, other baseline parameters including systolic and diastolic blood pressure and highest values of peripheral leukocyte count and plasma glucose within 24 h of admission were extracted. A Charleson Co-morbidity Index (CCI) score was calculated for each patient to provide an aggregate measure of comorbidity. Pre- and post-morbid (i.e. at discharge or death) modified Rankin scores were also calculated. The outcome measured was in-hospital mortality. 2.2. Statistical analysis Statistical analysis was undertaken using IBM SPSS Statistics for Windows version 19 (IBM Corporation, New York, USA). Baseline data was compared across the outcome (mortality) for differences
in baseline demographics, co-morbidities (as CCI) and baseline parameters. Significant differentiators, along with sex and premorbid modified Rankin Score were forced into a logistic regression model to predict survival. Comparison of means (for normal data) was performed using ttests, comparison of medians (for non-normal data) was performed using Mann–Whitney U tests and proportions compared with Pearson chi-squared tests.
3. Results 113 patients were analysed (55 female), of whom 73 survived the admission and 40 were deceased. There was no significant difference in age, sex nor co-morbidity across survival (Table 1), although sex is of borderline non-significance (p = 0.079). Comparison of admission clinical and laboratory parameters (Table 2) revealed admission plasma glucose, leukocyte and neutrophil counts to be significantly higher in patients who died. Patients with complete sets of plasma glucose, leukocyte count, sex and pre-morbid modified Rankin Scores (as a control for baseline morbidity) was entered into a logistic regression model predicting survival (n = 90). Sex was entered as a categorical covariate, with a value of 0 representing male and 1 representing female patients. Neutrophil count was not entered as its effect was found to account for a significant proportion of variability in survival attributed to leukocyte count. Increased leukocyte count (OR 1.189), glucose (OR 1.243), pre-morbid modified Rankin score (OR 1.513) and male sex (OR 0.257) increased risk of mortality (Table 3). Model accuracy was variable; overall, the outcome of 72.2% of cases was predicted correctly (Table 4). Prediction of survival was more accurate (83.9%) than death (52.9%). There was no statistically significant difference in pre-morbid modified Rankin scores between male and female patients in either the total cohort (p = 0.282) nor when subgrouped into deceased (p = 0.193) and survivors (p = 0.585). Similarly, there were no differences for leukocyte count nor plasma glucose between sexes.
Table 1 Demographics and co-morbidities of patients presenting with intracerebral haemorrhage. Survived
Deceased Quartiles
Age Sex, male CCI* Smoking** Premorbid Rankin Score * **
78 26 1 15 0.00
(73,85) (0,2) (0.00,2.00)
p value Quartiles
82 21 3 13 2.50
(80,85) (1,4) (1.00,4.00)
0.551 0.158 0.062 0.610 0.163
CCI at time of admission. Smoker at time of admission.
Table 2 Admission clinical and laboratory data of patients presenting with intracerebral haemorrhage. Survived
Deceased Quartiles
Glucose BP (systolic) BP (diastolic) Leukocyte count Neutrophil count Lymphocyte count Basophil count Eosinophil count Monocyte count *
6.75 168 84 9.48 7.17 1.60 0.05 0.19 0.61
(5.65,8.30) (150.0,189.0) (75.0,99.0) (8.42,12.48) (5.91,10.14) (1.19,1.98) (0.03,0.07) (0.10,0.28) (0.46,0.80)
p value Quartiles
8.85 177 89 12.15 8.19 1.67 0.06 0.10 0.63
(6.15,10.13) (146.8,209.5) (80.0,107.0) (9.58,15.79) (6.85,15.13) (0.90,2.60) (0.03,0.09) (0.07,0.20) (0.47,0.85)
0.009* 0.129 0.174 0.001* 0.021* 0.598 0.318 0.090 0.507
Significant value.
Please cite this article in press as: Kayhanian S et al. Prognostic value of peripheral leukocyte counts and plasma glucose in intracerebral haemorrhage. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.03.032
3
S. Kayhanian et al. / Journal of Clinical Neuroscience xxx (2017) xxx–xxx Table 3 Model Predictors used in logistic regression model predicting survival.
