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(Stroke. 2001;32:1079.)
© 2001 American Heart Association, Inc.

Original Contributions

Timing of Spontaneous Recanalization and Risk of Hemorrhagic Transformation in Acute Cardioembolic Stroke

Carlos A. Molina, MD; Joan Montaner, MD; Sonia Abilleira, MD; Bernardo Ibarra, MD; Francisco Romero, MD; Juan F. Arenillas, MD José Alvarez-Sabín, MD

From the Cerebrovascular Unit, Departments of Neurology (C.A.M., J.M., S.A., J.F.A., J.A.-S.) and Neuroradiology (B.I., F.R.), Hospital Vall d’Hebrón, Barcelona, Spain.

Correspondence to Carlos A. Molina, MD, Cerebrovascular Unit, Department of Neurology, Hospital Vall d’Hebrón, Passeig Vall d’Hebron 119-129, 08035 Barcelona, Spain. E-mail carmolcate{at}demasiado.com

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose—The relationship between reperfusion and hemorrhagic transformation (HT) remains uncertain. Therefore, we aimed to clarify the relationship between the time course of recanalization and the risk of HT in patients with cardioembolic stroke studied within 6 hours of symptom onset.

Methods—Fifty-three patients with atrial fibrillation and nonlacunar stroke in the middle cerebral artery (MCA) territory admitted within the first 6 hours after symptom onset were prospectively studied. Serial TCD examinations were performed on admission and at 6, 12, 24, and 48 hours. CT was performed within 6 hours after stroke onset and again at 36 to 48 hours.

Results—Proximal and distal MCA occlusions were detected in 32 patients (60.4%) and 18 patients (34%), respectively. Early spontaneous recanalization occurring within 6 hours was identified in 10 patients (18.8%). Delayed recanalization (>6 hours) occurred in 28 patients (52.8%). HT on CT scan was detected in 17 patients (32%) within the first 48 hours. Only large parenchymal hemorrhage (PH2) was significantly associated with an increase (P=0.038, Kruskal-Wallis test) in the National Institutes of Health Stroke Scale (NIHSS) score compared with the other subtypes of HT. Univariate analysis revealed that an NIHSS score of >14 on baseline (P=0.001), proximal MCA occlusion (P=0.004), hypodensity >33% of the MCA territory (P=0.012), and delayed recanalization occurring >6 hours of stroke onset (P=0.003) were significantly associated with HT. With a multiple logistic regression model, delayed recanalization (OR 8.9; 95% CI 2.1 to 33.3) emerged as independent predictor of HT.

Conclusions—Delayed recanalization occurring >6 hours after acute cardioembolic stroke is an independent predictor of HT.

Key Words: cardioembolic stroke • hemorrhage • reperfusion • ultrasonography

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Spontaneous or thrombolysis-induced recanalization of main stem cerebral arteries within a few hours after acute ischemic stroke may lead to a good clinical outcome. However, the beneficial effect obtained by thrombolysis-induced recanalization may be counteracted by an increased risk of hemorrhagic transformation (HT). HT is a natural consequence of cerebral infarction, occurring in up to 65% of stroke patients¹ and up to 90% of patients with cardioembolic stroke within the first week after symptom onset.^{2 3}

The timing of arterial recanalization has been shown to be an important determinant of the risk of HT in animal models of acute stroke,^{4 5} in which delayed recanalization (>3 hours) has been associated with the presence of HT at 24 hours. These findings have not been confirmed by angiographic studies in humans,^{6 7 8 9} which suggests that this type of hemorrhage may occur from other sources, including collateral channels.¹⁰ However, data on systematic arterial assessment of the time course of recanalization and its relationship with HT are lacking.

Prior transcranial Doppler (TCD) studies^{11 12} focusing on recanalization in acute stroke failed to demonstrate an association between the rate and time course of spontaneous recanalization and the risk of HT. However, these studies were based on a heterogeneous group of patients, with various stroke subtypes with different patterns of arterial occlusion. In addition, clot characteristics and response to endogenous fibrinolysis may differ depending on embolic sources. Therefore, we attempted to clarify the relationship between the time course of spontaneous recanalization assessed by TCD and the risk of HT in a subset of patients with acute ischemic cardioembolic stroke presenting within 6 hours after symptom onset.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Our target group consisted of patients with acute ischemic stroke admitted within the first 6 hours after symptom onset. Stroke onset was defined as the last time the patient was known to be without any neurological deficit. A total of 146 consecutive patients were evaluated between February 1999 and January 2000. Ninety-eight patients (66%) had a nonlacunar stroke involving the vascular territory of the middle cerebral artery (MCA). Of these, 68 patients (46%) who had clinical and ECG evidence of atrial fibrillation (AF) on admission underwent urgent carotid ultrasound and TCD examinations. We excluded patients who had an inadequate temporal bone window (n=11) and those who had carotid artery stenosis of >50% (n=4). Finally, 53 patients with AF and nonlacunar stroke in the MCA territory were included in the study.

