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Early brain injury after aneurysmal subarachnoid hemorrhage: a multimodal neuromonitoring study.

Helbok R, Schiefecker AJ, Beer R, Dietmann A, Antunes AP, Sohm F, Fischer M, Hackl WO, Rhomberg P, Lackner P, Pfausler B, Thomé C, Humpel C, Schmutzhard E - Crit Care (2015)

Bottom Line: Baseline CMD-IL-6 and CMD-MMP-9 levels were elevated in all patients (median = 4,059 pg/mL, interquartile range (IQR) = 1,316 to 12,456 pg/mL and median = 851 pg/mL, IQR = 98 to 25,860 pg/mL) and significantly decreased over days (P <0.05).A higher pro-inflammatory response was associated with the development of delayed cerebral ischemia (P = 0.04), whereas admission disease severity and early brain tissue hypoxia were associated with higher CMD-MMP-9 levels (P <0.03).The results may be used as endpoints for future interventions targeting EBI in poor-grade aSAH patients.

View Article: PubMed Central - PubMed

Affiliation: Neurological Intensive Care Unit, Department of Neurology, Medical University of Innsbruck, Anichstreet 35, 6020, Innsbruck, Austria. raimund.helbok@uki.at.

ABSTRACT

Introduction: There is a substantial amount of evidence from animal models that early brain injury (EBI) may play an important role for secondary brain injury after aneurysmal subarachnoid hemorrhage (aSAH). Cerebral microdialysis (CMD) allows online measurement of brain metabolites, including the pro-inflammatory cytokine interleukin-6 (IL-6) and matrix metalloproteinase-9 (MMP-9), which is indicative for disruption of the blood-brain barrier.

Methods: Twenty-six consecutive poor-grade aSAH patients with multimodal neuromonitoring were analyzed for brain hemodynamic and metabolic changes, including CMD-IL-6 and CMD-MMP-9 levels. Statistical analysis was performed by using a generalized estimating equation with an autoregressive function.

Results: The baseline cerebral metabolic profile revealed brain metabolic distress and an excitatory response which improved over the following 5 days (P <0.001). Brain tissue hypoxia (brain tissue oxygen tension of less than 20 mm Hg) was common (more than 60% of patients) in the first 24 hours of neuromonitoring and improved thereafter (P <0.05). Baseline CMD-IL-6 and CMD-MMP-9 levels were elevated in all patients (median = 4,059 pg/mL, interquartile range (IQR) = 1,316 to 12,456 pg/mL and median = 851 pg/mL, IQR = 98 to 25,860 pg/mL) and significantly decreased over days (P <0.05). A higher pro-inflammatory response was associated with the development of delayed cerebral ischemia (P = 0.04), whereas admission disease severity and early brain tissue hypoxia were associated with higher CMD-MMP-9 levels (P <0.03). Brain metabolic distress and increased IL-6 levels were associated with poor functional outcome (modified Rankin Scale of more than 3, P ≤0.01). All models were adjusted for probe location, aneurysm securing procedure, and disease severity as appropriate.

Conclusions: Multimodal neuromonitoring techniques allow insight into pathophysiologic changes in the early phase after aSAH. The results may be used as endpoints for future interventions targeting EBI in poor-grade aSAH patients.

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Related in: MedlinePlus

Mean lactate-to-pyruvate ratio (LPR), glutamate, glucose, lactate, and pyruvate levels in the cerebral microdialysate and systemic glucose levels of 26 aneurysmal subarachnoid hemorrhage patients at given time points after neuromonitoring was started. Significant decrease of CMD-LPR (A), CMD-glutamate (B), and CMD-glucose (C). **P <0.01, ***P <0.001. Dashed lines indicate commonly used cutoffs (CMD-LPR at 40 and CMD-glucose at 0.7 mmol/L). Panel (D-F) Shows CMD-lactate, CMD-pyruvate and systemic glucose levels over time with significant increase of CMD-pyruvate levels (E) (*P <0.05). CMD-lactate (D) and systemic glucose levels (F) remained stable over the neuromonitoring time. Values are presented as mean ± standard error of the mean.
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Fig2: Mean lactate-to-pyruvate ratio (LPR), glutamate, glucose, lactate, and pyruvate levels in the cerebral microdialysate and systemic glucose levels of 26 aneurysmal subarachnoid hemorrhage patients at given time points after neuromonitoring was started. Significant decrease of CMD-LPR (A), CMD-glutamate (B), and CMD-glucose (C). **P <0.01, ***P <0.001. Dashed lines indicate commonly used cutoffs (CMD-LPR at 40 and CMD-glucose at 0.7 mmol/L). Panel (D-F) Shows CMD-lactate, CMD-pyruvate and systemic glucose levels over time with significant increase of CMD-pyruvate levels (E) (*P <0.05). CMD-lactate (D) and systemic glucose levels (F) remained stable over the neuromonitoring time. Values are presented as mean ± standard error of the mean.