Glucose Pre-morbid modified Rankin score Sex Leukocyte count
Odds ratio
p
1.243 1.513 .257 1.189
.045 .028 .012 .013
95% C.I. for OR Lower
Upper
1.005 1.045 .088 1.037
1.538 2.190 .745 1.364
Table 4 Prediction Accuracy of a logistic regression model for survival. Observed
Predicted Survival
Survival
Survived Dead
Overall Percentage
Percentage Correct
Survived
Dead
47 16
9 18
83.9 52.9 72.2
Plasma glucose and leukocyte count have differential predictive ability depending on whether the values are in or out of the normal range (normal ranges: glucose 4–8 mmol/L, leukocyte count 4– 11 1000 cells/mm3) (Fig. 1); further, this effect is different between male and female patients. Outcome is correctly predicted for (92.3%) 12/13 female patients with normal range values vs. 68 (17/25) male patients.
4. Discussion This study shows that elevated plasma glucose and peripheral leukocyte count, within the first 24 h of hospital admission, both predict in-hospital mortality after ICH. This correlation was independent of the patient’s sex and previous health. Further, there was found to be no significant correlation between either systolic or diastolic blood pressure and the in-hospital mortality.
Fig. 1. Plasma glucose and leukocyte count have differential predictive ability depending on whether the values are in or out of the normal range (normal ranges: glucose 4–8 mmol/L, leukocyte count 4–11 1000 cells/mm3).
4.2. Peripheral leukocyte count 4.1. Plasma glucose levels The relationship between hyperglycaemia and poor outcomes in ICH has been demonstrated in previous findings [6,7]. However, in contrast to previous studies, we have looked specifically only at mortality, rather than combined measures of disability and death, and found that this relationship remains true. A number of pathophysiological mechanisms have been proposed to explain the adverse effects of hyperglycaemia in ICH. Studies in a rat model of ICH [8] have shown that hyperglycaemia induces neuronal apoptosis and, interestingly, there is some evidence for this cell death being secondary to a glucose-induced inflammatory response [7,9,10]. This may suggest that our two purported markers, of peripheral leukocyte count and plasma glucose levels, are not unrelated parameters but in fact surrogate markers for the same pathological process. These findings support the growing body of evidence that plasma glucose measurement may be a good candidate for a marker of mortality in ICH; it has strong predictive value and is a routine measurement that is available to clinicians. It would be valuable for further studies to demonstrate this in larger cohorts and to quantify this relationship. The clinical implications of this relationship beyond its use as a marker are unclear. Finfer et al. have demonstrated that intensive glycaemic control after ICH is undesirable since it usually results in a slight hypoglycaemia that also leads to poorer outcomes.
Prior clinical studies have demonstrated that inflammatory markers correlate with poor outcomes in ICH [11–13]. Our results demonstrate that this association holds true for in-hospital mortality with a routinely available clinical measure, rather than neutrophil–lymphocyte ratio or other markers of inflammatory response e.g. interleukin levels. This study, taken in the context of the growing number of studies demonstrating a relationship between inflammation and poor outcomes in ICH, further supports the hypothesis that activation of the peripheral immune system may enhance injury after ICH. This is consistent with laboratory studies of secondary brain injury [13]. These studies have also highlighted hyper-metabolism leading to inflammation as one potential mediator of neuronal cell death, lending weight to the suggestion that peripheral leukocyte count and plasma glucose’s predictive value may be interrelated. It will be important to better understand this relationship before drawing any conclusions on possible treatment strategies targeting inflammation post-ICH. 4.3. Blood pressure Our finding that blood pressure readings do not correlate well to in-hospital mortality support the main finding of the large, multi-centre INTERACT2 trial for blood pressure treatment after ICH, which found that ‘‘early intensive lowering of blood pressure
Please cite this article in press as: Kayhanian S et al. Prognostic value of peripheral leukocyte counts and plasma glucose in intracerebral haemorrhage. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.03.032
4
S. Kayhanian et al. / Journal of Clinical Neuroscience xxx (2017) xxx–xxx
did not result in a significant reduction in the rate of the primary outcome of death or major disability”.
