Time spent with impaired autoregulation is linked with outcome in severe infant/paediatric traumatic brain injury.

BACKGROUND: It could be shown in traumatic brain injury (TBI) in adults that the functional status of cerebrovascular autoregulation (AR), determined by the pressure reactivity index (PRx), correlates to and even predicts outcome. We investigated PRx, cerebral perfusion pressure (CPP) and intracranial pressure (ICP) and their correlation to outcome in severe infant and paediatric TBI. METHODS: Seventeen patients (range, 1 day to 14 years) with severe TBI (median GCS at presentation, 4) underwent long-term computerised ICP and mean arterial pressure (MAP) monitoring using dedicated software to determine CPP and PRx and optimal CPP (CPP level where PRx shows best autoregulation) continuously. Outcome was determined at discharge and at follow-up using the Glasgow Outcome Scale. RESULTS: Favourable outcome was reached in eight patients, unfavourable outcome in seven patients. Two patients died. Nine patients underwent decompressive craniectomy to control ICP during Intensive Care Unit treatment. When dichotomised to outcome, no significant difference was found for overall ICP, CPP and PRx. The time with severely impaired AR (PRx >0.2) was significantly longer for patients with unfavourable outcome (64 h vs 6 h, p = 0.001). Continuously impaired AR of ≥24 h and age <1 year was associated to unfavourable outcome. Children with favourable outcome spent the entire monitoring time at or above the optimal CPP. CONCLUSIONS: Integrity of AR has a similar role for outcome after TBI in the paediatric population as in adults. The amount of time spent with deranged AR seems to be associated with outcome; a factor especially critical for infant patients. The results of this preliminary study need to be validated in the future.

Effect of Intra-Arterial and Intravenous Nimodipine Therapy of Cerebral Vasospasm After Subarachnoid Hemorrhage on Cerebrovascular Reactivity and Oxygenation.

BACKGROUND: For the treatment and prevention of delayed cerebral ischemia after subarachnoid hemorrhage, the vasodilating agent nimodipine (NDP) is widely employed. This study investigates the effect of NDP on cerebrovascular autoregulation, assessed by pressure reactivity index (PRx), and brain tissue oxygenation (pbrO2) when given continuously intravenously as an intra-arterial bolus or during continuous intra-arterial therapy. METHODS: Computerized continuous neuromonitoring data (intracranial pressure, mean arterial pressure, cerebral perfusion pressure [CPP], pbrO2, PRx) of 105 patients with aneurysmal SAH were retrospectively evaluated. The effect of NDP on all parameters was compared when applied intra-arterially for the treatment of severe macrovasospasm leading to perfusion deficits as either bolus treatment (n = 111 in 37 patients) or continuous infusion (n = 20 patients) to patients without or with only mild macrovasospasm who received either intravenous NDP or no NDP at all. RESULTS: Compared with patients without treatment, the intravenous application of NDP was associated with a significantly higher PRx. Autoregulation was strongly and long lastingly affected (high PRx) in continuous intra-arterial NDP infusion, accompanied by a sustained improvement of pbrO2. Intra-arterial bolus NDP application resulted as well in a significant increase of pbrO2 and PRx; the induced effect, however, was transient and subsided within 6 hours. Intracranial pressure, mean arterial pressure, and CPP were not affected during the monitoring period. CONCLUSION: The pharmacologically induced alteration of the cerebrovascular autoregulation by NDP correlates with changes of pbrO2 and indicates a beneficial effect on cerebral blood flow if CPP is maintained. This effect is limited to a few hours after bolus treatment and milder for intravenous compared with intra-arterial application.

Changes in electrocorticographic beta frequency components precede spreading depolarization in patients with acute brain injury.

OBJECTIVE: Spreading depolarization (SD) occurs after traumatic brain injury, subarachnoid hemorrhage, malignant hemispheric stroke and intracranial hemorrhage. SD has been associated with secondary brain injury, which can be reduced by ketamine. In this present study frequency bands of electrocorticographic (ECoG) recordings were investigated with regards to SDs. METHODS: A total of 43 patients after acute brain injury were included in this retrospective and explorative study. Relative delta 0.5-4Hz, theta 4-8Hz, alpha 8-13Hz and beta 13-40Hz bands were analyzed with regards to SD occurrence and analgesic and sedative administration. Higher frequencies, including gamma 40-70Hz, fast gamma 70-100Hz and high frequency oscillations 100-200Hz were analyzed in a subset of patients with a sampling rate of up to 400Hz. RESULTS: A close association of relative beta frequency and SD was found. Relative beta frequency was suppressed up to two hours prior to SD when compared to hours with no SD. This finding was partially explained by administration of ketamine. Even after removal of all patient data during administration of ketamine, SDs occurred predominantly during times with low relative beta frequency in a patient-independent analysis. CONCLUSION: Suppression of beta frequency by ketamine or without ketamine is associated with low SD counts. SIGNIFICANCE: Alteration of beta frequency might help to predict occurrence of SDs in acutely brain injured patients.

