Reduced Pretreatment Ipsilateral Middle Cerebral Artery Cerebral Blood Flow Is Predictive of Symptomatic Hemorrhage Post–Intra-Arterial Thrombolysis in Patients With Middle Cerebral Artery Occlusion
Background and Purpose— Intracerebral hemorrhage (ICH) can be a devastating complication associated with thrombolytic therapy for acute ischemic stroke. We hypothesized that patients with lower prethrombolysis cerebral blood flow (CBF) were at a higher risk of symptomatic ICH (sICH).
Methods— Twenty-three patients who underwent quantitative CBF assessment with Xenon CT studies for acute stroke before intra-arterial (IA) thrombolysis for a middle cerebral artery (MCA) or internal carotid artery terminus occlusion within 6 hours of symptom onset were studied. Univariate and multivariate analysis were carried out to determine predictors of sICH post-IA thrombolysis. Receiver operating characteristic curves were generated to determine the association between mean ipsilateral CBF and the occurrence of sICH.
Results— The mean age of our cohort was 68±12 years and a mean National Institutes of Health Stroke Scale (NIHSS) score of 18±3. In univariate analysis, patients with higher percent of core infarct, hyperglycemia, and reduced mean ipsilateral CBF were at risk of sICH. In multivariate analysis only mean ipsilateral CBF was associated with higher rates of sICH (odds ratio 1.58; 95% CI, 1.01 to 2.51; P<0.04). The area under the receiver operating characteristic curve was 0.87 (95% CI, 0.76 to 0.97; P<0.005).
Conclusions— Patients with lower pre-IA thrombolysis mean ipsilateral MCA CBF are at significantly higher risk for sICH in the setting of a MCA or carotid terminus occlusion. The threshold identified in this study may be useful for selection of patients with acute MCA occlusions for acute stroke thrombolysis.
Symptomatic intracerebral hemorrhage (sICH) after thrombolytic therapy for acute ischemic stroke is associated with a high morbidity and mortality.1 Thrombolysis-related ICH has been classified into 2 types2: hemorrhagic infarct (HI), usually without clinical consequence, and parenchymal hemorrhage (PH), which commonly causes clinical deterioration. The latter has been further subclassified into PH1 representing blood clots in ≤30% of the infarcted area with slight space-occupying effect and PH2 representing blood clots in >30% of the infarcted area with substantial space-occupying effect.3
Other studies have noted that the extent of hypoattenuation on initial head CT4,5 and the use of tissue plasminogen activator (t-PA)5,6,7 are associated with a higher risk of developing PH-type sICH. Additionally, it has been observed that patients with lower regional cerebral blood flow (CBF) on single-photon emission CT in the hemisphere ipsilateral to an occluded cerebral artery is at a higher likelihood of undergoing hemorrhagic changes post–intra-arterial (IA) thrombolysis.8 The objective of this study was to quantify the relationship between different CBF thresholds in the ipsilateral middle cerebral artery (MCA) and the development of sICH. Additionally, we sought to determine the relationship between core infarct, penumbra and sICH.
Patients and Methods
This study was conducted with institutional Institutional Review Board approval.
Twenty-three acute ischemic stroke patients who underwent a Xenon CBF CT (Xe-CT-CBF) study were included in the study according to the following inclusion criteria: CBF study within 6 hours of symptom onset, patient taken to angiography for administration of IA or a combination of IV/IA thrombolytics, presence of an MCA or carotid terminus occlusion demonstrated by catheter angiography, and a Xe-CT-CBF study free of significant movement artifact allowing reliable interpretation of the quantitative CBF data.
The patients included in our study were selected from a prospective registry of 378 consecutive individuals admitted to the University of Pittsburgh Stroke Service between January 1997 and April 2001 who underwent a Xe-CT-CBF study during that admission. Of these 378 patients, 160 patients were studied within 6 hours of symptom onset, and of these, 50 patients had MCA or carotid terminus occlusions. Fourteen of these 50 patients were excluded because of excessive motion artifact, and 10 additional patients were not treated with any thrombolytic agents because of an exclusion criterion, and 3 patients were treated with IV t-PA alone and not taken for catheter angiography. Thus, a total of 23 patients were analyzed as part of this study.
The IA therapy protocol was to infuse t-PA or urokinase within the thrombus without aggressive mechanical manipulation. A maximum dose of 22 mg of t-PA (Genentech, Inc) was administered in the thrombus over 2 hours unless recanalization occurred before maximal dose administration. IA urokinase was administered in similar fashion: increments of 250 000 U every 15 minutes for a maximal dose of 2 million units over 2 hours. The end point of IA therapy was vessel recanalization or 2 hours whichever came first as was the protocol at the time of this study period. These patients were treated in the 3- to 6-hour time window. Patients who presented <3 hours and met inclusion criteria were treated with IV t-PA. Patients who received combined IV/IA therapy (n=12) were treated with a full dose of 0.9 mg/kg IV t-PA if symptom onset was under 3 hours and then the patient was taken to Xenon CT and angiography if persistent MCA or internal carotid artery terminus occlusion was suspected at the discretion of the treating stroke neurologist.