Mentions: Continuous variables were assessed for normality. Normally distributed data were reported as mean and standard error of the mean, and non-parametric data were reported as median and interquartile range (IQR). Categorical variables were reported as count and proportions in each group. Hourly recorded concentrations in the cerebral microdialysate were matched to continuously recorded parameters (ICP, CPP, and PbtO2) averaged over the sampling period (as shown in Figures 1, 2, and 3). Figure 4 displays the percentage of patients with at least one episode (hourly averaged data matched to microdialysis sampling time) in the abnormal range. CMD-derived metabolic parameters and PbtO2 were categorized as previously defined according to international accepted definitions to associate with CMD-IL-6 and CMD-MMP-9 levels. Time series data were analyzed by using a generalized linear model using a normal distribution and identity-link function and were extended by generalized estimating equations (GEEs) with an autoregressive process of the first order to handle repeated observations within a subject [20]. Data were transformed (log for CMD-IL-6 and CMD-MMP-9) to meet assumptions of normality. In these GEE models, outcome was the dependent variable and important covariates were included (age and admission disease severity). For all tests, significance level was set at a P value of less than 0.05. All analyses were performed with IBM-SPSS V20.0 (SPSS Inc., Chicago, IL, USA).Figure 1


Early brain injury after aneurysmal subarachnoid hemorrhage: a multimodal neuromonitoring study.

Helbok R, Schiefecker AJ, Beer R, Dietmann A, Antunes AP, Sohm F, Fischer M, Hackl WO, Rhomberg P, Lackner P, Pfausler B, Thomé C, Humpel C, Schmutzhard E - Crit Care (2015)

Mean lactate-to-pyruvate ratio (LPR), glutamate, glucose, lactate, and pyruvate levels in the cerebral microdialysate and systemic glucose levels of 26 aneurysmal subarachnoid hemorrhage patients at given time points after neuromonitoring was started. Significant decrease of CMD-LPR (A), CMD-glutamate (B), and CMD-glucose (C). **P <0.01, ***P <0.001. Dashed lines indicate commonly used cutoffs (CMD-LPR at 40 and CMD-glucose at 0.7 mmol/L). Panel (D-F) Shows CMD-lactate, CMD-pyruvate and systemic glucose levels over time with significant increase of CMD-pyruvate levels (E) (*P <0.05). CMD-lactate (D) and systemic glucose levels (F) remained stable over the neuromonitoring time. Values are presented as mean ± standard error of the mean.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4384312&req=5