State of Cerebrovascular Autoregulation Correlates with Outcome in Severe Infant/Pediatric Traumatic Brain Injury.

OBJECTIVE: It could be shown in adults with severe traumatic brain injury (TBI) that the functional status of cerebrovascular autoregulation (AR), determined by the pressure reactivity index (PRx), correlates with and even predicts outcome. We investigated PRx and its correlation with outcome in infant and pediatric TBI. Methods Ten patients (median age 2.8 years, range 1 day to 14 years) with severe TBI (Glasgow Coma Scale score <9 at presentation) underwent long-term computerized intracranial pressure (ICP) and mean arterial pressure (MAP) monitoring using dedicated software for continuous determination of cerebral perfusion pressure (CPP) and PRx. Outcome was determined at discharge and at follow-up at 6 months using the Glasgow Outcome Scale (GOS) score. RESULTS: Median monitoring time was 182 h (range 22-355 h). Seven patients underwent decompressive craniectomy to control ICP during treatment in the intensive care unit. Favorable outcome (GOS 4 and 5) was reached in 4 patients, an unfavorable outcome (GOS 1-3) in 6 patients. When dichotomized to outcome, no correlation was found with ICP and CPP, but median PRx correlated well with outcome (r = -0.79, p = 0.006) and tended to be lower for GOS 4 and 5 (-0.04) than for GOS 1-3 (0.32; p = 0.067). CONCLUSION: The integrity of AR seems to play the same fundamental role after TBI in the pediatric population as in adults and should be determined routinely. It carries an important prognostic value. PRx seems to be an ideal candidate parameter to guide treatment in the sense of optimizing CPP, aiming at improvement of cerebrovascular autoregulation (CPPopt concept).

Increasing Intracranial Pressure After Head Injury: Impact on Respiratory Oscillations in Cerebral Blood Flow Velocity.

Experiments have shown that closed-box conditions alter the transmission of respiratory oscillations (R waves) to organ blood flow already at a marginal pressure increase. How does the increasing intracranial pressure (ICP) interact with R waves in cerebral blood flow after head injury (HI)?Twenty-two head-injured patients requiring sedation and mechanical ventilation were monitored for ICP, Doppler flow velocity (FV) in the middle cerebral arteries, and arterial blood pressure (ABP). The analysis included transfer function gains of R waves (9-20 cpm) from ABP to FV, and indices of pressure-volume reserve (RAP) and autoregulation (Mx). Increasing ICP has dampened R-wave gains from day 1 to day 4 after HI in all patients. A large impact (ΔGain /ΔICP right: 0.14 ± 0.06; left: 0.18 ± 0.08) was associated with exhausted reserves (RAP ≥0.85). When RAP was <0.85, rising ICP had a lower impact on R-wave gains (ΔGain /ΔICP right: 0.05 ± 0.02; left: 0.06 ± 0.04; p < 0.05), but increased the pulsatility indices (right: 1.35 ± 0.55; left: 1.25 ± 0.52) and Mx indices (right: 0.30 ± 0.12; left: 0.28 ± 0.08, p < 0.05). Monitoring of R waves in blood pressure and cerebral blood flow velocity has suggested that rising ICP after HI might have an impact on cerebral blood flow directly, even before autoregulation is impaired.

Autonomic Impairment in Severe Traumatic Brain Injury: A Multimodal Neuromonitoring Study.