[2]
5. Conclusions The strengths of this study were that simple clinical parameters were being measured- those that would be routinely available to clinicians upon admission. Moreover, the measure of in-hospital mortality, rather than long-term outcomes or disability, allows for predictive value for clinicians in making immediate clinical decisions and considering prognosis. However, this study is limited in that it is a retrospective, single centre analysis. Moreover, it should be considered that infection is a possible confounding factor in these results. We did not attempt to exclude patients with infection- which could itself lead to poor outcomes- though it would clearly cause leucocytosis and can cause hyperglycaemia. In summary, our findings have shown that plasma glucose levels and peripheral leukocyte count in the first 24 h after an ICH show strong association with in-hospital mortality. We envisage that good markers for mortality after ICH could transform the management of this acute condition in the same way that cardiac markers such a troponin have revolutionised care post-myocardial infarction. We have shown two routine clinical parameters that may be good candidates for this role. References
[3] [4] [5]
[6]
[7]
[8]
[9]
[10] [11]
[12]
[13]
ethnic origin: a systematic review and meta-analysis. Lancet Neurol 2010;9:167–76. Krishnamurthi RV, Feigin VL, Forouzanfar MH, et al. Global and regional burden of first-ever ischaemic and haemorrhagic stroke during 1990–2010: findings from the Global Burden of Disease Study 2010. Lancet Glob Health 2013;1:e259–81. Qureshi AI, Mendelow AD, Hanley DF. Intracerebral haemorrhage. Lancet 2009;373(9675):1632–44. Andersen KK, Olsen TS, Dehlendorff C, et al. Hemorrhagic and ischemic strokes compared: stroke severity. Mortality Risk Factors Stroke 2009;40:2068–72. Forde CT, Karri SK, Young AM, et al. Predictive markers in traumatic brain injury: opportunities for a serum biosignature. Br J Neurosurg 2014;28 (1):8–15. Fogelholm R, Murros K, Rissanen A, et al. Admission blood glucose and short term survival in primary intracerebral haemorrhage: a population based study. J Neurol Neurosurg Psychiatry 2005;76(3):349–53. Saxena A, Anderson CS, Wang X, et al. Prognostic significance of hyperglycemia in acute intracerebral hemorrhage: the INTERACT2 Study. Stroke 2016;47 (3):682–8. Zhu DD, Tang RN, Lv LL, et al. Interleukin-1b mediates high glucose induced phenotypic transition in human aortic endothelial cells. Cardiovasc Diabetol 2016;5(15):42. Asakawa H, Miyagawa J, Hanafusa T, et al. High glucose and hyperosmolarity increase secretion of interleukin-1 beta in cultured human aortic endothelial cells. J Diabetes Complications 1997;11:176–9. Finfer S, Liu B, Chittock DR, et al. Hypoglycemia and risk of death in critically ill patients. N Engl J Med 2012;367:1108–18. Whiteley W, Jackson C, Lewis S, et al. Inflammatory markers and poor outcome after stroke: a prospective cohort study and systematic review of interleukin6. PLoS Med 2009;6(9):e1000145. Lattanzi S, Cagnetti C, Provinciali L, et al. Neutrophil-to-lymphocyte ratio predicts the outcome of acute intracerebral hemorrhage. Stroke 2016;47:1654–7. Aronowski J, Zhao X. Molecular pathophysiology of cerebral hemorrhage: secondary brain injury. Stroke 2011;42:1781–6.
[1] Van Asch CJ, Luitse MJ, Rinkel GJ, et al. Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and
Please cite this article in press as: Kayhanian S et al. Prognostic value of peripheral leukocyte counts and plasma glucose in intracerebral haemorrhage. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.03.032
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical commentary
Prognostic value of peripheral leukocyte counts and plasma glucose in intracerebral haemorrhage S. Kayhanian a,1, C.K. Weerasuriya b,1, U. Rai c, A.M.H. Young d,⇑ a
School of Clinical Medicine, University of Cambridge, Cambridge, UK Department of Medicine, Addenbrooke’s Hospital, Cambridge, UK c Department of Stroke Medicine, Queen Elizabeth Hospital, King’s Lynn, UK d Department of Clinical Neurosciences, Addenbrooke’s Hospital, University of Cambridge, Cambridge, UK b
a r t i c l e
i n f o
Article history: Received 30 December 2016 Accepted 6 March 2017 Available online xxxx Keywords: Stroke Haemorrhage Glucose Leukocyte Outcome
a b s t r a c t Introduction: The value of routine blood markers as prognostic indicators is increasingly established in acute ischaemic stroke. The relationship is less well defined in haemorrhagic stroke. In this study, we examined routine admission blood markers and applied a logistic regression model to predict outcome in haemorrhagic stroke. Method: A retrospective study was performed between September 2009–2011 in a general admission stroke unit in the UK. 1400 patients were admitted with stroke during this period, of which 117 were haemorrhagic. Admission systolic and diastolic blood pressure, venous blood samples and pre- and post-morbid (i.e. at discharge or death) modified Rankin scores were also recorded. Patients were controlled for age, sex, smoking status, hypertension status and co-morbidities (using Charleson Comorbidity Index scores). Logistic regression models were generated using SPSS. Results: 113 patients were analysed (58 male/55 female). Lower admission blood glucose (p = 0.009), lower total leukocyte count (p = 0.001) and lower neutrophil count (p = 0.021) were found to be significantly associated with survival vs. death. 90 patients with complete glucose, leukocyte count, sex (forced) and pre-morbid Rankin score (forced) data were entered into a logistic regression model. This predicted correct group membership (survived/deceased) in 72.2% of cases (83.9% survivors/52.9% deceased correctly predicted). In females with normal leukocyte count and glucose, survival was predicted with 68% accuracy. Conclusion: These results suggest that a logistic regression model using low admission glucose and low total leukocyte count may be markers of better prognosis in acute haemorrhagic stroke with a differential effect between sexes. Ó 2017 Published by Elsevier Ltd.