On arrival in the emergency room, patients underwent standard neurological and cardiological examinations, ECG, blood chemistry, and noncontrast CT before enrollment in the study. Most patients were included in clinical trials of neuroprotective drugs. No patient received thrombolytic therapy. Anticoagulant therapy was started in the absence of HT on the second CT performed at 36 to 48 hours after stroke onset. Informed consent was obtained from all patients or their next of kin. The study protocol was approved by the local ethics committee.

TCD Assessment
A standard TCD examination was performed in the emergency room on admission (<6 hours) and to assess spontaneous recanalization on follow-up at 6, 12, 24, and 48 hours after symptom onset. Baseline and follow-up studies were conducted by the same neurologist. Systolic blood pressure, diastolic blood pressure, and heart rate were measured at the time of each TCD recording. The TCD examination was carried out by using Multi-Dop X4 equipment (DWL Electronic Systems), with a hand-held probe in a range-gated, pulsed-wave mode at a frequency of 2 MHz. Flow velocity of the MCAs, the anterior cerebral arteries (ACAs), and the posterior cerebral arteries (PCAs) were bilaterally recorded using the transtemporal approach. The MCA was identified as a flow signal directed toward the probe at an insonation depth of 55 mm and traced up and down to 35 and 65 mm, respectively. The ACA was identified as a flow signal directed away from the probe at a depth of 65 mm and traced down to 80 mm. The flow signal from the PCA was detected at 65 mm, as a signal directed toward the probe, and traced from a 60- to 70-mm depth. Doppler shifts from all arteries were recorded each 2-mm step.

Proximal MCA occlusion was defined as the absence of flow or the presence of minimal flow signal throughout the MCA at an insonation depth between 45 and 65 mm, accompanied by flow diversion in the ipsilateral ACA and PCA. Distal MCA occlusion was defined as a diffuse dampening of the mean flow velocity in the affected MCA of >21% compared with the unaffected MCA.¹¹ Spontaneous recanalization on follow-up TCD recordings was diagnosed when a dampened or normal waveform appeared in a previously demonstrated proximal MCA occlusion or when a previously dampened waveform came within the normal range in a previously occluded distal MCA.¹¹ No change in the abnormal waveforms indicated that no recanalization had occurred.

CT Criteria of HT
On admission, all patients underwent a CT scan within the first 6 hours after stroke onset; the scan was repeated after 36 to 48 hours (or earlier when rapid neurological deterioration occurred). CT scans were reviewed by a neuroradiologist with extensive experience in acute stroke who was blinded to the clinical and TCD details. The presence of hyperdense MCA sign, early focal hypodensity, or swelling due to developing infarction on baseline CT were assessed according to European Cooperative Acute Stroke Study (ECASS) criteria.^{13 14} The presence and type of HT were defined according to previously published criteria.^{14 15} Hemorrhagic infarction (HI) was defined as a petechial infarction without space-occupying effect, and parenchymal hematoma (PH) was defined as hemorrhage with mass effect. HI was categorized into HI1 (small petechiae) and HI2 (more confluent petechiae). PH was also categorized into PH1 (when hematoma involved 30% of the infarcted area with some mild space-occupying effect) and PH2 (when hematoma involved >30% of the infarcted area with significant mass effect or clot remote to the infarcted area).

Clinical Assessment
We assessed clinical status at baseline and at 6, 12, 24, and 48 hours after symptom onset by means of the National Institutes of Health Stroke Scale (NIHSS), which was conducted by a neurologist or a senior neurology resident, who were video trained and certified for application of the NIHSS.¹⁶ Early neurological deterioration or improvement was defined as an increase or decrease of 4 points on the NIHSS score after 48 hours from baseline assessment.¹⁷ The modified Rankin scale¹⁸ (MRS) was used to assess clinical outcome at 90 days. We defined unfavorable outcome as MRS score >2.

Statistical Analysis
The analyses were performed with the use of SPSS 8.0 software (SPSS, Inc). Statistical significance for intergroup differences was assessed by the 2-tailed Fisher exact test and ² test for categorical variables and the Kruskal-Wallis test and Student t test for continuous variables. The risk of HT and poor outcome at 3 months was assessed by forward stepwise logistic regression analysis based on the maximum likelihood ratio. Variables with a value of P0.1 on univariate testing were included. A level of P<0.05 was accepted as statistically significant.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Fifty-three patients (27 men and 26 women) with an acute stroke in the MCA territory and AF were included in the study. Demographic data, risk factor profile, and baseline clinical findings are shown in Table 1. The mean±SD age was 73.7±15.2 (range 21 to 95) years. Fifty-six percent of patients were hypertensive, and 22% had a history of diabetes mellitus. The NIHSS score on admission was 17.2±5.3 (range 4 to 26).