Xe-CT-CBF studies were ordered by the treating stroke neurologist according to the established prospective protocol during the study period. It is thus unlikely that a significant number of patients were missed attributable to ordering patterns of the treating neurologist. Admission head CTs were reviewed for the presence of hypodensity using a previously published scale (ASPECTS).9 The score was dichotomized to >7 or ≤7 because this has been previously shown to have good inter-rater reliability. Data were obtained from a clinical database that included clinical, laboratory and demographic data as well as follow-up CT data at 24 hours post-treatment. Digitally subtracted angiograms were reviewed by 1 of the authors (S.Z.G.) to determine the location of the clot (ie, carotid terminus or M1 MCA). The final run after administration of IA therapy was also reviewed by the same author to determine whether recanalization had occurred. Follow-up imaging studies at 24 hours were assessed for the presence of hemorrhage using the ECASS-2 classification.3 All patients screened had a documented time of symptom onset as well as a documented time at which the CBF study was performed, enabling accurate determination between symptom onset and the CBF study. The admission blood glucose level of each patient was recorded and included as part of the analysis. Systolic blood pressures were averaged over the first 48 hours of admission for all patients. Patients with a decline of their National Institutes of Health Stroke Scale (NIHSS) score by ≥4 points and evidence of PH1- or PH2-type hemorrhage were considered to have a symptomatic ICH.10
Xe-CBF-CT Data Analysis
The stable Xe-CT-CBF technique has been previously published.11,12 Xenon data analysis, calculation of ipsilateral MCA CBF, percent core, penumbra, noncore/nonpenumbra (NC/NP) and the validation of this method has also been previously published using region of interest (ROI).13 The same approach was used for tabulating percent core (ROIs <8 mL/100 g per minute), penumbra (ROIs 8 to 20 mL/100 g per minute), NC/NP (ROIs >20 mL/100 g per minute) and mean hemispheric CBF’s in this study.
Statistical analyses were performed using SPSS 13.0. Correlations were performed using Spearman correlation coefficients for mean ipsilateral CBF and ipsilateral percent core, penumbra, and NC/NP. Baseline clinical and Xenon CT values were compared using a Fisher exact test for categorical variables and a Student t test for continuous variables with regards to predictors of sICH. A binary logistic regression model was constructed to determine independent predictors of developing sICH with variables found to have a P value <0.10 in the univariate analysis.
A receiver operating characteristic (ROC) curve was constructed for the mean ipsilateral CBF values with respect to the risk of subsequent sICH. The values for the area under the curve are reported.
There were 23 total patients studied with a mean age of 68±12 years and a mean NIHSS of 18±3. Eleven patients received IA and 12 patients received combined IV/IA thrombolytic therapy. There were 5 patients (22%) who developed sICH in this cohort. All of these patients showed evidence of clinical decline in the first 24 hours post-thrombolysis and 4 of the hemorrhages were classified as PH2 and 1 as PH1. One patient was found to have clinical deterioration attributable to a large infarct with mass effect and petechial blood within the infarct. This patient was not considered in the sICH group because the deterioration was felt to be secondary to the edema from the infarct.
The median time from onset of symptoms to the CBF study was 210 minutes (range 120 to 360 minutes). The Table summarizes the univariate analysis comparing patients with and without sICH. Of note, patients with sICH were more likely to have a reduced ipsilateral mean MCA CBF, a higher percent of core, and presence of hyperglycemia. Additionally, patients with an ipsilateral MCA CBF of <13 mL/100 g per minute who recanalized had a significantly higher risk of developing sICH in univariate analysis. A multivariate binary logistic regression model was constructed with these variables and the only variable found to be independently predictive of sICH was mean ipsilateral MCA CBF (odds ratio [OR] 1.58; 95% CI, 1.01 to 2.51; P<0.04). There was a highly significant correlation between ipsilateral MCA CBF and percent core (Spearman ρ=−0.916; P<0.0001), and thus these variables were tested separately in multivariate modeling. When ipsilateral MCA CBF was removed from the multivariate model the percent ipsilateral core was found to be independently predictive of sICH (OR 1.03; 95% CI, 1.001 to 1.10; P<0.05).
The area under the curve for the ROC curve for comparing mean ipsilateral MCA CBF and sICH was 0.87 (95% CI, 0.76 to 0.97; P<0.005). We identified the mean ipsilateral MCA CBF of <13 mL/100 g per minute as most strongly predictive of developing sICH (OR 5.0; 95% CI, 2.2 to 10.5; P<0.008) based on the ROC curve. The Figure outlines the distribution of CBF values and percent core values for each individual patient.