1. Introduction Acute non-traumatic intracerebral haemorrhage (ICH) is a major public health problem with an incidence that has remained unchanged over the past thirty years [1]. It currently accounts for only about one-fifth of the 16.8 million strokes that occur annually but is known to have a higher mortality than other stroke subtypes and, unlike ischaemic stroke, mortality from this disease has not improved over the past decade [2–4]. It also accounts for a disproportionately greater number of the ‘‘productive life years lost” due ⇑ Corresponding author at: Department of Academic Neurosurgery, Department of Clinical Neurosciences, Addenbrooke’s Hospital, University of Cambridge, Cambridge, UK. E-mail address: [email protected] (A.M.H. Young). 1 Both authors contributed equally.
to strokes since it tends to affect people at earlier ages compared with acute ischaemic stroke [2]. The treatment options for ICH range from supportive care to more aggressive interventions such as decompressive surgery. These interventions may carry a significantly higher risk to the patient yet it is not currently possible to clearly identify which patients should be treated most intensively. A reliable and accurate prognostic biomarker in ICH would be valuable for a number of reasons. Firstly, it would allow patients to be stratified according to their expected clinical outcomes. This would be enormously useful in informing clinical decision-making as well as by aiding in the selection of patients for trials of new treatments. A routine marker that gives an early impression of prognosis would also be useful to clinicians when counselling patients and their families. Moreover, since the pathophysiology of neuronal damage in ICH is poorly understood, new biomarkers
http://dx.doi.org/10.1016/j.jocn.2017.03.032 0967-5868/Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Kayhanian S et al. Prognostic value of peripheral leukocyte counts and plasma glucose in intracerebral haemorrhage. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.03.032
2
S. Kayhanian et al. / Journal of Clinical Neuroscience xxx (2017) xxx–xxx
may direct and inform studies to understand the disease mechanisms of this devastating condition. Various biomarkers for brain injury have been extensively studied in recent decades, with recognition that these could revolutionise the delivery of care post-injury [5]. However, relatively few studies have focused on biomarkers for non-traumatic brain injuries. In this retrospective study, we aimed to identify markers that could be suitable in offering predictive value for mortality during hospital-stay. We only examined clinical parameters that would be routinely available for every patient who is admitted to hospital. 2. Methods 2.1. Patient selection We retrospectively reviewed of all cases of stroke admitted to Queen Elizabeth Hospital, King’s Lynn between 2009 and 2011, and selected all radiologically confirmed cases of haemorrhagic stroke (intracerebral haemorrhage) for further analysis. Cases of acute ischaemic stroke, sub-arachnoid and sub-dural haemorrhage were excluded. Routine data on demographics and co-morbidities were obtained. Additionally, other baseline parameters including systolic and diastolic blood pressure and highest values of peripheral leukocyte count and plasma glucose within 24 h of admission were extracted. A Charleson Co-morbidity Index (CCI) score was calculated for each patient to provide an aggregate measure of comorbidity. Pre- and post-morbid (i.e. at discharge or death) modified Rankin scores were also calculated. The outcome measured was in-hospital mortality. 2.2. Statistical analysis Statistical analysis was undertaken using IBM SPSS Statistics for Windows version 19 (IBM Corporation, New York, USA). Baseline data was compared across the outcome (mortality) for differences
in baseline demographics, co-morbidities (as CCI) and baseline parameters. Significant differentiators, along with sex and premorbid modified Rankin Score were forced into a logistic regression model to predict survival. Comparison of means (for normal data) was performed using ttests, comparison of medians (for non-normal data) was performed using Mann–Whitney U tests and proportions compared with Pearson chi-squared tests.