OBJECTIVES: Autonomic impairment after acute traumatic brain injury has been associated independently with both increased morbidity and mortality. Links between autonomic impairment and increased intracranial pressure or impaired cerebral autoregulation have been described as well. However, relationships between autonomic impairment, intracranial pressure, impaired cerebral autoregulation, and outcome remain poorly explored. Using continuous measurements of heart rate variability and baroreflex sensitivity we aimed to test whether autonomic markers are associated with functional outcome and mortality independently of intracranial variables. Further, we aimed to evaluate the relationships between autonomic functions, intracranial pressure, and cerebral autoregulation. DESIGN: Retrospective analysis of a prospective database. SETTING: Neurocritical care unit in a university hospital. SUBJECTS: Sedated patients with severe traumatic brain injury. MEASUREMENTS AND MAIN RESULTS: Waveforms of intracranial pressure and arterial blood pressure, baseline Glasgow Coma Scale and 6 months Glasgow Outcome Scale were recorded. Baroreflex sensitivity was assessed every 10 seconds using a modified cross-correlational method. Frequency domain analyses of heart rate variability were performed automatically every 10 seconds from a moving 300 seconds of the monitoring time window. Mean values of baroreflex sensitivity, heart rate variability, intracranial pressure, arterial blood pressure, cerebral perfusion pressure, and impaired cerebral autoregulation over the entire monitoring period were calculated for each patient. Two hundred and sixty-two patients with a median age of 36 years entered the analysis. The median admission Glasgow Coma Scale was 6, the median Glasgow Outcome Scale was 3, and the mortality at 6 months was 23%. Baroreflex sensitivity (adjusted odds ratio, 0.9; p = 0.02) and relative power of a high frequency band of heart rate variability (adjusted odds ratio, 1.05; p < 0.001) were individually associated with mortality, independently of age, admission Glasgow Coma Scale, intracranial pressure, pressure reactivity index, or cerebral perfusion pressure. Baroreflex sensitivity showed no correlation with intracranial pressure or cerebral perfusion pressure; the correlation with pressure reactivity index was strong in older patients (age, > 60 yr). The relative power of high frequency correlated significantly with intracranial pressure and cerebral perfusion pressure, but not with pressure reactivity index. The relative power of low frequency correlated significantly with pressure reactivity index. CONCLUSIONS: Autonomic impairment, as measured by heart rate variability and baroreflex sensitivity, is significantly associated with increased mortality after traumatic brain injury. These effects, though partially interlinked, seem to be independent of age, trauma severity, intracranial pressure, or autoregulatory status, and thus represent a discrete phenomenon in the pathophysiology of traumatic brain injury. Continuous measurements of heart rate variability and baroreflex sensitivity in the neuromonitoring setting of severe traumatic brain injury may carry novel pathophysiological and predictive information.

Long-Term, Continuous Intra-Arterial Nimodipine Treatment of Severe Vasospasm After Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Secondary vasospasm and disturbances in cerebrovascular autoregulation are associated with the development of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. An intra-arterial application of nimodipine has been shown to increase the vessel diameter, although this effect is transient. The feasibility of long-term, continuous, intra-arterial nimodipine treatment and its effects on macrovasospasm, autoregulation parameters, and outcome were evaluated in patients with refractory severe macrovasospasm. METHODS: Ten patients were included with refractory macrovasospasm despite bolus nimodipine application (n = 4) or with primary severe vasospasm (n = 6). The patients were assessed with continuous multimodal neuromonitoring (mean arterial pressure, intraceranial pressure, cerebral perfusion pressure, brain tissue oxygen tension probe), daily transcranial Doppler examinations, and computed tomography angiography/perfusion. Autoregulation indices, the pressure reactivity index, and oxygen reactivity index were calculated. Indwelling microcatheters were placed in the extracranial internal carotid arteries and 0.4 mg nimodipine was continuously infused at 50 mL/hour. RESULTS: The duration of continuous, intra-arterial nimodipine ranged from 9 to 15 days. During treatment intracranial pressure remained stable, transcranial Doppler flow velocity decreased, and brain tissue oxygen tension improved by 37%. Macrovasospasm, as assessed via computed tomography angiography, had improved (n = 5) or disappeared (n = 5) at the end of treatment. Cerebrovascular autoregulation according to the pressure reactivity index and oxygen reactivity index significantly worsened during treatment. All patients showed a favorable outcome (median Glasgow Outcome Scale 5) at 3 months. CONCLUSIONS: In well-selected patients with prolonged severe macrovasospasm, continuous intra-arterial nimodipine treatment can be applied as a rescue therapy with relative safety for more than 2 weeks to prevent secondary cerebral ischemia. The induced impairment of cerebrovascular autoregulation during treatment seems to have no negative effects.

ß-Blockers, Pneumonia, and Outcome After Ischemic Stroke: Evidence From Virtual International Stroke Trials Archive.

