Blood-brain barrier compromise does not predict perihematoma edema growth in intracerebral hemorrhage.

BACKGROUND AND PURPOSE: There are limited data on the extent of blood-brain barrier (BBB) compromise in acute intracerebral hemorrhage patients. We tested the hypotheses that BBB compromise measured with permeability-surface area product (PS) is increased in the perihematoma region and predicts perihematoma edema growth in acute intracerebral hemorrhage patients. METHODS: Patients were randomized within 24 hours of symptom onset to a systolic blood pressure (SBP) treatment of <150 (n=26) or <180 mm Hg (n=27). Permeability maps were generated using computed tomographic perfusion source data acquired 2 hours after randomization, and mean PS was measured in the hematoma, perihematoma, and hemispheric regions. Hematoma and edema volumes were measured on noncontrast computed tomographic scans obtained at baseline, 2 hours and 24 hours after randomization. RESULTS: Patients were randomized at a median (interquartile range) time of 9.3 hours (14.1) from symptom onset. Treatment groups were balanced with respect to baseline SBP and hematoma volume. Perihematoma PS (5.1±2.4 mL/100 mL per minute) was higher than PS in contralateral regions (3.6±1.7 mL/100 mL per minute; P<0.001). Relative edema growth (0-24 hours) was not predicted by perihematoma PS (ß=-0.192 [-0.06 to 0.01]) or SBP change (ß=-0.092 [-0.002 to 0.001]). SBP was lower in the <150 target group (139.2±22.1 mm Hg) than in the <180 group (159.7±12.3 mm Hg; P<0.0001). Perihematoma PS was not different between groups (4.9±2.4 mL/100 mL per minute for the <150 group, 5.3±2.4 mL/100 mL per minute for the <180 group; P=0.51). CONCLUSIONS: BBB permeability is focally increased in the hematoma and perihematoma regions of acute intracerebral hemorrhage patients. BBB compromise does not predict acute perihematoma edema volume or edema growth. SBP reduction does not affect BBB permeability. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00963976.

Acute blood pressure reduction in patients with intracerebral hemorrhage does not result in borderzone region hypoperfusion.

BACKGROUND AND PURPOSE: The Intracerebral Hemorrhage Acutely Decreasing Arterial Pressure Trial (ICH ADAPT) demonstrated blood pressure (BP) reduction does not affect mean perihematoma or hemispheric cerebral blood flow. Nonetheless, portions of the perihematoma and borderzones may reach ischemic thresholds after BP reduction. We tested the hypothesis that BP reduction after intracerebral hemorrhage results in increased critically hypoperfused tissue volumes. METHODS: Patients with Intracerebral hemorrhage were randomized to a target systolic BP (SBP) of <150 or <180 mm Hg and imaged with computed tomographic perfusion 2 hours later. The volumes of tissue below cerebral blood flow thresholds for ischemia (<18 mL/100 g/min) and infarction (<12 mL/100 g/min) were calculated as a percentage of the total volume within the internal and external borderzones and the perihematoma region. RESULTS: Seventy-five patients with intracerebral hemorrhage were randomized a median (interquartile range) of 7.8 (13.3) hours from onset. Acute hematoma volume was 17.8 (27.1) mL and mean SBP was 183±22 mm Hg. At the time of computed tomographic perfusion (2.3 [1.0] hours after randomization), SBP was lower in the <150 mm Hg (n=37; 140±18 mm Hg) than in the <180 mm Hg group (n=36; 162±12 mm Hg; P<0.001). BP treatment did not affect the percentage of total borderzone tissue with cerebral blood flow<18 (14.7±13.6 versus 15.6±13.7%; P=0.78) or <12 mL/100 g/min (5.1±5.1 versus 5.8±6.8%; P=0.62). Similar results were found in the perihematoma region. Low SBP load (fraction of time with SBP<150 mmHg) did not predict borderzone tissue volume with cerebral blood flow<18 mL/100 g/min (ß=0.023 [-0.073, 0.119]). CONCLUSIONS: BP reduction does not increase the volume of critically hypoperfused borderzone or perihematoma tissue. These data support the safety of early BP reduction in intracerebral hemorrhage. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00963976.

Cerebral perfusion and blood pressure do not affect perihematoma edema growth in acute intracerebral hemorrhage.