3. Results 113 patients were analysed (55 female), of whom 73 survived the admission and 40 were deceased. There was no significant difference in age, sex nor co-morbidity across survival (Table 1), although sex is of borderline non-significance (p = 0.079). Comparison of admission clinical and laboratory parameters (Table 2) revealed admission plasma glucose, leukocyte and neutrophil counts to be significantly higher in patients who died. Patients with complete sets of plasma glucose, leukocyte count, sex and pre-morbid modified Rankin Scores (as a control for baseline morbidity) was entered into a logistic regression model predicting survival (n = 90). Sex was entered as a categorical covariate, with a value of 0 representing male and 1 representing female patients. Neutrophil count was not entered as its effect was found to account for a significant proportion of variability in survival attributed to leukocyte count. Increased leukocyte count (OR 1.189), glucose (OR 1.243), pre-morbid modified Rankin score (OR 1.513) and male sex (OR 0.257) increased risk of mortality (Table 3). Model accuracy was variable; overall, the outcome of 72.2% of cases was predicted correctly (Table 4). Prediction of survival was more accurate (83.9%) than death (52.9%). There was no statistically significant difference in pre-morbid modified Rankin scores between male and female patients in either the total cohort (p = 0.282) nor when subgrouped into deceased (p = 0.193) and survivors (p = 0.585). Similarly, there were no differences for leukocyte count nor plasma glucose between sexes.
Table 1 Demographics and co-morbidities of patients presenting with intracerebral haemorrhage. Survived
Deceased Quartiles
Age Sex, male CCI* Smoking** Premorbid Rankin Score * **
78 26 1 15 0.00
(73,85) (0,2) (0.00,2.00)
p value Quartiles
82 21 3 13 2.50
(80,85) (1,4) (1.00,4.00)
0.551 0.158 0.062 0.610 0.163
CCI at time of admission. Smoker at time of admission.
Table 2 Admission clinical and laboratory data of patients presenting with intracerebral haemorrhage. Survived
Deceased Quartiles
Glucose BP (systolic) BP (diastolic) Leukocyte count Neutrophil count Lymphocyte count Basophil count Eosinophil count Monocyte count *
6.75 168 84 9.48 7.17 1.60 0.05 0.19 0.61
(5.65,8.30) (150.0,189.0) (75.0,99.0) (8.42,12.48) (5.91,10.14) (1.19,1.98) (0.03,0.07) (0.10,0.28) (0.46,0.80)
p value Quartiles
8.85 177 89 12.15 8.19 1.67 0.06 0.10 0.63
(6.15,10.13) (146.8,209.5) (80.0,107.0) (9.58,15.79) (6.85,15.13) (0.90,2.60) (0.03,0.09) (0.07,0.20) (0.47,0.85)
0.009* 0.129 0.174 0.001* 0.021* 0.598 0.318 0.090 0.507
Significant value.
Please cite this article in press as: Kayhanian S et al. Prognostic value of peripheral leukocyte counts and plasma glucose in intracerebral haemorrhage. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.03.032
3
S. Kayhanian et al. / Journal of Clinical Neuroscience xxx (2017) xxx–xxx Table 3 Model Predictors used in logistic regression model predicting survival.
Glucose Pre-morbid modified Rankin score Sex Leukocyte count
Odds ratio
p
1.243 1.513 .257 1.189
.045 .028 .012 .013
95% C.I. for OR Lower
Upper
1.005 1.045 .088 1.037
1.538 2.190 .745 1.364
Table 4 Prediction Accuracy of a logistic regression model for survival. Observed
Predicted Survival
Survival
Survived Dead
Overall Percentage
Percentage Correct
Survived
Dead
47 16
9 18
83.9 52.9 72.2
Plasma glucose and leukocyte count have differential predictive ability depending on whether the values are in or out of the normal range (normal ranges: glucose 4–8 mmol/L, leukocyte count 4– 11 1000 cells/mm3) (Fig. 1); further, this effect is different between male and female patients. Outcome is correctly predicted for (92.3%) 12/13 female patients with normal range values vs. 68 (17/25) male patients.
