Spreading depolarizations in ischaemia after subarachnoid haemorrhage, a diagnostic phase III study.

Focal brain damage after aneurysmal subarachnoid haemorrhage predominantly results from intracerebral haemorrhage, and early and delayed cerebral ischaemia. The prospective, observational, multicentre, cohort, diagnostic phase III trial, DISCHARGE-1, primarily investigated whether the peak total spreading depolarization-induced depression duration of a recording day during delayed neuromonitoring (delayed depression duration) indicates delayed ipsilateral infarction. Consecutive patients (n = 205) who required neurosurgery were enrolled in six university hospitals from September 2009 to April 2018. Subdural electrodes for electrocorticography were implanted. Participants were excluded on the basis of exclusion criteria, technical problems in data quality, missing neuroimages or patient withdrawal (n = 25). Evaluators were blinded to other measures. Longitudinal MRI, and CT studies if clinically indicated, revealed that 162/180 patients developed focal brain damage during the first 2 weeks. During 4.5 years of cumulative recording, 6777 spreading depolarizations occurred in 161/180 patients and 238 electrographic seizures in 14/180. Ten patients died early; 90/170 developed delayed infarction ipsilateral to the electrodes. Primary objective was to investigate whether a 60-min delayed depression duration cut-off in a 24-h window predicts delayed infarction with >0.60 sensitivity and >0.80 specificity, and to estimate a new cut-off. The 60-min cut-off was too short. Sensitivity was sufficient [= 0.76 (95% confidence interval: 0.65-0.84), P = 0.0014] but specificity was 0.59 (0.47-0.70), i.e. <0.80 (P < 0.0001). Nevertheless, the area under the receiver operating characteristic (AUROC) curve of delayed depression duration was 0.76 (0.69-0.83, P < 0.0001) for delayed infarction and 0.88 (0.81-0.94, P < 0.0001) for delayed ischaemia (reversible delayed neurological deficit or infarction). In secondary analysis, a new 180-min cut-off indicated delayed infarction with a targeted 0.62 sensitivity and 0.83 specificity. In awake patients, the AUROC curve of delayed depression duration was 0.84 (0.70-0.97, P = 0.001) and the prespecified 60-min cut-off showed 0.71 sensitivity and 0.82 specificity for reversible neurological deficits. In multivariate analysis, delayed depression duration (ß = 0.474, P < 0.001), delayed median Glasgow Coma Score (ß = -0.201, P = 0.005) and peak transcranial Doppler (ß = 0.169, P = 0.016) explained 35% of variance in delayed infarction. Another key finding was that spreading depolarization-variables were included in every multiple regression model of early, delayed and total brain damage, patient outcome and death, strongly suggesting that they are an independent biomarker of progressive brain injury. While the 60-min cut-off of cumulative depression in a 24-h window indicated reversible delayed neurological deficit, only a 180-min cut-off indicated new infarction with >0.60 sensitivity and >0.80 specificity. Although spontaneous resolution of the neurological deficit is still possible, we recommend initiating rescue treatment at the 60-min rather than the 180-min cut-off if progression of injury to infarction is to be prevented.

Incidence and Outcome of Aneurysmal Subarachnoid Hemorrhage: The Swiss Study on Subarachnoid Hemorrhage (Swiss SOS).

BACKGROUND AND PURPOSE: The purpose of this study was to assess nationwide incidence and outcomes of aneurysmal subarachnoid hemorrhage (aSAH). The Swiss SOS (Swiss Study on Subarachnoid Hemorrhage) was established in 2008 and offers the unique opportunity to provide this data from the point of care on a nationwide level. METHODS: All patients with confirmed aneurysmal subarachnoid hemorrhage admitted between January 1, 2009 and December 31, 2014, within Switzerland were recorded in a prospective registry. Incidence rates were calculated based on time-matched population data. Admission parameters and outcomes at discharge and at 1 year were recorded. RESULTS: We recorded data of 1787 consecutive patients. The incidence of aneurysmal subarachnoid hemorrhage in Switzerland was 3.7 per 100 000 persons/y. The number of female patients was 1170 (65.5%). With a follow-up rate of 91.3% at 1 year, 1042 patients (58.8%) led an independent life according to the modified Rankin Scale (0-2). About 1 in 10 patients survived in a dependent state (modified Rankin Scale, 3-5; n=185; 10.4%). Case fatality was 20.1% (n=356) at discharge and 22.1% (n=391) after 1 year. CONCLUSIONS: The current incidence of aneurysmal subarachnoid hemorrhage in Switzerland is lower than expected and an indication of a global trend toward decreasing admissions for ruptured intracranial aneurysms. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03245866.

