Jennifer Diedler

Safety of Intravenous Thrombolysis for Acute Ischemic Stroke in Patients Receiving Antiplatelet Therapy at Stroke Onset

Background and Purpose— Antiplatelets (APs) may increase the risk of symptomatic intracerebral hemorrhage (ICH) following intravenous thrombolysis after ischemic stroke. Methods— We assessed the safety of thrombolysis under APs in 11 865 patients compliant with the European license criteria and recorded between 2002 and 2007 in the Safe Implementation of Treatments in Stroke (SITS) International Stroke Thrombolysis Register (SITS-ISTR). Outcome measures of univariable and multivariable analyses included symptomatic ICH (SICH) per SITS Monitoring Study (SITS-MOST [deterioration in National Institutes of Health Stroke Scale ≥4 plus ICH type 2 within 24 hours]), per European Cooperative Acute Stroke Study II (ECASS II [deterioration in National Institutes of Health Stroke Scale ≥4 plus any ICH]), functional outcome at 3 months and mortality. Results— A total of 3782 (31.9%) patients had received 1 or 2 AP drugs at baseline: 3016 (25.4%) acetylsalicylic acid (ASA), 243 (2.0%) clopidogrel, 175 (1.5%) ASA and dipyridamole, 151 (1.3%) ASA and clopidogrel, and 197 (1.7%) others. Patients receiving APs were 5 years older and had more risk factors than AP naïve patients. Incidences of SICH per SITS-MOST (ECASS II respectively) were as follows: 1.1% (4.1%) AP naïve, 2.5% (6.2%) any AP, 2.5% (5.9%) ASA, 1.7% (4.2%) clopidogrel, 2.3% (5.9%) ASA and dipyridamole, and 4.1% (13.4%) ASA and clopidogrel. In multivariable analyses, the combination of ASA and clopidogrel was associated with increased risk for SICH per ECASS II (odds ratio, 2.11; 95% CI, 1.29 to 3.45; P=0.003). However, we found no significant increase in the risk for mortality or poor functional outcome, irrespective of the AP subgroup or SICH definition. Conclusion— The absolute excess of SICH of 1.4% (2.1%) in the pooled AP group is small compared with the benefit of thrombolysis seen in randomized trials. Although caution is warranted in patients receiving the combination of ASA and clopidogrel, AP treatment should not be considered a contraindication to thrombolysis.

Impaired baroreflex sensitivity predicts outcome of acute intracerebral hemorrhage

Objective:Impaired blood pressure regulation in the acute phase of stroke has been associated with less favorable outcome. Mechanisms and effects of blood pressure dysregulation in stroke are not well understood; however, central autonomic impairment with sympathetic overactivity and baroreflex involvement are discussed. Baroreflex sensitivity (BRS) in spontaneous intracerebral hemorrhage has not been investigated. We sought to examine BRS in patients with intracerebral hemorrhage and evaluate the relationship between BRS and short-term outcome measures. Design:An open, prospective study. Setting:Neurocritical care unit and stroke unit in a university hospital. Patients and Measurements:We studied 45 patients with acute intracerebral hemorrhage within 72 hrs from onset of symptoms and 38 control subjects. BRS was measured noninvasively using a hemodynamic monitoring device. Beat-to-beat blood pressure variability was derived. The effects of the BRS, hemorrhage volume, intraventricular blood, and admission scores on outcome at 10 days were studied using a multivariate regression model. Main Results:Compared with the control group, patients with intracerebral hemorrhage had significantly decreased BRS (p = 0.002) and significantly increased systolic, diastolic, and mean beat-to-beat blood pressure variability (p < 0.0001, p = 0.007, p = 0.015). After adjusting for age, National Institute of Heath Stroke Scale at admission, volume of intracerebral hemorrhage and presence of intraventricular blood in a multivariate regression model, BRS gain was an independent predictor of outcome at 10 days. Conclusions:We found that BRS was decreased in patients with acute intracerebral hemorrhage and correlated with increased beat-to-beat blood pressure variability. BRS independently predicted outcome at 10 days. Modulation of baroreceptor reflex sensitivity may represent a new therapeutic target in acute stroke and warrants future studies.