4. Discussion This study shows that elevated plasma glucose and peripheral leukocyte count, within the first 24 h of hospital admission, both predict in-hospital mortality after ICH. This correlation was independent of the patient’s sex and previous health. Further, there was found to be no significant correlation between either systolic or diastolic blood pressure and the in-hospital mortality.
Fig. 1. Plasma glucose and leukocyte count have differential predictive ability depending on whether the values are in or out of the normal range (normal ranges: glucose 4–8 mmol/L, leukocyte count 4–11 1000 cells/mm3).
4.2. Peripheral leukocyte count 4.1. Plasma glucose levels The relationship between hyperglycaemia and poor outcomes in ICH has been demonstrated in previous findings [6,7]. However, in contrast to previous studies, we have looked specifically only at mortality, rather than combined measures of disability and death, and found that this relationship remains true. A number of pathophysiological mechanisms have been proposed to explain the adverse effects of hyperglycaemia in ICH. Studies in a rat model of ICH [8] have shown that hyperglycaemia induces neuronal apoptosis and, interestingly, there is some evidence for this cell death being secondary to a glucose-induced inflammatory response [7,9,10]. This may suggest that our two purported markers, of peripheral leukocyte count and plasma glucose levels, are not unrelated parameters but in fact surrogate markers for the same pathological process. These findings support the growing body of evidence that plasma glucose measurement may be a good candidate for a marker of mortality in ICH; it has strong predictive value and is a routine measurement that is available to clinicians. It would be valuable for further studies to demonstrate this in larger cohorts and to quantify this relationship. The clinical implications of this relationship beyond its use as a marker are unclear. Finfer et al. have demonstrated that intensive glycaemic control after ICH is undesirable since it usually results in a slight hypoglycaemia that also leads to poorer outcomes.
Prior clinical studies have demonstrated that inflammatory markers correlate with poor outcomes in ICH [11–13]. Our results demonstrate that this association holds true for in-hospital mortality with a routinely available clinical measure, rather than neutrophil–lymphocyte ratio or other markers of inflammatory response e.g. interleukin levels. This study, taken in the context of the growing number of studies demonstrating a relationship between inflammation and poor outcomes in ICH, further supports the hypothesis that activation of the peripheral immune system may enhance injury after ICH. This is consistent with laboratory studies of secondary brain injury [13]. These studies have also highlighted hyper-metabolism leading to inflammation as one potential mediator of neuronal cell death, lending weight to the suggestion that peripheral leukocyte count and plasma glucose’s predictive value may be interrelated. It will be important to better understand this relationship before drawing any conclusions on possible treatment strategies targeting inflammation post-ICH. 4.3. Blood pressure Our finding that blood pressure readings do not correlate well to in-hospital mortality support the main finding of the large, multi-centre INTERACT2 trial for blood pressure treatment after ICH, which found that ‘‘early intensive lowering of blood pressure
Please cite this article in press as: Kayhanian S et al. Prognostic value of peripheral leukocyte counts and plasma glucose in intracerebral haemorrhage. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.03.032
4
S. Kayhanian et al. / Journal of Clinical Neuroscience xxx (2017) xxx–xxx
did not result in a significant reduction in the rate of the primary outcome of death or major disability”.
[2]
5. Conclusions The strengths of this study were that simple clinical parameters were being measured- those that would be routinely available to clinicians upon admission. Moreover, the measure of in-hospital mortality, rather than long-term outcomes or disability, allows for predictive value for clinicians in making immediate clinical decisions and considering prognosis. However, this study is limited in that it is a retrospective, single centre analysis. Moreover, it should be considered that infection is a possible confounding factor in these results. We did not attempt to exclude patients with infection- which could itself lead to poor outcomes- though it would clearly cause leucocytosis and can cause hyperglycaemia. In summary, our findings have shown that plasma glucose levels and peripheral leukocyte count in the first 24 h after an ICH show strong association with in-hospital mortality. We envisage that good markers for mortality after ICH could transform the management of this acute condition in the same way that cardiac markers such a troponin have revolutionised care post-myocardial infarction. We have shown two routine clinical parameters that may be good candidates for this role. References
[3] [4] [5]
[6]
[7]
[8]
[9]
[10] [11]
[12]
[13]
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Please cite this article in press as: Kayhanian S et al. Prognostic value of peripheral leukocyte counts and plasma glucose in intracerebral haemorrhage. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.03.032