Nimodipine Dose Reductions in the Treatment of Patients with Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: The incidence of cerebral infarction and poor outcome in patients with aneurysmal subarachnoid hemorrhage (aSAH) is reduced by oral nimodipine but acute effects of the drug may include a significant decrease in mean arterial blood pressure (MAP). A dose reduction or discontinuation of the drug is recommended if recurrent MAP drops occur. The aim of our study was to evaluate the frequency and clinical significance of nimodipine dose modifications in patients suffering from aSAH. METHODS: 270 patients were included in our retrospective analysis of consecutively collected data of patients suffering from aSAH. The local treatment protocol was in accordance to national and international guidelines. Nimodipine was intended to be applied orally with a dosage of 60 mg every 4 h. RESULTS: Only 43.6 % of patients eligible for vasospasm prophylaxis with nimodipine received the full daily dose of 60 mg every 4 h. In 28.6 %, the dose had to be reduced by 50 % due to a significant reduction in blood pressure after administration and/or high dose of catecholamines. In 27.7 % of patients, oral administration of the drug was discontinued for the same reason. Dose reduction and discontinuation occurred with a significantly higher frequency in patients in poor clinical condition. Application of the full nimodipine dosage decreased the risk of unfavorable clinical outcome in multivariate analysis (OR 0.895, p = 0.029). CONCLUSIONS: Our results show that dose reduction or discontinuation of nimodipine due to changes in MAP occur frequently in clinical routine and may be associated with unfavorable clinical outcome.

Measuring Serum Amyloid A for Infection Prediction in Aneurysmal Subarachnoid Hemorrhage.

Aneurysmal subarachnoid hemorrhage (aSAH) is associated with high rates of mortality and morbidity. Nosocomial infections, such as pneumonia or urinary tract infections, are among the main causes of worsening outcomes and death. The aim of this study was to discover a biomarker to predict infection in aSAH patients. For this purpose, the plasma of infected and noninfected patients was compared using quantitative mass spectrometry. The most interesting differentially expressed proteins were selected for validation by immunoassays on plasma samples taken from patients (n = 81) over 10 days of hospitalization. Predictive performances were established using Mann-Whitney U tests and receiver operating characteristic curves. Quantitative proteomics identified 17 significantly regulated proteins. Of these, levels of serum amyloid A (SAA) were significantly higher in infected patients (p < 0.007). ELISA confirmed that the concentrations were significantly higher (p < 0.002) already at hospital admission in patients who subsequently developed an infection during their hospitalization, (AUC of 76%) for a cutoff value of 90.9 µg/mL. Our data suggested that measuring SAA could be an efficient means of detecting patients susceptible of developing an infection during hospitalization after an aSAH. Its predictive capacity could lead to earlier antibiotherapy, improved patient management, and potentially better long-term outcomes.

Clusters of spreading depolarizations are associated with disturbed cerebral metabolism in patients with aneurysmal subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: We studied the dynamics of extracellular brain tissue concentrations of glucose, lactate, pyruvate, and glutamate during the occurrence of spreading depolarizations (SDs) in patients with aneurysmal subarachnoid hemorrhage. METHODS: In this prospective observational study, patients with aneurysmal subarachnoid hemorrhage received multimodal cerebral monitoring, including intracranial pressure, cerebral microdialysis, and subdural electrocorticography. RESULTS: Seven of the 17 recruited patients had intracerebral hemorrhage, acute ischemia and severe brain oedema leading to acute ischemic neurological deficits associated with early disturbance of metabolism at the recording site. They displayed a total of 130 SDs. The remaining 10 patients without acute ischemic neurological deficits exhibited 138 single SDs and 68 SDs in clusters. In patients without acute ischemic neurological deficits, clustered SDs were associated with a significant transient decrease in glucose and increase in lactate compared with baseline during the first 140 minutes after SDs. Moreover, the number of clustered SDs correlated with the outcome (R=-0.659; P<0.01). CONCLUSIONS: SDs can propagate in nonischemic human brain tissue. Clusters of SDs are related to metabolic changes suggestive of ongoing secondary damage in primarily nonischemic brain tissue.

Cerebral glucose and spreading depolarization in patients with aneurysmal subarachnoid hemorrhage.