Impaired Cerebral Vasomotor Activity in Spontaneous Intracerebral Hemorrhage

Background and Purpose— Impairment of cerebrovascular autoregulation may promote secondary brain injury in acute brain insults. Until now, only limited data are available on autoregulation in patients with spontaneous intracerebral hemorrhage. In the current study, we aimed to investigate cerebrovascular reactivity and its significance for outcome in spontaneous intracerebral hemorrhage. Methods— We continuously recorded mean arterial pressure, intracranial pressure, and cerebral perfusion pressure for mean 95 hours in 20 patients with spontaneous intracerebral hemorrhage. The moving correlation coefficient between mean arterial pressure and intracranial pressure (pressure reactivity index), an index of cerebral vasoreactivity, was calculated from the available artifact-free monitoring time (mean, 50.4 hours). Results— In the univariate analysis pressure reactivity index (r=0.66; P=0.002), hemorrhage volume (r=0.62; P=0.007), cerebral perfusion pressure (r=−0.71; P=0.001), mean arterial pressure (r=−0.61; P=0.005), and hematoma growth (r=0.53; P=0.02) significantly correlated with National Institutes of Health Stroke Scale Score at discharge. In a multivariate stepwise linear regression model, pressure reactivity index remained the only independent predictor of outcome (&bgr;=0.659; P=0.004). In the subgroup of patients with pressure reactivity index greater than a functional threshold of >0.2, the correlation between mean cerebral perfusion pressure and outcome remained significant (r=−0.73; P=0.0102), whereas National Institutes of Health Stroke Scale Score at discharge did not correlate with cerebral perfusion pressure in patients with pressure reactivity index <0.2 (r=−0.05; P=0.9078). Conclusions— We found evidence for impaired cerebral vasomotor activity as measured by pressure reactivity index in patients with spontaneous intracerebral hemorrhage. We suggest that impaired cerebrovascular reactivity contributes to poor outcome in intracerebral hemorrhage patients. This effect may be mediated by fluctuations in cerebral perfusion.

Baroreflex: A New Therapeutic Target in Human Stroke?

Background and Purpose— Autonomic dysfunction, including increased sympathetic drive and blunted baroreflex, has repeatedly been observed in acute stroke. Of clinical importance is that the stroke-related autonomic imbalance seems to be linked to worse outcome after stroke. Here, we discuss the role of baroreflex impairment in acute stroke and its possible pathophysiological and therapeutic relevance. Summary of Review— Possible mechanisms linking baroreflex impairment with unfavorable outcome in stroke may include increased cardiovascular morbidity and mortality, promotion of secondary brain injury due to local inflammation, hyperglycemia, or altered cerebral perfusion. Conclusions— We suggest therefore that the modifying of autonomic functions may have important therapeutic implications in acute ischemic as well as in hemorrhagic stroke.

Impaired Baroreceptor Reflex Sensitivity in Acute Stroke Is Associated With Insular Involvement, But Not With Carotid Atherosclerosis

Background and Purpose— Impaired baroreflex sensitivity (BRS) has been previously shown to be of prognostic value in patients with cardiovascular disease and stroke. Because baroreflex seems to be blunted by both carotid atherosclerosis and by lesions affecting central processing, controversy exists regarding the etiology of stroke-related baroreflex changes. The insula may play a central role in baroreflex modulation. The aim of the study was therefore to examine BRS in patients with acute stroke with regard to carotid atherosclerosis and insular involvement. Methods— We evaluated spontaneous BRS in 96 patients with acute stroke within 72 hours of ictus and 41 control subjects using a sequential crosscorrelation method. Results— Fifty-two patients with ischemic stroke and 44 patients with intracerebral hemorrhage, mean age 58.4 years, were included. With comparable carotid atherosclerosis profiles, patients with stroke had significantly lower BRS than control subjects (3.3 versus 5.3, P<0.001). Carotid atherosclerosis had no influence on variance of the BRS values in the acute stroke group. Patients with insular involvement had significantly lower BRS than patients with no insular involvement (2.55 versus 4.35, P=0.001) or control subjects (2.55 versus 5.3, P<0.001). Furthermore, patients with left insular involvement had significantly lower BRS than patients with right insular involvement (2.3 versus 3.5, P=0.049). There was no significant difference between patients with no insular lesions and control subjects (P=0.263). Conclusions— We demonstrated that baroreflex impairment in acute stroke is not associated with carotid atherosclerosis but with insular involvement. Both insulae seem to participate in processing the baroreceptor information with the left insula being more dominant.

What comes first? The dynamics of cerebral oxygenation and blood flow in response to changes in arterial pressure and intracranial pressure after head injury