View this table: [in this window] [in a new window]   Table 1. Demographic Data, Risk Factor Profile, and Baseline Clinical Findings of the Series

The time interval between stroke onset and baseline TCD examination ranged from 40 minutes to 5.3 hours (mean 3.6±3.2 hours). On baseline TCD assessment, proximal MCA occlusion was detected in 32 patients (60.4%) and distal MCA occlusion in 18 (34%), and in 3 patients (5.7%) TCD examination was normal. Early spontaneous recanalization (occurring at 6 hours) was identified in 10 patients (18.8%); 2 had proximal and 5 had distal MCA occlusions. The 3 patients with normal TCD results were considered to have completely reperfused before evaluation. Delayed recanalization (>6 hours) occurred in 28 patients (52.8%), 18 with proximal and 10 with distal MCA occlusions. Nineteen patients (35.8%) recanalized between 6 and 12 hours, 6 (11.3%) between 12 and 24 hours, and 3 (5.7%) between 24 and 48 hours after stroke onset. In 15 patients (28.3%) the MCA remained occluded at 48 hours.

Clinical assessment revealed that 16 patients (30.1%) worsened, 20 (37.7%) improved, and 17 (32.1%) remained stable during the first 48 hours after admission. Table 2 shows the variables associated with early neurological deterioration. Early hypodensity involving >33% of the MCA territory was significantly (P=0.038) associated with neurological deterioration at 48 hours.

View this table: [in this window] [in a new window]   Table 2. Variables Associated With Early Neurological Deterioration Within 48 hours After Symptom Onset

The second CT was performed at 44.4±2.5 hours after stroke onset. HT on CT was detected in 17 patients (32%). Distribution of HT subtypes occurring within the first 48 hours was as follows: HI1 was identified in 4 patients (27%), HI2 in 6 (35.3%), PH1 in 4 (27%), and PH2 in 3 (29.3%). Early HT (<48 hours) was located in the deep MCA territory in 15 patients, 14 reperfused and 1 nonreperfused. In the remaining 2 nonreperfused patients, HT involved the superficial MCA territory. Figure 1 illustrates the time course of spontaneous recanalization according to presence of HT within the first 48 hours after onset. No patient who recanalized in <6 hours had HT. Conversely, 11 of 19 (58%) and 3 of 6 (50%) patients who recanalized between 6 to 12 hours and 12 to 24 hours, respectively, experienced HT. Moreover, 3 of 15 patients (20%) who did not recanalize had HT. The 3 PH2 occurred in patients who recanalized between 6 and 12 hours. Figure 2 shows changes in NIHSS score at 48 hours by presence and type of HT. Neurological deterioration at 48 hours was unrelated to the presence of HT. However, only presence of PH2 was significantly associated with a greater increase (P=0.038, Kruskal-Wallis test) in NIHSS score compared with other subtypes of HT, indicating a more severe neurological deterioration.

View larger version (55K): [in this window] [in a new window]   Figure 1. Stacked bars showing the proportion of patients with HT at 36 to 48 hours, according to the time of recanalization. NR indicates no recanalization.

View larger version (16K): [in this window] [in a new window]   Figure 2. Scatterplot of changes of NIHSS score between baseline and 48-hour assessment, according to type of HT. PH2 was significantly associated with an increase (P=0.038, Kruskal-Wallis test) in the NIHSS score compared with the other subtypes of HT, indicating a more severe neurological deterioration.

The factors associated with HT are shown in Table 1. An NIHSS score of >14 on baseline assessment (P=0.001), proximal MCA occlusion on baseline TCD recording (P=0.004), hypodensity of >33% of the MCA territory on baseline CT scan (P=0.012), and delayed recanalization occurring >6 hours after stroke onset (P=0.003) were significantly associated with HT on univariate analysis. Variables with a value of P0.1 on univariate testing were included in a stepwise logistic regression analysis. These factors were NIHSS score >14, proximal MCA occlusion, delayed recanalization, hypodensity >33%, coronary heart disease, and platelet count. Because NIHSS score >14, proximal MCA occlusion, and hypodensity >33% are closely related to one another, NIHSS score >14 was chosen among them to enter into the model. Only delayed recanalization (OR 8.9, 95% CI 2.1 to 33.3) emerged as independent predictor of HT with a multiple logistic regression model (Table 3).