The pathogenesis of delayed cerebral ischemia (DCI) is multifactorial and not completely elucidated. Our objective was to determine if episodes of spreading depolarization (SD) are reflected in compromised levels of extracellular glucose monitored by bedside microdialysis (MD) in aneurysmal subarachnoid hemorrhage (aSAH) patients. Patients with aSAH, prospectively included in the COSBID (CoOperative Study on Brain Injury Depolarisations) protocol (Berlin, Heidelberg), had hourly monitoring of cerebral glucose by MD and in parallel electrocorticographic (ECoG) monitoring for SD detection on day of admission until days 10-14 after aSAH. Cerebral MD probes were placed in the vascular territory at risk for DCI. Twenty-one aSAH patients (53.3 ± 9.1 years; mean ± standard deviation), classified according to the World Federation of Neurosurgical Societies (WFNS) in low (I-III, 11) and high (IV-V, 10) grades, were studied. Of these, 13 patients (62%) presented with DCI. Median glucose was 1.48 (0.00-8.79). Median occurrence of SD was 7 (0-66)/patients. High WFNS grade (WFNS grades IV-V) patients had more SDs (p = 0.027), while the overall glucose level did not differ. In high-grade SAH patients, SDs were more frequent. Individually, the occurrence of SD was not linked to local deviations (neither high nor low) from the LOWESS (locally weighted scatterplot smoothing) trend curve for extracellular glucose concentrations. Rapid-sampling MD techniques and analyses of SD clusters may elucidate more detail of the relationship between SD and brain energy metabolism.

Intraoperative angiography reloaded: a new hybrid operating theater for combined endovascular and surgical treatment of cerebral arteriovenous malformations: a pilot study on 25 patients.

BACKGROUND: Multimodality treatment suites for patients with cerebral arteriovenous malformations (AVM) have recently become available. This study was designed to evaluate feasibility, safety and impact on treatment of a new intraoperative flat-panel (FP) based integrated surgical and imaging suite for combined endovascular and surgical treatment of cerebral AVM. METHODS: Twenty-five patients with AVMs to treat with combined endovascular and surgical interventions were prospectively enrolled in this consecutive case series. The hybrid suite allows combined endovascular and surgical approaches with intraoperative scanner-like imaging (XperCT®) and intraoperative 3D rotational angiography (3D-RA). The impact of intraoperative multimodal imaging on feasibility, workflow of combined interventions, surgery, and unexpected imaging findings were analyzed. RESULTS: Twenty-five patients (mean age 38 ± 18.6 year) with a median Spetzler-Martin grade 2 AVM (range 1-4) underwent combined endovascular and surgical procedures. Sixteen patients presented with a ruptured AVM and nine with an unruptured AVM. In 16 % (n = 4) of cases, intraoperative imaging visualized AVM remnants ≤3 mm and allowed for completion of the resections in the same sessions. Complete resection was confirmed in all n = 16 patients who had follow-up angiography one year after surgery so far. All diagnostic and therapeutical steps, including angiographic control, were performed without having to move the patients CONCLUSION: The hybrid neurointerventional suite was shown to be a safe and useful setup which allowed for unconstrained combined microsurgical and neuroradiological workflow. It reduces the need for extraoperative angiographic controls and subsequent potential surgical revisions a second time, as small AVM remnants can be detected with high security.

Immunodepression after aneurysmal subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: immunodepression after stroke is associated with complications like high infection rate, but its role in aneurysmal subarachnoid hemorrhage (aSAH) is unclear. This pilot study aimed to assess the presence of immunodepression and its association with infections after aSAH. METHODS: sixteen aSAH patients were enrolled in a prospective study on immune function in a single institution. Detailed immune monitoring (peripheral blood leukocyte subsets, monocyte human leukocyte antigen-DR expression, ex vivo lipopolysaccharide-induced monocytic, Concanavalin A-induced lymphocytic cytokine secretion) was performed until day 10 after aSAH. Occurrence of infection was assessed within 14 days after aSAH. RESULTS: sixteen consecutive aSAH patients (53.1 ± 10.2 years; mean ± SD) met the inclusion criteria, classified as asymptomatic (World Federation of Neurological Surgeons; median, 1; quartile, 1-1; n=7) and symptomatic (median, 4; quartile, 3-5; n=9), all presenting with acute neurological deficits, and 5 of these had additional delayed cerebral ischemia. T-lymphopenia, impaired ex vivo lymphocytic/monocytic cytokine secretion, and decreased monocyte human leukocyte antigen-DR expression occurred over all World Federation of Neurological Surgeons grades but persisted beyond day 3 only in symptomatic patients. Pneumonia (67%; P=0.011) was more frequent in symptomatic patients. Already at day 1, patients with pneumonia showed significantly lower T-cell counts and mitogen-induced interferon-γ production compared to patients without infections. CONCLUSIONS: a pronounced SAH-induced immunodepression was observed early after aSAH but persisted only in symptomatic patients. Immunodepression was associated with a high incidence of pneumonia. Early diagnosis of immunodepression might allow targeted treatment to prevent infectious complications after aSAH.