BACKGROUND AND PURPOSE: Increased sympathetic drive after stroke is involved in the pathophysiology of several complications including poststroke immunudepression. ß-Blocker (BB) therapy has been suggested to have neuroprotective properties and to decrease infectious complications after stroke. We aimed to examine the effects of random pre- and on-stroke BB exposure on mortality, functional outcome, and occurrence of pneumonia after ischemic stroke. METHODS: Data including standard demographic and clinical variables as well as prestroke and on-stroke antihypertensive medication, incidence of pneumonia, functional outcome defined using modified Rankin Scale and mortality at 3 months were extracted from the Virtual International Stroke Trials Archive. For statistical analysis multivariable Poisson regression was used. RESULTS: In total, 5212 patients were analyzed. A total of 1155 (22.2%) patients were treated with BB before stroke onset and 244 (4.7%) patients were newly started with BB in the acute phase of stroke. Mortality was 17.5%, favorable outcome (defined as modified Rankin Scale, 0-2) occurred in 58.2% and pneumonia in 8.2% of patients. Prestroke BB showed no association with mortality. On-stroke BB was associated with reduced mortality (adjusted risk ratio, 0.63; 95% confidence interval, 0.42-0.96). Neither prestroke BB nor on-stroke BB showed an association with functional outcome. Both prestroke and on-stroke BB were associated with reduced frequency of pneumonia (adjusted risk ratio, 0.77; 95% confidence interval, 0.6-0.98 and risk ratio, 0.49; 95% confidence interval, 0.25-0.95). CONCLUSIONS: In this large nonrandomized comparison, on-stroke BB was associated with reduced mortality. Prestroke and on-stroke BB were inversely associated with incidence of nosocomial pneumonia. Randomized trials investigating the potential of ß-blockade in acute stroke may be warranted.

Traumatic brain injury: increasing ICP attenuates respiratory modulations of cerebral blood flow velocity.

In vitro experiments have suggested that respiratory oscillations (R waves) in cerebral blood flow velocity are reduced as soon as the intracranial pressure-volume reserve is exhausted. Could R waves hence, provide indication for increasing ICP after traumatic brain injury (TBI)? On days 1 to 4 after TBI, 22 sedated and ventilated patients were monitored for intracranial pressure (ICP) in brain parenchyma, Doppler flow velocity (FV) in the middle cerebral arteries (MCA), and arterial blood pressure (ABP). The analysis included the transfer function gains of R waves (respiratory rate of 9-20 cpm) between ABP and FV (GainFv) as well as between ABP and ICP (GainICP). Also, the index of the intracranial pressure-volume reserve (RAP) was calculated. The rise of ICP (day 1: 14.10 ± 6.22 mmHg; to day 4: 29.69 ± 12.35 mmHg) and increase of RAP (day 1: 0.72 ± 0.22; to day 4: 0.85 ± 0.18) were accompanied by a decrease of GainFv (right MCA; day 1: 1.78 ± 1.0; day 4: 0.84 ± 0.47; left MCA day 1: 1.74 ± 1.10; day 4: 0.86 ± 0.46; p < 0.01) but no significant change in GainICP day 1: 1.50 ± 0.77; day 4: 1.15 ± 0.47; p = 0.07). The transfer of ventilatory oscillations to the intracerebral arteries after TBI appears to be dampened by increasing ICP and exhausted intracranial pressure-volume reserves. Results warrant prospective studies of whether respiratory waves in cerebral blood flow velocity may anticipate intracranial hypertension non-invasively.

Rapid Induction of COOLing in Stroke Patients (iCOOL1): a randomised pilot study comparing cold infusions with nasopharyngeal cooling.

INTRODUCTION: Induction methods for therapeutic cooling are under investigated. We compared the effectiveness and safety of cold infusions (CI) and nasopharyngeal cooling (NPC) for cooling induction in stroke patients. METHODS: A prospective, open-label, randomised (1:1), single-centre pilot trial with partially blinded safety endpoint assessment was conducted at the neurointensive care unit of Heidelberg University. Intubated stroke patients with an indication for therapeutic cooling and an intracranial pressure (ICP)/temperature brain probe were randomly assigned to CI (4°C, 2L at 4L/h) or NPC (60L/min for 1 h). Previous data suggested a maximum decrease of tympanic temperature for CI (2.1L within 35 min) after 52 min. Therefore the study period was 1 hour (15 min subperiods I-IV). The brain temperature course was the primary endpoint. Secondary measures included continuous monitoring of neurovital parameters and extracerebral temperatures. Statistical analysis based on repeated-measures analysis of variance. RESULTS: Of 221 patients screened, 20 were randomized within 5 months. Infusion time of 2L CI was 33 ± 4 min in 10 patients and 10 patients received NPC for 60 min. During active treatment (first 30 min), brain temperature decreased faster with CI than during NPC (I: -0.31 ± 0.2 versus -0.12 ± 0.1°C, P = 0.008; II: -1.0 ± 0.3 versus -0.49 ± 0.3°C, P = 0.001). In the CI-group, after the infusion was finished, the intervention no longer decreased brain temperature, which increased after 3.5 ± 3.3 min. Oesophageal temperature correlated best with brain temperature during CI and NPC. Tympanic temperature reacted similarly to relative changes of brain temperature during CI, but absolute values slightly differed. CI provoked three severe adverse events during subperiods II-IV (two systolic arterial pressure (SAP), one shivering) compared with four in the NPC-group, all during subperiod I (three SAP, one ICP). Classified as possibly intervention-related, two cases of ventilator failure occurred during NPC. CONCLUSIONS: In intubated stroke patients, brain cooling is faster during CI than during NPC. Importantly, contrary to previous expectations, brain cooling stopped soon after CI cessation. Oesophageal but neither bladder nor rectal temperature is suited as surrogate for brain temperature during CI and NPC. Several severe adverse events in CI and in NPC demand further studying of safety. TRIAL REGISTRATION: ClinicalTrials.gov NCT01573117. Registered 31 March 2012.

