Neurocrit Care DOI 10.1007/s12028-015-0140-y
ORIGINAL ARTICLE
Cerebral Taurine Levels are Associated with Brain Edema and Delayed Cerebral Infarction in Patients with Aneurysmal Subarachnoid Hemorrhage Mario Kofler1 • Alois Schiefecker1 • Boris Ferger2 • Ronny Beer1 • Florian Sohm3 Gregor Broessner1 • Werner Hackl4 • Paul Rhomberg5 • Peter Lackner1 • Bettina Pfausler1 • Claudius Thome´3 • Erich Schmutzhard1 • Raimund Helbok1
•
Ó Springer Science+Business Media New York 2015
Abstract Background Cerebral edema and delayed cerebral infarction (DCI) are common complications after aneurysmal subarachnoid hemorrhage (aSAH) and associated with poor functional outcome. Experimental data suggest that the amino acid taurine is released into the brain extracellular space secondary to cytotoxic edema and brain tissue hypoxia, and therefore may serve as a biomarker for secondary brain injury after aSAH. On the other hand, neuroprotective mechanisms of taurine treatment have been described in the experimental setting. Methods We analyzed cerebral taurine levels using highperformance liquid chromatography in the brain extracellular fluid of 25 consecutive aSAH patients with
multimodal neuromonitoring including cerebral microdialysis (CMD). Patient characteristics and clinical course were prospectively recorded. Associations with CMD-taurine levels were analyzed using generalized estimating equations with an autoregressive process to handle repeated observations within subjects. Results CMD-taurine levels were highest in the first days after aSAH (11.2 ± 3.2 lM/l) and significantly decreased over time (p < 0.001). Patients with brain edema on admission or during hospitalization (N = 20; 80 %) and patients developing DCI (N = 5; 20 %) had higher brain extracellular taurine levels compared to those without (Wald = 7.3, df = 1, p < 0.01; Wald = 10.1, df = 1, p = 0.001, respectively) even after adjusting for disease
& Raimund Helbok [email protected]
Bettina Pfausler [email protected]
Mario Kofler [email protected]
Claudius Thome´ [email protected]
Alois Schiefecker [email protected]
Erich Schmutzhard [email protected]
Boris Ferger [email protected]
1
Neurological Intensive Care Unit, Department of Neurology, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria
2
CNS Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397 Biberach an der Riss, Germany
Gregor Broessner [email protected]
3
Department of Neurosurgery, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria
Werner Hackl [email protected]
4
UMIT – University for Health Sciences, Medical Informatics and Technology, Eduard-Wallno¨fer-Zentrum 1, 6060 Hall, Austria
5
Department of Radiology, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria
Ronny Beer [email protected] Florian Sohm [email protected]
Paul Rhomberg [email protected] Peter Lackner [email protected]
123
Neurocrit Care
severity and CMD-probe location. There was no correlation between parenteral taurine supplementation and brain extracellular taurine (p = 0.6). Moreover, a significant correlation with brain extracellular glutamate (r = 0.82, p < 0.001), lactate (r = 0.56, p < 0.02), pyruvate (r = 0.39, p < 0.01), potassium (r = 0.37, p = 0.01), and lactate-to-pyruvate ratio (r = 0.24, p = 0.02) was found. Conclusions Significantly higher CMD-taurine levels were found in patients with brain edema or DCI after aneurysmal subarachnoid hemorrhage. Its value as a potential biomarker deserves further investigation. Keywords Cerebral microdialysis Taurine Aminoacids Subarachnoid hemorrhage Multimodal neuromonitoring
described in healthy brain tissue of brain tumor patients [25]. Higher CMD-taurine levels have been reported in aSAH patients, although the exact distance of the microdialysis probe to adjacent brain lesions was not specified in all patients [21, 22, 24, 26, 27]. An association between brain extracellular taurine levels and functional outcome has been reported [22] and higher levels were described in small case series of SAH patients with vasospasm-related DCI, radiologic evidence of restricted cerebral perfusion, or cerebral infarctions associated with aneurysm repair [21, 24, 27]. The aim of the current study was to further elucidate the association of brain extracellular taurine levels with brain metabolism, cerebral edema, and DCI in a cohort of poorgrade aSAH patients.