Severe traumatic brain injury in children--a single center experience regarding therapy and long-term outcome.

OBJECT: The impact of intracranial pressure (ICP), decompressive craniectomy (DC), extent of ICP therapy, and extracranial complications on long-term outcome in a single-center pediatric patient population with severe traumatic brain injury (TBI) is examined. METHODS: Data of pediatric (≤16 years) TBI patients were retrospectively reviewed using a prospectively acquired database on neurosurgical interventions between April 1996 and March 2007 at the Charité Berlin. The patients' records, neuroimages, admission Glasgow Coma Scale (GCS) score, the time to craniectomy for hematoma evacuation/DC, and the extent of ICP therapy were reviewed. Twelve-month and long-term outcome was evaluated (Glasgow Outcome Scale). RESULTS: Fifty-three pediatric TBI patients [mean age 8.41 (0-16) years] were studied. Patients were categorized into two groups, with DC (n = 14) and without DC (n = 39). DC was performed 3 ± 3.98 median, quartiles 2 (0-3.75) days post-trauma. In the majority of children (n = 9; 64%), surgical decompression was performed early within 2 days post-trauma. (0.8 ± 0.9 days). The DC group tended to be older (median age 12 vs. 7 years, p = 0.052), had a lower GCS (3 vs. 6.5, p < 0.01), and had a 3-fold longer stay on the ICU (20 vs. 6.5 days, p < 0.03) compared to the conservatively treated group. Mean follow-up duration (n = 30) was 5.2 ± 2.4 years (range 1-10.5). At the most recent follow-up examination, 92% of survivors had returned to school. CONCLUSION: Though initial GCS was worse in pediatric TBI patients who underwent decompressive craniectomy compared to the conservatively treated patients, long-term outcome was comparable. In children, decompressive craniectomy might be favored early in the management of uncontrollable ICP.

Relevance of cerebral interleukin-6 after aneurysmal subarachnoid hemorrhage.

BACKGROUND: This study examines the inflammatory response via interleukin-6 (IL-6) in aneurysmal subarachnoid hemorrhage (aSAH) patients and its association with their clinical course (occurrence of acute focal neurological deficits, AFND; and delayed cerebral ischemia, DCI). METHODS: A total of 38 consecutive aSAH patients were studied prospectively within 14 days after admission and classified as asymptomatic (n = 9; WFNS grade 1 (1-2), median and quartiles) and symptomatic (n = 29; WFNS grade 4 (2-5)); the latter presenting with AFND (n = 13), DCI (n = 10) or both (n = 6). Levels of pro-inflammatory cytokine IL-6 were determined in cerebral extracellular fluid (ECF, using cerebral microdialysis), cerebrospinal fluid (CSF) and plasma for 10 days after aSAH. Additionally, C-reactive protein (CRP) levels were measured in plasma. RESULTS: High IL-6 levels in CSF, ECF and plasma were found in all patients, reflecting a pronounced local inflammatory response after aSAH, followed only in symptomatic patients by a delayed systemic inflammation (CRP P < 0.025, days 7-9 after aSAH). In all compartments, IL-6 levels appeared to be higher in symptomatic patients, accompanied also by a higher ECF lactate-pyruvate ratio (P = 0.04). Cerebral, but not plasma IL-6, levels were indicative of the development of DCI in symptomatic patients (ECF P = 0.003; CSF P = 0.001). CONCLUSIONS: A pronounced initial cerebral inflammatory state was observed in patients of all WFNS grades, suggesting that IL-6 elevations are not necessarily detrimental. Cerebral, but not plasma IL-6, levels were predictive of the development of delayed ischemic deficits in symptomatic patients, suggesting that CSF or ECF are the best sampling media for future studies.