BACKGROUND Brain tissue partial oxygen pressure (Pbt(O(2))) and near-infrared spectroscopy (NIRS) are novel methods to evaluate cerebral oxygenation. We studied the response patterns of Pbt(O(2)), NIRS, and cerebral blood flow velocity (CBFV) to changes in arterial pressure (AP) and intracranial pressure (ICP). METHODS Digital recordings of multimodal brain monitoring from 42 head-injured patients were retrospectively analysed. Response latencies and patterns of Pbt(O(2)), NIRS-derived parameters [tissue oxygenation index (TOI) and total haemoglobin index (THI)], and CBFV reactions to fluctuations of AP and ICP were studied. RESULTS One hundred and twenty-one events were identified. In reaction to alterations of AP, ICP reacted first [4.3 s; inter-quartile range (IQR) -4.9 to 22.0 s, followed by NIRS-derived parameters and CBFV (10.9 s; IQR: -5.9 to 39.6 s, 12.1 s; IQR: -3.0 to 49.1 s, 14.7 s; IQR: -8.8 to 52.3 s for THI, CBFV, and TOI, respectively), with Pbt(O(2)) reacting last (39.6 s; IQR: 16.4 to 66.0 s). The differences in reaction time between NIRS parameters and Pbt(O(2)) were significant (P<0.001). Similarly when reactions to ICP changes were analysed, NIRS parameters preceded Pbt(O(2)) (7.1 s; IQR: -8.8 to 195.0 s, 18.1 s; IQR: -20.6 to 80.7 s, 22.9 s; IQR: 11.0 to 53.0 s for THI, TOI, and Pbt(O(2)), respectively). Two main patterns of responses to AP changes were identified. With preserved cerebrovascular reactivity, TOI and Pbt(O(2)) followed the direction of AP. With impaired cerebrovascular reactivity, TOI and Pbt(O(2)) decreased while AP and ICP increased. In 77% of events, the direction of TOI changes was concordant with Pbt(O(2)). CONCLUSIONS NIRS and transcranial Doppler signals reacted first to AP and ICP changes. The reaction of Pbt(O(2)) is delayed. The results imply that the analysed modalities monitor different stages of cerebral oxygenation.

Cerebral Oxygen Transport Failure?: Decreasing Hemoglobin and Hematocrit Levels After Ischemic Stroke Predict Poor Outcome and Mortality: STroke: RelevAnt Impact of hemoGlobin, Hematocrit and Transfusion (STRAIGHT)—an Observational Study

Background and Purpose— Although conceivably relevant for penumbra oxygenation, the optimal levels of hemoglobin (Hb) and hematocrit (Hct) in patients with acute ischemic stroke are unknown. Methods— We identified patients from our prospective local stroke database who received intravenous thrombolysis based on multimodal magnet resonance imaging during the years 1998 to 2009. A favorable outcome at 3 months was defined as a modified Rankin Scale score ⩽2 and a poor outcome as a modified Rankin Scale score ≥3. The dynamics of Hemoglobin (Hb), Hematocrit (Hct), and other relevant laboratory parameters as well as cardiovascular risk factors were retrospectively assessed and analyzed between these 2 groups. Results— Of 217 patients, 114 had a favorable and 103 a poor outcome. In a multivariable regression model, anemia until day 5 after admission (odds ratio [OR]=2.61; 95% CI, 1.33 to 5.11; P=0.005), Hb nadir (OR=0.81; 95% CI, 0.67 to 0.99; P=0.038), and Hct nadir (OR=0.93; 95% CI, 0.87 to 0.99; P=0.038) remained independent predictors for poor outcome at 3 months. Mortality after 3 months was independently associated with Hb nadir (OR=0.80; 95% CI, 0.65 to 0.98; P=0.028) and Hb decrease (OR=1.34; 95% CI, 1.01 to 1.76; P=0.04) as well as Hct decrease (OR=1.12; 95% CI, 1.01 to 1.23; P=0.027). Conclusions— Poor outcome and mortality after ischemic stroke are strongly associated with low and further decreasing Hb and Hct levels. This decrease of Hb and Hct levels after admission might be more relevant and accessible to treatment than are baseline levels.

The limitations of near-infrared spectroscopy to assess cerebrovascular reactivity: the role of slow frequency oscillations.