BACKGROUND AND PURPOSE: The pathogenesis of perihematoma edema in intracerebral hemorrhage (ICH) is unknown but has been hypothesized to be ischemic. In the ICH Acutely Decreasing Arterial Pressure Trial (ICH ADAPT), perihematoma cerebral blood flow (CBF) was reduced but was unaffected by blood pressure (BP) reduction. Using ICH ADAPT data, we tested the hypotheses that edema growth is associated with reduced CBF and lower systolic BP. METHODS: Noncontrast computed tomographic scans in patients with ICH were obtained at baseline, 2 hours, and 24 hours after randomization to target systolic BPs of <150 or <180 mm Hg. Computed tomography perfusion imaging was performed at 2 hours, and mean relative CBF was calculated in visibly edematous perihematoma tissue. Edema volumes were measured using a Hounsfield unit threshold of 5 to 23 at each time-point. RESULTS: Patients were randomized at a median (interquartile range) of 7.4 (12.8) hours after onset. Treatment groups (n=34, <150 and n=33, <180 target) were balanced with respect to baseline systolic BP and acute ICH volume. Relative edema growth at 24 hours in the <150 group (0.11±0.19) was similar to that in the <180 group (0.09±0.16 mL; P=0.727). Absolute CBF was lower in the edematous region (35.67±13.1 mL/100 g per minute) when compared with that in the contralateral tissue (43.7±11.7 mL/100 g per minute; P<0.0001). Linear regression indicated that neither systolic BP change (ß=-0.022; 95% confidence interval, -0.002 to 0.001) nor perihematoma relative CBF (ß=-0.144; 95% confidence interval, -0.647 to 0.167) predicted edema growth. CONCLUSIONS: Lower perihematoma CBF and BP treatment do not exacerbate edema growth. These data do not support a cytotoxic edema pathogenesis. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00963976.

The Intracerebral Hemorrhage Acutely Decreasing Arterial Pressure Trial.

BACKGROUND AND PURPOSE: Acute blood pressure (BP) reduction aimed at attenuation of intracerebral hemorrhage (ICH) expansion might also compromise cerebral blood flow (CBF). We tested the hypothesis that CBF in acute ICH patients is unaffected by BP reduction. METHODS: Patients with spontaneous ICH <24 hours after onset and systolic BP > 150 mm Hg were randomly assigned to an intravenous antihypertensive treatment protocol targeting a systolic BP of <150 mm Hg (n=39) or <180 mm Hg (n=36). Patients underwent computed tomography perfusion imaging 2 hours postrandomization. The primary end point was perihematoma relative (relative CBF). RESULTS: Treatment groups were balanced with respect to baseline systolic BP: 182±20 mm Hg (<150 mm Hg target group) versus 184±25 mm Hg (<180 mm Hg target group; P=0.60), and for hematoma volume: 25.6±30.8 versus 26.9±25.2 mL (P=0.66). Mean systolic BP 2 hours after randomization was significantly lower in the <150 mm Hg target group (140±19 vs 162±12 mm Hg; P<0.001). Perihematoma CBF (38.7±11.9 mL/100 g per minute) was lower than in contralateral homologous regions (44.1±11.1 mL/100 g per minute; P<0.001) in all patients. The primary end point of perihematoma relative CBF in the <150 mm Hg target group (0.86±0.12) was not significantly lower than that in the <180 mm Hg group (0.89±0.09; P=0.19; absolute difference, 0.03; 95% confidence interval -0.018 to 0.078). There was no relationship between the magnitude of BP change and perihematoma relative CBF in the <150 mm Hg (R=0.00005; 95% confidence interval, -0.001 to 0.001) or <180 mm Hg target groups (R=0.000; 95% confidence interval, -0.001 to 0.001). CONCLUSIONS: Rapid BP lowering after a moderate volume of ICH does not reduce perihematoma CBF. These physiological data indicate that acute BP reduction does not precipitate cerebral ischemia in ICH patients. Clinical Trial Registration Information- URL:http://clinicaltrials.gov. Unique Identifier: NCT00963976.