Preliminary evidence that ketamine inhibits spreading depolarizations in acute human brain injury.

BACKGROUND AND PURPOSE: Spreading depolarizations, characterized by large propagating, slow potential changes, have been demonstrated with electrocorticography in patients with cerebral hemorrhage and ischemic stroke. Whereas spreading depolarizations are harmless under normal conditions in animals, they cause or augment damage in the ischemic brain. A fraction of spreading depolarizations is abolished by N-methyl-d-aspartate receptor antagonists. Summary of Case- In 2 patients with severe acute brain injury (traumatic and spontaneous intracranial hemorrhage), spreading depolarizations were inhibited by the noncompetitive N-methyl-d-aspartate receptor antagonist ketamine. This restored electrocorticographic activity. CONCLUSIONS: These anecdotal electrocorticographic findings suggest that ketamine has an inhibitory effect on spreading depolarizations in humans. This is of potential interest for future neuroprotective trials.

Relevance of intracranial hypertension for cerebral metabolism in aneurysmal subarachnoid hemorrhage. Clinical article.

OBJECT: Intracranial hypertension, defined as intracranial pressure (ICP) >/= 20 mm Hg, is a complication typically associated with head injury. Its impact on cerebral metabolism, ICP therapy, and outcome has rarely been studied in patients with aneurysmal subarachnoid hemorrhage (aSAH); such an assessment is the authors' goal in the present study. METHODS: Cerebral metabolism was prospectively studied in 182 patients with aSAH. The database was retrospectively analyzed with respect to ICP. Patients were classified into 2 groups based on ICP. There were 164 with low ICP (<20 mm Hg) and 18 with high ICP (>or=20 mm Hg, measured>6 hours/day). Cerebral microdialysis parameters of energy metabolism, glycerol, and glutamate levels were analyzed hourly from the brain parenchyma of interest for 7 days. The 12-month outcome in these patients was evaluated. RESULTS: In the high ICP group, extended ICP therapy including decompressive craniectomy was necessary in 7 patients (39%). Cerebral glycerol levels and the lactate/pyruvate ratio were pathologically increased on Days 1-7 after aSAH (p<0.001). The excitotoxic neurotransmitter glutamate and glycerol, a marker of membrane degradation, further increased on Days 5-7, probably reflecting the development of secondary brain damage. An ICP>or=20 mm Hg was shown to have a significant influence on the 12-month Glasgow Outcome Scale (GOS) score (p=0.001) and was a strong predictor of mortality (OR=24.6; p<0.001). Glutamate (p=0.012), the lactate/pyruvate ratio as a marker of anaerobic metabolism (p=0.028), age (p<0.001), and Fisher grade (p=0.001) also influenced the GOS score at 12 months. CONCLUSIONS: The authors confirmed the relevance of intracranial hypertension as a severe complication in patients with aSAH. Because high ICP is associated with a severely deranged cerebral metabolism and poor outcome, future studies focusing on metabolism-guided, optimized ICP therapy could help minimize secondary brain damage and improve prognosis in patients with aSAH.

Cerebral microdialysis for detection of bacterial meningitis in aneurysmal subarachnoid hemorrhage patients: a cohort study.

INTRODUCTION: Bacterial meningitis (BM) is a severe complication in patients with aneurysmal subarachnoid haemorrhage (SAH). Clinical signs of meningitis are often masked by SAH-related symptoms, and routine cerebrospinal fluid (CSF) analysis fails to indicate BM. Microdialysis (MD) is a technique for monitoring cerebral metabolism in patients with SAH. A cohort study was performed to investigate the value of MD for the diagnosis of BM. METHODS: Retrospectively, 167 patients with SAH in an ongoing investigation on cerebral metabolism monitored by MD were analysed for the presence of BM and related MD changes. Diagnosis of BM was based on microbiological CSF culture or clinical symptoms responding to antibiotic treatment, combined with an increased CSF cell count and/or fever. Levels of MD parameters before and after diagnosis of BM were analysed and compared with the spontaneous course in controls. RESULTS: BM developed in 20 patients, of which 12 underwent MD monitoring at the time of diagnosis. A control group was formed using 147 patients with SAH not developing meningitis. On the day BM was diagnosed, cerebral glucose was lower compared with the value three days before (p = 0.012), and the extent of decrease was significantly higher than in controls (p = 0.044). A decrease in cerebral glucose by 1 mmol/L combined with the presence of fever >or= 38 degrees C indicated BM with a sensitivity of 69% and a specificity of 80%. CSF chemistry failed to indicate BM, but the cell count increased during the days before diagnosis (p < 0.05). CONCLUSIONS: A decrease in MD glucose combined with the presence of fever detected BM with acceptable sensitivity and specificity, while CSF chemistry failed to indicate BM. In patients with SAH where CSF cell count is not available or helpful, MD might serve as an adjunct criterion for early diagnosis of BM.