Association of intracranial pressure with outcome in comatose patients with intracerebral hemorrhage.

BACKGROUND: Therapeutic targets for intracranial pressure (ICP) in patients with severe intracerebral hemorrhage (ICH) are approximated from data of traumatic brain injury. However, specific data for ICH are lacking. Here, we aimed to investigate the association between ICP, mortality and functional outcome following severe ICH. METHODS: We analyzed consecutive comatose patients with ICH in whom ICP monitoring was applied. Outcome at 3 months was assessed using the modified Rankin scale (mRS). Multivariate logistic regression including pre-defined predictors was used in order to identify the effects of ICP on outcome. RESULTS: 121 patients with ICH and ICP monitoring were analyzed. Mean ICP (OR 1.2, CI 1.08-1.45, p=0.003), ICP variability (OR 1.3, CI 1.03-1.73, p=0.03) and relative frequency of ICP values >20 mm Hg (OR 1.1, CI 1.02- 1.15, p=0.008) were independently associated with mortality at 3 months. Relative frequency of ICP values >20 mm Hg (OR 1.1, CI 1.001-1.3, p=0.04) was associated also with poor functional outcome at 3 months. CONCLUSIONS: Our data suggest that in the context of other predictors as age, admission clinical status, hemorrhage volume and intraventricular hemorrhage, average ICP, ICP variability and the frequency of ICP values >20 mm Hg are independently associated with mortality and poor outcome after ICH. Further studies and prospective validations of ICP thresholds for ICH patients are highly warranted.

Optimal cerebral perfusion pressure in patients with intracerebral hemorrhage: an observational case series.

INTRODUCTION: Current guidelines for spontaneous intracerebral hemorrhage (ICH) recommend maintaining cerebral perfusion pressure (CPP) between 50 and 70 mmHg, depending on the state of autoregulation. We continuously assessed dynamic cerebral autoregulation and the possibility of determination of an optimal CPP (CPPopt) in ICH patients. Associations between autoregulation, CPPopt and functional outcome were explored. METHODS: Intracranial pressure (ICP), mean arterial pressure (MAP) and CPP were continuously recorded in 55 patients, with 38 patients included in the analysis. The pressure reactivity index (PRx) was calculated as moving correlation between MAP and ICP. CPPopt was defined as the CPP associated with the lowest PRx values. CPPopt was calculated using hourly updated of 4 hour windows. The modified Rankin Scale (mRS) was assessed at 3 months and associations between PRx, CPPopt and outcomes were explored using Pearson correlation and Fisher's exact test. Multivariate stepwise logistic regression models were calculated including standard outcome predictors along with percentage of time with PRx >0.2 and percentage of time within the CPPopt range. RESULTS: An overall PRx indicating impairment of pressure reactivity was found in 47% of patients (n = 18). The mean PRx and the time spent with a PRx > 0.2 significantly correlated with mRS at 3 months (r = 0.50, P = 0.002; r = 0.46, P = 0.004). CPPopt was calculable during 57% of the monitoring time. The median CPP was 78 mmHg, the median CPPopt 83 mmHg. Mortality was lowest in the group of patients with a CPP close to their CPPopt. However, for none of the CPPopt variables a significant association to outcome was found. The percentage of time with impaired autoregulation and hemorrhage volume were independent predictors for acceptable outcome (mRS 1 to 4) at three months. CONCLUSIONS: Failure of pressure reactivity seems common following severe ICH and is associated with unfavorable outcome. Real-time assessment of CPPopt is feasible in ICH and might provide a tool for an autoregulation-oriented CPP management. A larger trial is needed to explore if a CPPopt management results in better functional outcomes.

Safety evaluation of nasopharyngeal cooling (RhinoChill®) in stroke patients: an observational study.