Autoregulation of cerebral blood flow is preserved in primary intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Treatment of acute hypertension after intracerebral hemorrhage (ICH) is controversial. In the context of disrupted cerebral autoregulation, blood pressure (BP) reduction may cause decreased cerebral blood flow (CBF). We used serial computed tomography perfusion to test the hypothesis that CBF remains stable after BP reduction. METHODS: Patients recruited within 72 hours of ICH were imaged with computed tomography perfusion before and after BP treatment. Change in perihematoma relative (r) CBF after BP treatment was the primary end point. RESULTS: Twenty patients were imaged with computed tomography perfusion at a median (interquartile range) time from onset of 20.2 (25.7) hours and reimaged 2.1 (0.5) hours later, after BP reduction. Mean systolic BP in treated patients (n=16; 4 untreated as BP

Peri-hematoma corticospinal tract integrity in intracerebral hemorrhage patients: A diffusion-tensor imaging study.

BACKGROUND: The impact of perihematoma edema in Intracerebral Hemorrhage (ICH) on white matter integrity is uncertain. Fractional Anisotropy (FA), as measured with Diffusion Tensor Imaging (DTI), can be used to assess white matter microstructure. We tested the hypotheses that sections of the Corticospinal Tract (CST) passing through perihematoma edema would 1) have low FA relative to the contralateral CST and 2) would predict NIHSS motor score in ICH patients. METHODS: Patients were prospectively imaged with DTI at 48 h and 7 days after onset. Edema volume/extent was measured on CT at baseline and 24 h. FA, mean, axial and radial diffusivity were measured in the perihematoma edema, contralateral CST and sections of CST passing through the edema ('edematous CST'). RESULTS: Patients (n = 27, mean age 67 ± 13) were scanned with DTI at a median (IQR) of 42.3 (24.5) hours and 7.7 (1.8) days from onset. Median acute ICH volume was 8.8 (22) ml. FA in edematous CST at 72 h was decreased (0.37 ± 0.03) relative to contralateral CST (0.52 ± 0.06; p < 0.0001). Day 7 FA in edematous CST (0.35 ± 0.08) was also decreased compared to contralateral CST (0.54 ± 0.06; p < 0.0001). FA remained stable between 72 h (0.37 ± 0.03) and day 7 (0.35 ± 0.07; p = 0.350). FA at 72 h (ρ = -0.22, p = 0.420) and day 7 (ρ = -0.14, p = 0.624) was unrelated to 90-day motor score. CONCLUSIONS: FA is decreased in the CST where it passes through the edema. Decreased FA in the edematous CST remained stable over time, was unrelated to motor score, and may represent water infiltration into the tracts rather than axonal injury.

Aggressive blood pressure reduction is not associated with decreased perfusion in leukoaraiosis regions in acute intracerebral hemorrhage patients.

Leukoaraiosis regions may be more vulnerable to decreases in cerebral perfusion. We aimed to assess perfusion in leukoaraiosis regions in acute intracerebral hemorrhage (ICH) patients. We tested the hypothesis that aggressive acute BP reduction in ICH patients is associated with hypoperfusion in areas of leukoaraiosis. In the ICH Acutely Decreasing Arterial Pressure Trial (ICH ADAPT), patients with ICH <24 hours duration were randomized to two systolic BP (SBP) target groups (<150 mmHg vs. <180 mmHg). Computed tomography perfusion (CTP) imaging was performed 2h post-randomization. Leukoaraiosis tissue volumes were planimetrically measured using semi-automated threshold techniques on the acute non-contrast CT. CTP source leukoaraiosis region-of-interest object maps were co-registered with CTP post-processed maps to assess cerebral perfusion in these areas. Seventy-one patients were included with a mean age of 69±11.4 years, 52 of whom had leukoaraiosis. The mean relative Tmax (rTmax) of leukoaraiotic tissue (2.3±2s) was prolonged compared to that of normal appearing white matter in patients without leukoaraiosis (1.1±1.2s, p = 0.04). In the 52 patients with leukoaraiosis, SBP in the aggressive treatment group (145±20.4 mmHg, n = 27) was significantly lower than that in the conservative group (159.9±13.1 mmHg, n = 25, p = 0.001) at the time of CTP. Despite this SBP difference, mean leukoaraiosis rTmax was similar in the two treatment groups (2.6±2.3 vs. 1.8±1.6 seconds, p = 0.3). Cerebral perfusion in tissue affected by leukoaraiosis is hypoperfused in acute ICH patients. Aggressive BP reduction does not appear to acutely aggravate cerebral hypoperfusion.

Absolute risk and predictors of the growth of acute spontaneous intracerebral haemorrhage: a systematic review and meta-analysis of individual patient data.