Decompressive craniectomy in aneurysmal subarachnoid hemorrhage: relation to cerebral perfusion pressure and metabolism.

INTRODUCTION: Outcome is poor in aneurysmal subarachnoid hemorrhage (SAH) patients with intracranial hypertension. As one treatment option for increased intracranial pressure (ICP), decompressive craniectomy (DC) is discussed. Its impact on cerebral metabolism and outcome in SAH patients is evaluated in this pilot study. METHODS: A prospectively collected database of cerebral metabolism in SAH patients was analyzed retrospectively for individuals developing high ICP (>20 mmHg > 6 h/day, n = 18). Patients with intracranial hypertension were classified into groups with (n = 7) and without DC (n = 11). An age-matched control group was established (n = 89). Cerebral perfusion pressure (CPP) and high ICP treatment were analyzed for 7 days after SAH (or 72 h after craniectomy, respectively). Cerebral microdialysates were analyzed hourly. Twelve-month outcome was evaluated. RESULTS: Groups were comparable for age, WFNS grade, and outcome. ICP was significantly reduced by DC (P < 0.01), however, in 43% of patients the effect was transient. An increase in the lactate/pyruvate ratio (P < 0.001) and glycerol levels (>200 muM) was observed before DC. In the DC group, glucose (P = 0.005) and pyruvate (P = 0.04) were higher, while glycerol levels were lower (P = 0.007) compared to the non-DC group, reflecting better aerobic glucose utilization and reduced cellular stress. CONCLUSION: Outcome was poor in all SAH patients with intracranial hypertension. Although glucose utilization was improved after DC, no improvement in outcome could be shown for this small patient population. Future studies will have to demonstrate whether markers of cerebral crisis may support the decision for DC in aneurysmal SAH patients.

Hyperglycemia and cerebral glucose in aneurysmal subarachnoid hemorrhage.

OBJECTIVE: To determine whether hyperglycemia exerts deleterious effects via cerebral energy metabolism and to illuminate the effects of cerebral high/low glucose in patients with aneurysmal subarachnoid hemorrhage. DESIGN AND SETTING: Prospective, nonrandomized single-center study over a 2-year period in an intensive care unit at a primary-level university hospital. PATIENTS: 28 subarachnoid hemorrhage patients (age 53 +/- 10 years, WFNS grade 2.8 +/- 1.5) classified as asymptomatic (n = 5) or symptomatic with acute focal or delayed ischemic neurological deficits (n = 23). MEASUREMENTS AND RESULTS: Hyperglycemia (> 7.8 mmol/l; >140 mg/dl) was more frequent in symptomatic patients and was reflected in higher glycerol concentrations than in asymptomatic patients. In all patients a microdialysis catheter was inserted into the tissue at risk; dialysates were collected hourly for 10 days. Cerebral low-glucose episodes (0.6 mmol/l) and high-glucose episodes (>2.6 mmol/l) occurred independently of blood glucose levels. During high-glucose episodes cerebral microdialysate levels were normal, while cerebral low glucose, occurring more frequently in symptomatic patients, was associated with severe cellular distress (increase in lactate/pyruvate ratio, glutamate, glycerol) and with unfavorable outcome if combined with hyperglycemia. CONCLUSIONS: Although hyperglycemia was more frequent in symptomatic patients and associated with high glycerol levels, hyperglycemia was not related to cerebral high glucose. It appears that the association of adverse outcome with acute-phase hyperglycemia is not mediated by cerebral glucose metabolism. Cerebral low glucose was associated with severe metabolic distress and may present a target for therapy to improve clinical outcome.

Insulin-related decrease in cerebral glucose despite normoglycemia in aneurysmal subarachnoid hemorrhage.