INTRODUCTION: New technologies for therapeutic cooling have become available. The objective of our study was to investigate the safety of nasopharyngeal cooling with the RhinoChill(®) device in stroke patients, focusing on systemic and neurovital parameters. METHODS: In this prospective observational study, consecutive patients with severe ischemic or hemorrhagic stroke who underwent intracranial pressure (ICP) and brain temperature monitoring have been enrolled. Ten patients who were treated with the RhinoChill(®) device were analyzed. Brain and bladder temperature and systemic and neurovital parameters were monitored continuously. Additional evaluations of safety included bleeding complications and otolaryngological examinations. RESULTS: Baseline brain temperature of 36.7 °C (SD 0.9) decreased by an average of 1.21 °C (SD 0.46) within 1 h, the effect of brain temperature decrease ranged from a maximum of 2 °C (patients 3 and 7) to a minimum of 0.6 °C (patient 4). Within the first several minutes after initiating RhinoChill(®) treatment, 3 of 10 patients experienced an increase in systolic arterial pressure by 30, 30, and 53 mmHg, respectively. Heart rate rose as well (mean 3 bpm, SD 2.9). ICP and oxygen saturation were unaffected by the treatment. We observed 1 bleeding complication in the control CT scan of patient 10. Rhinoscopical findings 3 days after nasopharyngeal cooling and at the follow-up (>6 months) and a 16-item smell test were normal. CONCLUSION: The RhinoChill(®) system cools the brain efficiently. However, steep increases in blood pressure raise serious concerns regarding the safety of its use in stroke patients.

Glycosylated hemoglobin A1 predicts risk for symptomatic hemorrhage after thrombolysis for acute stroke.

BACKGROUND AND PURPOSE: Symptomatic intracerebral hemorrhage (sICH) is the most feared acute complication after intravenous thrombolysis. The aim of this study was to determine the predictive value of parameters of glycosylated hemoglobin A1 (HbA1c) on sICH. METHODS: In a retrospective single center series, 1112 consecutive patients treated with thrombolysis were studied. Baseline blood glucose was obtained at admission. HbA1c was determined within hospital stay. A second head computed tomography was obtained after 24 hours or when neurological worsening occurred. Modified Rankin Scale was used to assess outcome at 90 days. RESULTS: A total of 222 patients (19.9%) had any hemorrhage; 43 of those had sICH (3.9%) per Safe Implementation of Treatments in Stroke definition and 95 (8.5%) per National Institute of Neurological Disorders and Stroke definition; 33.2% of patients had a dependent outcome (modified Rankin Scale score 3-5). In univariate analysis history of diabetes mellitus, HbA1c, blood glucose, and National Institute of Health Stroke Scale score on admission were associated with any hemorrhage and sICH. In multivariate analysis National Institute of Health Stroke Scale score, a history of diabetes mellitus, and HbA1c were predictors of sICH per National Institute of Neurological Disorders and Stroke, and only HbA1c when Safe Implementation of Treatments in Stroke criteria were used. CONCLUSIONS: In our study, HbA1c turns out to be an important predictor of sICH after thrombolysis for acute stroke. These results suggest that hemorrhage after thrombolysis may be a consequence of long-term vascular injury rather than of acute hyperglycemia, and that HbA1c may be a better predictor than acute blood glucose or a history of diabetes mellitus.

Induction of cooling with a passive head and neck cooling device: effects on brain temperature after stroke.

BACKGROUND AND PURPOSE: Therapeutic hypothermia improves clinical outcome after cardiac arrest and appears beneficial in other cerebrovascular diseases. We conducted this study to investigate the relationship between surface head/neck cooling and brain temperature. METHODS: Prospective observational study enrolling consecutive patients with severe ischemic or hemorrhagic stroke undergoing intracranial pressure (ICP) and brain temperature monitoring. Arterial pressure, ICP, cerebral perfusion pressure, heart rate, brain, tympanic, and bladder temperature were continuously registered. Fifty-one applications of the Sovika cooling device were analyzed in 11 individual patients. RESULTS: Sovika application led to a significant decrease of brain temperature compared with baseline with a maximum of -0.36°C (SD, 0.22) after 49 minutes (SD, 17). During cooling, dynamics of brain temperature differed significantly from bladder (-0.25°C [SD, 0.15] after 48 minutes [SD, 19]) and tympanic temperature (-1.79°C [SD, 1.19] after 37 minutes [SD, 16]). Treatment led to an increase in systolic arterial pressure by >20 mm Hg in 14 applications (n=7 patients) resulting in severe hypertension (>180 mm Hg) in 4 applications (n=3). ICP increased by >10 mm Hg in 7 applications (n=3), led to ICP crisis >20 mm Hg in 6 applications (n=3), and a drop of cerebral perfusion pressure <50 mm Hg in 1 application. CONCLUSIONS: Although the decrease of brain temperature after Sovika cooling device application was statistically significant, we doubt clinical relevance of this rather limited effect (-0.36°C). Moreover, the transient increases of blood pressure and ICP warrant caution.