BACKGROUND: Intracerebral haemorrhage growth is associated with poor clinical outcome and is a therapeutic target for improving outcome. We aimed to determine the absolute risk and predictors of intracerebral haemorrhage growth, develop and validate prediction models, and evaluate the added value of CT angiography. METHODS: In a systematic review of OVID MEDLINE-with additional hand-searching of relevant studies' bibliographies- from Jan 1, 1970, to Dec 31, 2015, we identified observational cohorts and randomised trials with repeat scanning protocols that included at least ten patients with acute intracerebral haemorrhage. We sought individual patient-level data from corresponding authors for patients aged 18 years or older with data available from brain imaging initially done 0·5-24 h and repeated fewer than 6 days after symptom onset, who had baseline intracerebral haemorrhage volume of less than 150 mL, and did not undergo acute treatment that might reduce intracerebral haemorrhage volume. We estimated the absolute risk and predictors of the primary outcome of intracerebral haemorrhage growth (defined as >6 mL increase in intracerebral haemorrhage volume on repeat imaging) using multivariable logistic regression models in development and validation cohorts in four subgroups of patients, using a hierarchical approach: patients not taking anticoagulant therapy at intracerebral haemorrhage onset (who constituted the largest subgroup), patients taking anticoagulant therapy at intracerebral haemorrhage onset, patients from cohorts that included at least some patients taking anticoagulant therapy at intracerebral haemorrhage onset, and patients for whom both information about anticoagulant therapy at intracerebral haemorrhage onset and spot sign on acute CT angiography were known. FINDINGS: Of 4191 studies identified, 77 were eligible for inclusion. Overall, 36 (47%) cohorts provided data on 5435 eligible patients. 5076 of these patients were not taking anticoagulant therapy at symptom onset (median age 67 years, IQR 56-76), of whom 1009 (20%) had intracerebral haemorrhage growth. Multivariable models of patients with data on antiplatelet therapy use, data on anticoagulant therapy use, and assessment of CT angiography spot sign at symptom onset showed that time from symptom onset to baseline imaging (odds ratio 0·50, 95% CI 0·36-0·70; p<0·0001), intracerebral haemorrhage volume on baseline imaging (7·18, 4·46-11·60; p<0·0001), antiplatelet use (1·68, 1·06-2·66; p=0·026), and anticoagulant use (3·48, 1·96-6·16; p<0·0001) were independent predictors of intracerebral haemorrhage growth (C-index 0·78, 95% CI 0·75-0·82). Addition of CT angiography spot sign (odds ratio 4·46, 95% CI 2·95-6·75; p<0·0001) to the model increased the C-index by 0·05 (95% CI 0·03-0·07). INTERPRETATION: In this large patient-level meta-analysis, models using four or five predictors had acceptable to good discrimination. These models could inform the location and frequency of observations on patients in clinical practice, explain treatment effects in prior randomised trials, and guide the design of future trials. FUNDING: UK Medical Research Council and British Heart Foundation.

National Institutes of Health Stroke Scale score is an unreliable predictor of perfusion deficits in acute stroke.

BACKGROUND: Perfusion-weighted magnetic resonance imaging is not routinely used to investigate stroke/transient ischemic attack. Many clinicians use perfusion-weighted magnetic resonance imaging selectively in patients with more severe neurological deficits, but optimal selection criteria have never been identified. AIMS AND/OR HYPOTHESIS: We tested the hypothesis that a National Institutes of Health Stroke Scale score threshold can be used to predict the presence of perfusion-weighted magnetic resonance imaging deficits in patients with acute ischemic stroke/transient ischemic attack. METHODS: National Institutes of Health Stroke Scale scores were prospectively assessed in 131 acute stroke/transient ischemic attack patients followed by magnetic resonance imaging, including perfusion-weighted magnetic resonance imaging within 72 h of symptom onset. Patients were dichotomized based on the presence or absence of perfusion deficits using a threshold of Tmax (time to peak maps after the impulse response) delay ≥four-seconds and a hypoperfused tissue volume of ≥1 ml. RESULTS: Patients with perfusion deficits (77/131, 59%) had higher median (interquartile range) National Institutes of Health Stroke Scale scores (8 [12]) than those without perfusion deficits (3 [4], P < 0.001). A receiver operator characteristic analysis indicated poor to moderate sensitivity of National Institutes of Health Stroke Scale scores for predicting perfusion deficits (area under the curve = 0.787). A National Institutes of Health Stroke Scale score of ≥6 was associated with specificity of 85%, but sensitivity of only 69%. No National Institutes of Health Stroke Scale score threshold identified all cases of perfusion-weighted magnetic resonance imaging deficits with sensitivity >94%. CONCLUSIONS: Although higher National Institutes of Health Stroke Scale scores are predictive of perfusion deficits, many patients with no clinically detectable signs have persisting cerebral blood flow changes. A National Institutes of Health Stroke Scale score threshold should therefore not be used to select patients for perfusion-weighted magnetic resonance imaging. Perfusion-weighted magnetic resonance imaging should be considered in all patients presenting with acute focal neurological deficits, even if these deficits are transient.