Introduction
Materials and Methods
Despite advances in neurocritical care management, aneurysmal subarachnoid hemorrhage (aSAH) is still associated with a high morbidity and mortality [1, 2]. Survivors of the initial bleed commonly develop cerebral edema or delayed cerebral infarction (DCI), which are both associated with poor functional outcome [3, 4]. Underlying pathophysiologic mechanisms are still incompletely understood and currently no biomarker precisely predicts their occurrence [5]. Detection of cerebral edema and DCI is based on clinical exam in good grade SAH patients and mostly relies on imaging parameters in unconscious patients [6]. Taurine (2-aminoethanesulfonic acid) is an abundant amino acid in mammalian brains and has a molecular weight of 0.125 kDa [7]. Located in the endothelium, glial cells, and neurons [8], it is released into the extracellular space secondary to cytotoxic edema [9, 10] and ischemia in cell culture and animal experiments [11, 12]. Yet, not only edema and infarction may be associated with cellular taurine efflux, but also preceding mechanisms, such as the disruption of the blood–brain barrier (BBB), glutamate stimulation, calcium accumulation, and oxidative stress [13–18]. Recently, high plasma taurine levels were associated with poor functional outcome after SAH [19]. However, local brain tissue-based biomarkers may better reflect secondary brain injury, i.e., cerebral edema and DCI, as plasma concentrations of molecules do not necessarily correlate with brain parenchymal levels [20]. Quantifying brain extracellular taurine levels in poor-grade SAH patients with cerebral microdialysis (CMD) using highperformance liquid chromatography (HPLC) of the microdialysate has been previously demonstrated [21–24]. Baseline CMD-taurine levels around 1–2 lM/l have been
Patient Selection and Care
123
Between April 2010 and September 2012, data of 25 consecutive aSAH patients fulfilling the criteria for multimodality neuromonitoring as approved by the institutional review board (Glasgow Coma Scale
ORIGINAL ARTICLE
Cerebral Taurine Levels are Associated with Brain Edema and Delayed Cerebral Infarction in Patients with Aneurysmal Subarachnoid Hemorrhage Mario Kofler1 • Alois Schiefecker1 • Boris Ferger2 • Ronny Beer1 • Florian Sohm3 Gregor Broessner1 • Werner Hackl4 • Paul Rhomberg5 • Peter Lackner1 • Bettina Pfausler1 • Claudius Thome´3 • Erich Schmutzhard1 • Raimund Helbok1
•
Ó Springer Science+Business Media New York 2015
Abstract Background Cerebral edema and delayed cerebral infarction (DCI) are common complications after aneurysmal subarachnoid hemorrhage (aSAH) and associated with poor functional outcome. Experimental data suggest that the amino acid taurine is released into the brain extracellular space secondary to cytotoxic edema and brain tissue hypoxia, and therefore may serve as a biomarker for secondary brain injury after aSAH. On the other hand, neuroprotective mechanisms of taurine treatment have been described in the experimental setting. Methods We analyzed cerebral taurine levels using highperformance liquid chromatography in the brain extracellular fluid of 25 consecutive aSAH patients with
multimodal neuromonitoring including cerebral microdialysis (CMD). Patient characteristics and clinical course were prospectively recorded. Associations with CMD-taurine levels were analyzed using generalized estimating equations with an autoregressive process to handle repeated observations within subjects. Results CMD-taurine levels were highest in the first days after aSAH (11.2 ± 3.2 lM/l) and significantly decreased over time (p < 0.001). Patients with brain edema on admission or during hospitalization (N = 20; 80 %) and patients developing DCI (N = 5; 20 %) had higher brain extracellular taurine levels compared to those without (Wald = 7.3, df = 1, p < 0.01; Wald = 10.1, df = 1, p = 0.001, respectively) even after adjusting for disease
& Raimund Helbok [email protected]
Bettina Pfausler [email protected]
Mario Kofler [email protected]
Claudius Thome´ [email protected]
Alois Schiefecker [email protected]
Erich Schmutzhard [email protected]
Boris Ferger [email protected]
1