The main finding of this study is that patients with lower mean ipsilateral CBF values and higher volume of infarcted tissue in the presence of an MCA occlusion are at the highest risk of developing sICH. The second finding is that there may be a threshold for mean ipsilateral CBF for which patients are at higher risk and revascularization therapies may be too high risk. Our data suggests that this threshold is 13 mL/100 g per minute for mean ipsilateral MCA CBF. In these patients, the risk of sICH after recanalization may be too high and other therapeutic approaches may be appropriate.
The risk of developing hemorrhagic transformation after thrombolysis has been linked to MRI variables such as lower apparent diffusion coefficient values.14,15 Other clinical parameters such as the severity of the NIHSS, older age5 and presence of hyperglycemia16 have been associated with a significantly higher risk of developing sICH. In our univariate analysis, we found that patients who developed sICH tended to have higher admission blood glucose levels as has been observed in other studies.16,17 This association was not significant in multivariate modeling likely attributable to the small sample size in our cohort. Unfortunately, many of these studies did not stratify the hemorrhages into PH- and HI-type bleeds and some patients may have deteriorated from cerebral edema and not the bleed itself.
HI and PH are 2 distinct types of hemorrhages noted post-thrombolysis with likely different mechanisms. HI has not been shown to impact clinical outcome18 and is associated with larger territories of infarcted tissue.7 In contrast, PH is associated with a poor outcome after thrombolysis and is linked to the use of thrombolytics5,6,7 and extent of infarct.4,5 In our cohort the 5 patients who experienced sICH all had PH-type bleeds.
The development of PH-type bleeds may result from a combination of the size of the infarct and the presence of thrombolytic agents.19 Patients with PH bleeds in the setting of t-PA administration have been found to have an increase in fibrinogen degradation products.20 In our cohort, all patients received thrombolytic agents. Thus, we are unable to assess the isolated effect of a reduced mean ipsilateral CBF and the risk of developing sICH after reperfusion therapy with other methods.
Other authors have observed that delayed recanalization of an occluded MCA leads to an increased risk of PH-type bleeds post-thrombolysis.21 This is likely attributable to reperfusion into large territories of infarcted tissue. We found that patients who were recanalized with a mean ipsilateral MCA CBF <13 mL/100 g per minute were more likely to develop sICH in the univariate analysis. These patients had larger infarcts at the time of recanalization and thus likely developed reperfusion sICH in the setting of IA thrombolysis.
Ueda et al noted that patients who develop ICH post-thrombolysis were noted to have a reduced pretreatment CBF via semiquantitative methods.8 This study did not separate patients into HI- and PH-type bleeds and symptomatic versus asymptomatic hemorrhage. Nonetheless, the authors found that patients who developed bleeds were more likely to have a lower baseline CBF using single-photon emission CT. Our study suggests that pretreatment CBF <13 mL/100 g per minute at the time of delivery of thrombolytics may be linked to the development of sICH. A quantitative approach may be more practical in the design of future studies examining which patients are most likely to benefit from thrombolytic therapy in acute ischemic stroke.
The number of patients developing sICH in our cohort is higher than that reported in the literature. This is likely because at the time of this protocol patients were selected for IA thrombolysis based on rigid time criterion (ie, under 6 hours from symptom onset). There were patients in this cohort with larger areas of hypodensity on head CT as evidenced by a low ASPECTS score before IA thrombolysis. Such patients are currently treated with endovascular mechanical maneuvers such as angioplasty or a clot-retrieving device at our institution. Additionally, although not statistically significant in this cohort, there were just over 50% of patient who received full-dose IV t-PA followed by IA thrombolysis. Higher doses of thrombolytics may lead to higher rates of sICH. Lastly, the higher percentage of sICH may be a result of a small sample size.
There are limitations of this study including the retrospective nature and the small number of patients studied. Although the number of patients is small, we were able to identify significant predictors for patients developing sICH post-IA thrombolysis that would require further validation. Another limitation of this study is that a selection bias may be present for patients unable to tolerate Xenon CT. Increasing the number of patients will aid in more precisely identifying the CBF threshold associated with a higher risk of sICH.
In conclusion, we have found that patients with a lower mean ipsilateral CBF and a high percent of core infarct are at a significantly higher risk of sICH after IA thrombolysis for MCA occlusion. The threshold of 13 mL/100 g per minute identified in this study may be useful for selection of patients with acute MCA occlusions for acute stroke thrombolysis.
H.Y. is a consultant for Diversified Diagnostics. The other authors report no conflicts of interest.
- Received March 28, 2006.
- Revision received June 14, 2006.
- Accepted July 4, 2006.
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