Perihematoma cerebral blood flow is unaffected by statin use in acute intracerebral hemorrhage patients.

Statin therapy has been associated with improved cerebral blood flow (CBF) and decreased perihematoma edema in animal models of intracerebral hemorrhage (ICH). We aimed to assess the relationship between statin use and cerebral hemodynamics in ICH patients. A post hoc analysis of 73 ICH patients enrolled in the Intracerebral Hemorrhage Acutely Decreasing Arterial Pressure Trial (ICH ADAPT). Patients presenting <24 hours from ICH onset were randomized to a systolic blood pressure target <150 or <180 mm Hg with computed tomography perfusion imaging 2 hours after randomization. Cerebral blood flow maps were calculated. Hematoma and edema volumes were measured planimetrically. Regression models were used to assess the relationship between statin use, perihematoma edema and cerebral hemodynamics. Fourteen patients (19%) were taking statins at the time of ICH. Statin-treated patients had similar median (IQR Q25 to 75) hematoma volumes (21.1 (9.5 to 38.3) mL versus 14.5 (5.6 to 27.7) mL, P=0.25), but larger median (IQR Q25 to 75) perihematoma edema volumes (2.9 (1.7 to 9.0) mL versus 2.2 (0.8 to 3.5) mL, P=0.02) compared with nontreated patients. Perihematoma and ipsilateral hemispheric CBF were similar in both groups. A multivariate linear regression model revealed that statin use and hematoma volumes were independent predictors of acute edema volumes. Statin use does not affect CBF in ICH patients. Statin use, along with hematoma volume, are independently associated with increased perihematoma edema volume.

Blood pressure reduction does not reduce perihematoma oxygenation: a CT perfusion study.

Blood pressure (BP) reduction after intracerebral hemorrhage (ICH) is controversial, because of concerns that this may cause critical reductions in perihematoma perfusion and thereby precipitate tissue damage. We tested the hypothesis that BP reduction reduces perihematoma tissue oxygenation.Acute ICH patients were randomized to a systolic BP target of <150 or <180 mm Hg. Patients underwent CT perfusion (CTP) imaging 2 hours after randomization. Maps of cerebral blood flow (CBF), maximum oxygen extraction fraction (OEF(max)), and the resulting maximum cerebral metabolic rate of oxygen (CMRO2(max)) permitted by local hemodynamics, were calculated from raw CTP data.Sixty-five patients (median (interquartile range) age 70 (20)) were imaged at a median (interquartile range) time from onset to CTP of 9.8 (13.6) hours. Mean OEF(max) was elevated in the perihematoma region (0.44±0.12) relative to contralateral tissue (0.36±0.11; P<0.001). Perihematoma CMRO2(max) (3.40±1.67 mL/100 g per minute) was slightly lower relative to contralateral tissue (3.63±1.66 mL/100 g per minute; P=0.025). Despite a significant difference in systolic BP between the aggressive (140.5±18.7 mm Hg) and conservative (163.0±10.6 mm Hg; P<0.001) treatment groups, perihematoma CBF was unaffected (37.2±11.9 versus 35.8±9.6 mL/100 g per minute; P=0.307). Similarly, aggressive BP treatment did not affect perihematoma OEF(max) (0.43±0.12 versus 0.45±0.11; P=0.232) or CMRO2(max) (3.16±1.66 versus 3.68±1.85 mL/100 g per minute; P=0.857). Blood pressure reduction does not affect perihematoma oxygen delivery. These data support the safety of early aggressive BP treatment in ICH.