INTRODUCTION: Hyperglycaemia following aneurysmal subarachnoid hemorrhage (SAH) is associated with complications and impaired neurological recovery. The aim of this study was to determine the effect of insulin treatment for glucose control on cerebral metabolism in SAH patients. METHODS: This prospective, nonrandomized study was conducted in 31 SAH patients in an intensive care unit (age 52 +/- 10 years, World Federation of Neurological Surgeons grade 2.9 +/- 1.6). A microdialysis catheter was inserted into the vascular territory of the aneurysm after clipping. Blood glucose levels above 140 mg/dl were treated with intravenous insulin and the microdialysates were analyzed hourly for the first 12 hours of infusion. RESULTS: No hypoglycaemia occurred. Twenty-four patients were treated with insulin for glucose control. Higher age and World Federation of Neurological Surgeons score were risk factors for need for insulin treatment (P < 0.05). Although blood glucose remained stable after initiation of insulin infusion, insulin induced a significant decrease in cerebral glucose at 3 hours after onset of the infusion until the end of the observation period (P < 0.05), reflecting high glucose utilization. The lactate:pyruvate ratio and glutamate did not increase, excluding ischaemia as possible cause of the decrease in glucose. Glycerol tended toward higher values at the end of the observation period (9 to 12 hours), reflecting either tissue damage after SAH or the beginning of cellular distress after insulin infusion. CONCLUSION: Higher SAH grade was among the risk factors for need for insulin. Intensive glycaemic control using insulin induced a decrease of cerebral glucose and a slight increase in glycerol, though blood glucose remained normal. Future studies might detect relevant metabolic derangements when insulin treatment starts at low cerebral glucose levels, and may allow us to design a strategy for avoidance of insulin-induced metabolic crisis in SAH patients.

Is continuous insulin treatment safe in aneurysmal subarachnoid hemorrhage?

OBJECTIVES: To investigate the long-term effect of continuous insulin infusion for glucose control on cerebral metabolism in aneurysmal subarachnoid hemorrhage (SAH) patients. METHODS: Prospective, nonrandomized study of 31 SAH patients in the ICU (52 +/- 10 years, WFNS Grade 2.9 +/- 1.6). A microdialysis catheter was inserted into the vascular territory of the aneurysm. Metabolic changes during 4 days after onset of insulin infusion were analyzed. Blood glucose levels >140 mg/dL after clinical stabilization were treated with intravenous insulin. RESULTS: 24 patients were treated with intravenous insulin. Though no insulin-induced hypoglycemia occurred, cerebral glucose decreased on days 1-4 after insulin onset without reaching critical levels. Glycerol, a marker of membrane degradation, showed a reversible increase on day 1 while the lactate/pyruvate ratio remained stable and glutamate even decreased indicating absence of severe cerebral crisis following insulin infusion and excluding ischemia as a cause for cerebral glucose depletion. CONCLUSIONS: Concerning cerebral metabolism, long-term continuous insulin infusion appears to be safe as long as cerebral glucose levels do not fall below the physiological range. In view of the high incidence of hyperglycemia and need for insulin treatment, future studies on the effect of insulin on cerebral metabolism in SAH patients are desirable.

A novel score to predict shunt dependency after aneurysmal subarachnoid hemorrhage.

OBJECTIVE Feasible clinical scores for predicting shunt-dependent hydrocephalus (SDHC) after aneurysmal subarachnoid hemorrhage (aSAH) are scarce. The chronic hydrocephalus ensuing from SAH score (CHESS) was introduced in 2015 and has a high predictive value for SDHC. Although this score is easy to calculate, several early clinical and radiological factors are required. The authors designed the retrospective analysis described here for external CHESS validation and determination of predictive values for the radiographic Barrow Neurological Institute (BNI) scoring system and a new simplified combined scoring system. METHODS Consecutive data of 314 patients with aSAH were retrospectively analyzed with respect to CHESS parameters and BNI score. A new score, the shunt dependency in aSAH (SDASH) score, was calculated from independent risk factors identified with multivariate analysis. RESULTS Two hundred twenty-five patients survived the initial phase after the hemorrhage, and 27.1% of these patients developed SDHC. The SDASH score was developed from results of multivariate analysis, which revealed acute hydrocephalus (aHP), a BNI score of ≥ 3, and a Hunt and Hess (HH) grade of ≥ 4 to be independent risk factors for SDHC (ORs 5.709 [aHP], 6.804 [BNI], and 4.122 [HH]; p < 0.001). All 3 SDHC scores tested (CHESS, BNI, and SDASH) reliably predicted chronic hydrocephalus (ORs 1.533 [CHESS], 2.021 [BNI], and 2.496 [SDASH]; p ≤ 0.001). Areas under the receiver operating curve (AUROC) for CHESS and SDASH were comparable (0.769 vs 0.785, respectively; p = 0.447), but the CHESS and SDASH scores were superior to the BNI grading system for predicting SDHC (BNI AUROC 0.649; p = 0.014 and 0.001, respectively). In contrast to CHESS and BNI scores, an increase in the SDASH score coincided with a monotonous increase in the risk of developing SDHC. CONCLUSIONS The newly developed SDASH score is a reliable tool for predicting SDHC. It contains fewer factors and is more intuitive than existing scores that were shown to predict SDHC. A prospective score evaluation is needed.