Fig2: Mean lactate-to-pyruvate ratio (LPR), glutamate, glucose, lactate, and pyruvate levels in the cerebral microdialysate and systemic glucose levels of 26 aneurysmal subarachnoid hemorrhage patients at given time points after neuromonitoring was started. Significant decrease of CMD-LPR (A), CMD-glutamate (B), and CMD-glucose (C). **P <0.01, ***P <0.001. Dashed lines indicate commonly used cutoffs (CMD-LPR at 40 and CMD-glucose at 0.7 mmol/L). Panel (D-F) Shows CMD-lactate, CMD-pyruvate and systemic glucose levels over time with significant increase of CMD-pyruvate levels (E) (*P <0.05). CMD-lactate (D) and systemic glucose levels (F) remained stable over the neuromonitoring time. Values are presented as mean ± standard error of the mean.
Mentions: Continuous variables were assessed for normality. Normally distributed data were reported as mean and standard error of the mean, and non-parametric data were reported as median and interquartile range (IQR). Categorical variables were reported as count and proportions in each group. Hourly recorded concentrations in the cerebral microdialysate were matched to continuously recorded parameters (ICP, CPP, and PbtO2) averaged over the sampling period (as shown in Figures 1, 2, and 3). Figure 4 displays the percentage of patients with at least one episode (hourly averaged data matched to microdialysis sampling time) in the abnormal range. CMD-derived metabolic parameters and PbtO2 were categorized as previously defined according to international accepted definitions to associate with CMD-IL-6 and CMD-MMP-9 levels. Time series data were analyzed by using a generalized linear model using a normal distribution and identity-link function and were extended by generalized estimating equations (GEEs) with an autoregressive process of the first order to handle repeated observations within a subject [20]. Data were transformed (log for CMD-IL-6 and CMD-MMP-9) to meet assumptions of normality. In these GEE models, outcome was the dependent variable and important covariates were included (age and admission disease severity). For all tests, significance level was set at a P value of less than 0.05. All analyses were performed with IBM-SPSS V20.0 (SPSS Inc., Chicago, IL, USA).Figure 1

Bottom Line: Baseline CMD-IL-6 and CMD-MMP-9 levels were elevated in all patients (median = 4,059 pg/mL, interquartile range (IQR) = 1,316 to 12,456 pg/mL and median = 851 pg/mL, IQR = 98 to 25,860 pg/mL) and significantly decreased over days (P <0.05).A higher pro-inflammatory response was associated with the development of delayed cerebral ischemia (P = 0.04), whereas admission disease severity and early brain tissue hypoxia were associated with higher CMD-MMP-9 levels (P <0.03).The results may be used as endpoints for future interventions targeting EBI in poor-grade aSAH patients.

View Article: PubMed Central - PubMed

Affiliation: Neurological Intensive Care Unit, Department of Neurology, Medical University of Innsbruck, Anichstreet 35, 6020, Innsbruck, Austria. raimund.helbok@uki.at.

ABSTRACT

Introduction: There is a substantial amount of evidence from animal models that early brain injury (EBI) may play an important role for secondary brain injury after aneurysmal subarachnoid hemorrhage (aSAH). Cerebral microdialysis (CMD) allows online measurement of brain metabolites, including the pro-inflammatory cytokine interleukin-6 (IL-6) and matrix metalloproteinase-9 (MMP-9), which is indicative for disruption of the blood-brain barrier.

Methods: Twenty-six consecutive poor-grade aSAH patients with multimodal neuromonitoring were analyzed for brain hemodynamic and metabolic changes, including CMD-IL-6 and CMD-MMP-9 levels. Statistical analysis was performed by using a generalized estimating equation with an autoregressive function.

Results: The baseline cerebral metabolic profile revealed brain metabolic distress and an excitatory response which improved over the following 5 days (P <0.001). Brain tissue hypoxia (brain tissue oxygen tension of less than 20 mm Hg) was common (more than 60% of patients) in the first 24 hours of neuromonitoring and improved thereafter (P <0.05). Baseline CMD-IL-6 and CMD-MMP-9 levels were elevated in all patients (median = 4,059 pg/mL, interquartile range (IQR) = 1,316 to 12,456 pg/mL and median = 851 pg/mL, IQR = 98 to 25,860 pg/mL) and significantly decreased over days (P <0.05). A higher pro-inflammatory response was associated with the development of delayed cerebral ischemia (P = 0.04), whereas admission disease severity and early brain tissue hypoxia were associated with higher CMD-MMP-9 levels (P <0.03). Brain metabolic distress and increased IL-6 levels were associated with poor functional outcome (modified Rankin Scale of more than 3, P ≤0.01). All models were adjusted for probe location, aneurysm securing procedure, and disease severity as appropriate.

Conclusions: Multimodal neuromonitoring techniques allow insight into pathophysiologic changes in the early phase after aSAH. The results may be used as endpoints for future interventions targeting EBI in poor-grade aSAH patients.

Show MeSH
Related in: MedlinePlus