Poststroke infections are an independent risk factor for poor functional outcome after three-months in thrombolysed stroke patients.

BACKGROUND: Infections are common complications in patients with acute ischemic stroke; however, the pathophysiology of the stroke-induced immunodepression is still under debate. Although it has been shown that increased mortality and longer hospital stay are associated with the presence of poststroke infections, it remains unclear if early poststroke infections occurring in the first seven-days have an effect on the overall functional outcome. AIMS: Aim of our study was to identify the frequency of poststroke infections in thrombolysed stroke patients and to analyze their effect on the outcome after three-months. METHODS: From 1998 to 2011, all patients in our institution undergoing thrombolysis for acute ischemic stroke were included into a prospective database. Baseline variables, clinical, radiographic, and laboratory data were collected prospectively. Outcome measures included symptomatic intracerebral hemorrhage per European-Australasian Acute Stroke Study II criteria, mortality, and modified Rankin Scale at three-months. Logistic regression models were used to identify independent predictors for poor outcome where appropriate. RESULTS: One thousand sixteen patients were included; of them, 36·3% had an infection during the first week. Pneumonia (9·6%) and urinary tract infections (5·4%) were most frequent. Severity of stroke (P < 0·0001), infarct size (P < 0·0001), atrial fibrillation (P = 0·005), and cardio embolic cause of stroke (P < 0·0001) were associated with infections. Age (odds ratio 1·089, 95% confidence interval 1·064-1·115, P < 0·0001), severity of stroke (odds ratio 1·111, 95% confidence interval 1·073-1·149; P < 0·0001) history of diabetes (odds ratio 0·555. 95% confidence interval 0·357-0·864; P = 0·009), infarct size (odds ratio 4·256 95% confidence interval 2·697-6·745; P < 0·0001), infections (odds ratio 1·548, 95% confidence interval 1·008-2·376; P = 0·046), and symptomatic intracerebral hemorrhage were independent predictors for poor outcome after three-months. CONCLUSIONS: In our cohort of thrombolysed stroke patients, poststroke infections were frequent in patients with severe cardio embolic stroke, a large infarct, and a longer hospital stay; those patients have a higher risk of infection and a poorer functional outcome after three-months. This risk increases after occurrence of symptomatic intracerebral hemorrhage. Prevention of infection with antibiotic therapy or other prophylactic treatment could potentially lead to a better functional outcome and further randomized studies on this aspect are needed.

Time constant of the cerebral arterial bed in normal subjects.

The time constant of cerebral arterial bed (in brief time constant) is a product of brain arterial compliance (C(a)) and resistance (CVR). We tested the hypothesis that in normal subjects, changes in end-tidal CO(2) (EtCO(2)) affect the value of the time constant. C(a) and CVR were estimated using mathematical transformations of arterial pressure (ABP) and transcranial Doppler (TCD) cerebral blood flow velocity waveforms. Responses of the time constant to controlled changes in EtCO(2) were compared in 34 young volunteers. Hypercapnia shortened the time constant (0.22 s [0.17, 0.26] vs. 0.16 s [0.13, 0.20]; p = 0.000001), while hypocapnia lengthened the time constant (0.22 s [0.17, 0.26] vs. 0.23 s [0.19, 0.32]; p < 0.0032). The time constant was negatively correlated with changes in EtCO(2) (R(partial) = -0.68, p < 0.000001). This was associated with a decrease in CVR when EtCO(2) increased (R(partial) = -0.80, p < 0.000001) and C(a) remained independent of changes in EtCO(2). C(a) was negatively correlated with mean ABP (R(partial) = -0.68, p < 0.000001). In summary, the time constant shortens with increasing EtCO(2). Its potential role in cerebrovascular investigations needs further studies.

Effect of analgesics and sedatives on the occurrence of spreading depolarizations accompanying acute brain injury.