Neurological Intensive Care Unit, Department of Neurology, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria
2
CNS Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397 Biberach an der Riss, Germany
Gregor Broessner [email protected]
3
Department of Neurosurgery, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria
Werner Hackl [email protected]
4
UMIT – University for Health Sciences, Medical Informatics and Technology, Eduard-Wallno¨fer-Zentrum 1, 6060 Hall, Austria
5
Department of Radiology, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria
Ronny Beer [email protected] Florian Sohm [email protected]
Paul Rhomberg [email protected] Peter Lackner [email protected]
123
Neurocrit Care
severity and CMD-probe location. There was no correlation between parenteral taurine supplementation and brain extracellular taurine (p = 0.6). Moreover, a significant correlation with brain extracellular glutamate (r = 0.82, p < 0.001), lactate (r = 0.56, p < 0.02), pyruvate (r = 0.39, p < 0.01), potassium (r = 0.37, p = 0.01), and lactate-to-pyruvate ratio (r = 0.24, p = 0.02) was found. Conclusions Significantly higher CMD-taurine levels were found in patients with brain edema or DCI after aneurysmal subarachnoid hemorrhage. Its value as a potential biomarker deserves further investigation. Keywords Cerebral microdialysis Taurine Aminoacids Subarachnoid hemorrhage Multimodal neuromonitoring
described in healthy brain tissue of brain tumor patients [25]. Higher CMD-taurine levels have been reported in aSAH patients, although the exact distance of the microdialysis probe to adjacent brain lesions was not specified in all patients [21, 22, 24, 26, 27]. An association between brain extracellular taurine levels and functional outcome has been reported [22] and higher levels were described in small case series of SAH patients with vasospasm-related DCI, radiologic evidence of restricted cerebral perfusion, or cerebral infarctions associated with aneurysm repair [21, 24, 27]. The aim of the current study was to further elucidate the association of brain extracellular taurine levels with brain metabolism, cerebral edema, and DCI in a cohort of poorgrade aSAH patients.
Introduction
Materials and Methods
Despite advances in neurocritical care management, aneurysmal subarachnoid hemorrhage (aSAH) is still associated with a high morbidity and mortality [1, 2]. Survivors of the initial bleed commonly develop cerebral edema or delayed cerebral infarction (DCI), which are both associated with poor functional outcome [3, 4]. Underlying pathophysiologic mechanisms are still incompletely understood and currently no biomarker precisely predicts their occurrence [5]. Detection of cerebral edema and DCI is based on clinical exam in good grade SAH patients and mostly relies on imaging parameters in unconscious patients [6]. Taurine (2-aminoethanesulfonic acid) is an abundant amino acid in mammalian brains and has a molecular weight of 0.125 kDa [7]. Located in the endothelium, glial cells, and neurons [8], it is released into the extracellular space secondary to cytotoxic edema [9, 10] and ischemia in cell culture and animal experiments [11, 12]. Yet, not only edema and infarction may be associated with cellular taurine efflux, but also preceding mechanisms, such as the disruption of the blood–brain barrier (BBB), glutamate stimulation, calcium accumulation, and oxidative stress [13–18]. Recently, high plasma taurine levels were associated with poor functional outcome after SAH [19]. However, local brain tissue-based biomarkers may better reflect secondary brain injury, i.e., cerebral edema and DCI, as plasma concentrations of molecules do not necessarily correlate with brain parenchymal levels [20]. Quantifying brain extracellular taurine levels in poor-grade SAH patients with cerebral microdialysis (CMD) using highperformance liquid chromatography (HPLC) of the microdialysate has been previously demonstrated [21–24]. Baseline CMD-taurine levels around 1–2 lM/l have been
Patient Selection and Care
123
Between April 2010 and September 2012, data of 25 consecutive aSAH patients fulfilling the criteria for multimodality neuromonitoring as approved by the institutional review board (Glasgow Coma Scale