Early measurement of interleukin-10 predicts the absence of CT scan lesions in mild traumatic brain injury.

Traumatic brain injury is a common event where 70%-90% will be classified as mild TBI (mTBI). Among these, only 10% will have a brain lesion visible via CT scan. A triage biomarker would help clinicians to identify patients with mTBI who are at risk of developing a brain lesion and require a CT scan. The brain cells damaged by the shearing, tearing and stretching of a TBI event set off inflammation cascades. These cause altered concentrations of a high number of both pro-inflammatory and anti-inflammatory proteins. This study aimed to discover a novel diagnostic biomarker of mTBI by investigating a broad panel of inflammation biomarkers and their capacity to correctly identify CT-positive and CT-negative patients. Patients enrolled in this study had been diagnosed with mTBI, had a GCS score of 15 and suffered from at least one clinical symptom. There were nine patients in the discovery group, 45 for verification, and 133 mTBI patients from two different European sites in the validation cohort. All patients gave blood samples, underwent a CT scan and were dichotomised into CT-positive and CT-negative groups for statistical analyses. The ability of each protein to classify patients was evaluated with sensitivity set at 100%. Three of the 92 inflammation proteins screened-MCP-1, MIP-1alpha and IL-10 -were further investigated in the verification group, and at 100% sensitivity their specificities reached 7%, 0% and 31%, respectively. IL-10 was validated on a larger cohort in comparison to the most studied mTBI diagnostic triage protein to date, S100B. Levels of both proteins were significantly higher in CT-positive than in CT-negative patients (p < 0.001). S100B's specificity at 100% sensitivity was 18% (95% CI 10.8-25.2), whereas IL-10 reached a specificity of 27% (95% CI 18.9-35.1). These results showed that IL-10 might be an interesting and clinically useful diagnostic tool, capable of differentiating between CT-positive and CT-negative mTBI patients.

Combining H-FABP and GFAP increases the capacity to differentiate between CT-positive and CT-negative patients with mild traumatic brain injury.

Mild traumatic brain injury (mTBI) patients may have trauma-induced brain lesions detectable using CT scans. However, most patients will be CT-negative. There is thus a need for an additional tool to detect patients at risk. Single blood biomarkers, such as S100B and GFAP, have been widely studied in mTBI patients, but to date, none seems to perform well enough. In many different diseases, combining several biomarkers into panels has become increasingly interesting for diagnoses and to enhance classification performance. The present study evaluated 13 proteins individually-H-FABP, MMP-1, MMP-3, MMP-9, VCAM, ICAM, SAA, CRP, GSTP, NKDA, PRDX1, DJ-1 and IL-10-for their capacity to differentiate between patients with and without a brain lesion according to CT results. The best performing proteins were then compared and combined with the S100B and GFAP proteins into a CT-scan triage panel. Patients diagnosed with mTBI, with a Glasgow Coma Scale score of 15 and one additional clinical symptom were enrolled at three different European sites. A blood sample was collected at hospital admission, and a CT scan was performed. Patients were divided into two two-centre cohorts and further dichotomised into CT-positive and CT-negative groups for statistical analysis. Single markers and panels were evaluated using Cohort 1. Four proteins-H-FABP, IL-10, S100B and GFAP-showed significantly higher levels in CT-positive patients. The best-performing biomarker was H-FABP, with a specificity of 32% (95% CI 23-40) and sensitivity reaching 100%. The best-performing two-marker panel for Cohort 1, subsequently validated in Cohort 2, was a combination of H-FABP and GFAP, enhancing specificity to 46% (95% CI 36-55). When adding IL-10 to this panel, specificity reached 52% (95% CI 43-61) with 100% sensitivity. These results showed that proteins combined into panels could be used to efficiently classify CT-positive and CT-negative mTBI patients.