Spreading depolarizations are waves of mass neuronal and glial depolarization that propagate across the injured human cortex. They can occur with depression of neuronal activity as spreading depressions or isoelectric spreading depolarizations on a background of absent or minimal electroencephalogram activity. Spreading depolarizations are characterized by the loss of neuronal ion homeostasis and are believed to damage functional neurons, leading to neuronal necrosis or neurological degeneration and poor outcome. Analgesics and sedatives influence activity-dependent neuronal ion homeostasis and therefore represent potential modulators of spreading depolarizations. In this exploratory retrospective international multicentre analysis, we investigated the influence of midazolam, propofol, fentanyl, sufentanil, ketamine and morphine on the occurrence of spreading depolarizations in 115 brain-injured patients. A surface electrode strip was placed on the cortex, and continuous electrocorticographical recordings were obtained. We used multivariable binary logistic regression to quantify associations between the investigated drugs and the hours of electrocorticographical recordings with and without spreading depolarizations or clusters of spreading depolarizations. We found that administration of ketamine was associated with a reduction of spreading depolarizations and spreading depolarization clusters (P < 0.05). Midazolam anaesthesia, in contrast, was associated with an increased number of spreading depolarization clusters (P < 0.05). By using a univariate odds ratio analysis, we also found a significant association between ketamine administration and reduced occurrence of isoelectric spreading depolarizations in patients suffering from traumatic brain injury, subarachnoid haemorrhage and malignant hemispheric stroke (P < 0.05). Our findings suggest that ketamine-or another N-methyl-d-aspartate receptor antagonist-may represent a viable treatment for patients at risk for spreading depolarizations. This hypothesis will be tested in a prospective study.

Impact of statin use and lipid profile on symptomatic intracerebral haemorrhage, outcome and mortality after intravenous thrombolysis in acute stroke.

BACKGROUND: It is unclear if a certain lipid profile and/or statin use contribute to symptomatic intracerebral haemorrhage (sICH), poor outcome or mortality after intravenous thrombolysis for ischaemic stroke. The aim of the current study was to assess the impact of statin use and lipid profile on sICH, outcome and mortality following thrombolysis in acute stroke. METHODS: From 2001 to 2010, all patients admitted to our hospital and undergoing intravenous thrombolysis for acute ischaemic stroke were included into an open, prospective database. Initial stroke severity was assessed using the National Institute of Health Stroke Scale. Demographics, vascular risk factors, admission blood pressure, glucose levels, previous medication including statin use, lipid profiles including low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglyceride levels were recorded. Outcome measures included sICH according to the European Cooperative Acute Stroke Study II criteria, modified Rankin scale and mortality at 3 months. RESULTS: 1,066 patients were included in the analysis; 5.3% (57 patients) had sICH. Mortality at 3 months was 17.6% (188 patients). A favourable outcome (modified Rankin scale 0-1) at 3 months was attained by 35.6% (379 patients). Prior statin use was not associated with increased odds for sICH (OR 1.05, 95% CI 0.55-2.04, p = 0.864), mortality (OR 1.32, 95% CI 0.90-1.93, p = 0.152) or favourable outcome (OR 0.89, 95% CI 0.65-1.24, p = 0.507). Similar results were found for the different lipid variables: high LDL (OR 0.96, 95% CI 0.36-2.60, p = 0.942), high triglyceride (OR 1.74, 95% CI 0.84-3.56, p = 0.132) and low HDL (OR 1.78, 95% CI 0.68-4.65, p = 0.279) were not associated with increased odds for sICH. Likewise, neither mortality nor functional outcome at 3 months was significantly associated with any of the lipid variables in the univariable analysis following Bonferroni adjustment for multiple comparisons. The same results were found in the multivariable analysis adjusting for imbalances in baseline characteristics. CONCLUSIONS: In contrast to previous studies, we found that in stroke patients receiving thrombolysis therapy, neither the lipid profile nor prior statin use were associated with increased odds for sICH, functional outcome or mortality at 3 months.

Time constant of the cerebral arterial bed.

We have defined a novel cerebral hemodynamic index, a time constant of the cerebral arterial bed (τ), the product of arterial compliance (C(a)) and cerebrovascular resistance (CVR). C(a) and CVR were calculated based on the relationship between pulsatile arterial blood pressure (ABP) and transcranial Doppler cerebral blood flow velocity. This new parameter theoretically estimates how fast the cerebral arterial bed is filled by blood volume after a sudden change in ABP during one cardiac cycle. We have explored this concept in 11 volunteers and in 25 patients with severe stenosis of the internal carotid artery (ICA). An additional group of 15 subjects with non-vascular dementia was studied to assess potential age dependency of τ. The τ was shorter (p = 0.011) in ICA stenosis, both unilateral (τ = 0.18 ± 0.04 s) and bilateral (τ = 0.16 ± 0.03 s), than in controls (τ = 0.22 ± 0.0 s). The τ correlated with the degree of stenosis (R = -0.62, p = 0.001). In controls, τ was independent of age. Further study during cerebrovascular reactivity tests is needed to establish the usefulness of τ for quantitative estimation of haemodynamics in cerebrovascular disease.