BACKGROUND:A total hemoglobin reactivity index (THx) derived from near-infrared spectroscopy (NIRS) has recently been introduced to assess cerebrovascular reactivity noninvasively. Analogously to the pressure reactivity index (PRx), THx is calculated as correlation coefficient with arterial blood pressure (ABP). However, the reliability of THx in the injured brain is uncertain. Although slow oscillations have been described in NIRS signals, their significance for assessment of autoregulation remains unclear. In the current study, we investigated the role of slow oscillations of total hemoglobin for NIRS-based cerebrovascular reactivity monitoring. METHODS:This study was based on a retrospective analysis of data that were consecutively recorded for a different project published previously. Thirty-seven patients with traumatic brain injury and admitted to Addenbrookes Neurosciences Critical Care Unit between June 2008 and June 2009 were included. After artifact removal, we performed spectral analysis of the tissue hemoglobin index (THI, a measure of oxy- and deoxygenated hemoglobin) and intracranial pressure (ICP) signal. PRx and THx were calculated as moving correlations between ICP and ABP, and THI and ABP, respectively. The agreement between PRx and THx as a function of normalized power of slow oscillations (0.015–0.055 Hz) contained in the input signals was assessed performing between-subject and within-subject correlation analyses. Furthermore, the correlation between the THx values derived from the right and left sides was analyzed. RESULTS:The agreement between PRx and THx depended on the power of slow oscillations in the input signals. Between-subject comparisons revealed a significant correlation between THx and PRx (r = 0.80, 95% confidence interval 0.53–0.92, P < 0.01) for patients with normalized slow wave activity >0.4 in the THI signal, compared with r = 0.07 (95% confidence interval −0.40 to 0.51, P = 0.79) in the remaining files. Furthermore, within-subject comparisons suggested that THx may be used as a substitute for PRx only when there is an at least moderate agreement (r = 0.36) between the THx values derived from the right and left sides. CONCLUSIONS:Our results suggest that the NIRS-based cerebrovascular reactivity index THx can be used as a noninvasive substitute for PRx, but only during phases with sufficient slow wave power in the input signal. Furthermore, a good agreement between the THx measures on both sides seems to be a prerequisite for comparison of a global (PRx) versus the more local (THx) index. Nevertheless, noninvasive assessment of cerebrovascular reactivity may be desirable in patients without ICP monitoring and help to guide ABP management in these patients.

Low hemoglobin is associated with poor functional outcome after non-traumatic, supratentorial intracerebral hemorrhage

IntroductionThe impact of anemia on functional outcome and mortality in patients suffering from non-traumatic intracerebral hemorrhage (ICH) has not been investigated. Here, we assessed the relationship between hemoglobin (HB) levels and clinical outcome after ICH.MethodsOne hundred and ninety six patients suffering from supratentorial, non-traumatic ICH were extracted from our local stroke database (June 2004 to June 2006). Clinical and radiologic computed tomography data, HB levels on admission, mean HB values and nadir during hospital stay were recorded. Outcome was assessed at discharge and 3 months using the modified Rankin score (mRS).ResultsForty six (23.5%) patients achieved a favorable functional outcome (mRS ≤ 3) and 150 (76.5%) had poor outcome (mRS 4 - 6) at discharge. Patients with poor functional outcome had a lower mean HB (12.3 versus 13.7 g/dl, P < 0.001) and nadir HB (11.5 versus 13.0 g/dl, P < 0.001). Ten patients (5.1%) received red blood cell (RBC) transfusions. In a multivariate logistic regression model, the mean HB was an independent predictor for poor functional outcome at three months (odds ratio (OR) 0.73, 95% confidence interval (CI) 0.58-0.92, P = 0.007), along with National Institute of Health Stroke Scale (NIHSS) at admission (OR 1.17, 95% CI 1.11 - 1.24, P < 0.001), and age (OR 1.08, 95% CI 1.04 - 1.12, P < 0.001).ConclusionsWe report an association between low HB and poor outcome in patients with non-traumatic, supratentorial ICH. While a causal relationship could not be proven, previous experimental studies and studies in brain injured patients provide evidence for detrimental effects of anemia on brain metabolism. However, the potential risk of anemia must be balanced against the risk of harm from red blood cell infusion.

Autonomic Shift and Increased Susceptibility to Infections After Acute Intracerebral Hemorrhage

Background and Purpose— High infection rate after severe stroke may partly relate to brain-induced immunodepression syndrome. However, the underlying pathophysiology remains unclear. The aim of the current study was to investigate the role of autonomic shift in increased susceptibility to infection after acute intracerebral hemorrhage (ICH). Methods— We retrospectively analyzed 62 selected patients with acute ICH from our prospective database. Autonomic shift was assessed using the cross-correlational baroreflex sensitivity (BRS). The occurrence and cause of in-hospital infections were assessed based on the clinical and laboratory courses. Demographic and clinical data including initial stroke severity, hemorrhage volume, intraventricular blood extension, history of aspiration, and invasive procedures such as mechanical ventilation, surgical hematoma evacuation, external ventricular drainage, central venous and urinary catheters, and nasogastric feeding were recorded and included in the analysis. Results— We identified 36 (58%) patients with infection during the first 5 days of hospital stay. Patients with infections had significantly lower BRS, higher initial NIHSS scores, larger hemorrhages, and more frequently had intraventricular blood extension and underwent invasive procedures. In the multivariate regression model, decreased BRS (OR, 0.54; 95% CI, 0.32–0.91; P=0.02) and invasive procedures (OR, 2.32; 95% CI, 1.5–3.6; P<0.001) remained independent predictors for an infection after ICH. Conclusions— Decreased BRS was independently associated with infections after ICH. Autonomic shift may play an important role in increased susceptibility to infections after acute brain injury including ICH. The possible therapeutic relevance of autonomic modulation warrants further studies.