View this table: [in this window] [in a new window]   Table 3. Stepwise Logistic Regression With Dependent Variable: Hemorrhagic Transformation1

The MRS score at 3 months was 2.74±1.83. The relative contribution of different variables for death and severe disability (MRS>2) at 3 months on univariate analysis are shown in Table 4. Proximal MCA occlusion (P=0.002), NIHSS score>14 on baseline (P<0.001), early signs of infarction on baseline CT (P<0.001), early neurological deterioration (P=0.019), and persistent occlusion on TCD at 48 hours (P<0.001) were significantly associated with poor clinical outcome. A logistic regression model was performed to determine independent predictors of poor outcome. NIHSS >14, early CT signs, persistent MCA occlusion, proximal MCA occlusion, early deterioration, diastolic blood pressure, serum glucose and history of diabetes entered into the model. Of these, only NIHSS score>14 (OR 14.1; 95% CI 3.2 to 59) emerged as independent risk factor for death and severe disability at 3 months (Table 5). In addition, the presence of HT appeared unrelated to clinical outcome at 3 months.

View this table: [in this window] [in a new window]   Table 4. Relative Contribution of Different Variables for Death and Severe Disability at 3 Months (MRS Score >2)

View this table: [in this window] [in a new window]   Table 5. Stepwise Logistic Regression With Dependent Variable: Death and Severe Disability at 3 months (MRS score >2)1

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
HT leading to clinical deterioration represents the main limitation for both intravenous and intra-arterial thrombolysis. Early hypodensity on CT, AF, high serum glucose levels, and delayed treatment have been shown to be associated with a higher risk of HT in patients receiving thrombolytic therapy.^{6 19 20 21 22} The time to artery reopening has been shown to be an important determinant of HT risk in rat models of cerebral ischemia. Unlike in animal models of acute thromboembolic stroke,^{4 5} the time to reperfusion has not been clearly demonstrated to increase hemorrhagic risk in nonselected acute stroke patients. Our study, performed in a highly selected and homogeneous stroke population, demonstrates that delayed recanalization, occurring >6 hours after symptom onset, independently predicts HT in patients with acute cardioembolic stroke, thus confirming the findings in experimental studies.

Previous studies^{2 23 24 25} in nonselected acute stroke patients have demonstrated that increasing age, hypertension, severity of initial neurological deficit, cardioembolic etiology of stroke, MCA main stem occlusion, and early focal hypodensity on CT were associated with an increased risk of HT. However, these studies did not consider a key variable, such as the systematic assessment of recanalization, at different time intervals after stroke and its contribution in HT risk.

Early (1 hour) administration of tissue plasminogen activator reduces infarct volume without increasing HT after focal embolization in rats.⁵ Furthermore, Fagan and Garcia⁴ observed that only 15% of rats that reperfused within 3 hours had HT at 18 to 24 hours compared with 84% of those that reperfused after 3 hours. Experimental studies²⁶ have shown a correlation between petechial hemorrhage and the loss of microvascular basal lamina/extracellular matrix antigens during the first 24 hours after MCA occlusion, which suggests blood extravasation. Similarly, the degree of capillary damage and endothelial tight junction disruption at 24 hours has been related to the severity and duration of initial ischemia.²⁷ In contrast to the growing evidence in animal models, in humans the relationship between recanalization and HT remains unclear. This may result from an incorrect appraisal of the mechanism of early bleeding into the infarcted area and its relationship with the time to artery reopening and clinical status at different times after stroke.

In our series, recanalization within 6 hours was not associated with hemorrhage. HT was seen in 46% and 20% of patients with delayed and no recanalization, respectively. These findings support the view that the duration of ischemia is associated with HT. Previous studies^{24 28 29} have demonstrated that a severe deficit in focal brain perfusion and absence of metabolic recovery, as measured by single-photon emission CT, predict a high risk of both secondary HT and adverse outcome in acute stroke patients. Furthermore, HT has been demonstrated to be localized in areas with a previous early hypodensity on CT.³⁰ In a recent diffusion-weighted MRI study,³¹ a low apparent diffusion coefficient value in ischemic lesions was associated with subsequent HT. These observations suggest that both duration and intensity of ischemia are important determinants in the development of HT.

The rate of early HT varies largely among clinical trials of thrombolysis in acute stroke,^{14 17 22 32 33} ranging from 5.6% to 19.8%. These studies did not monitor arterial occlusion and recanalization after thrombolysis. The timing of recanalization may be important to determine HT risk in patients receiving thrombolytic therapy. Delayed treatment leading to recanalization beyond the 6-hour time window may increase the risk of hemorrhage and may explain the observation that stroke patients treated with tissue plasminogen activator >5 hours after onset have the highest incidence of intracranial hemorrhage.²² However, whether delayed recanalization increases the risk of clinically relevant intracranial hemorrhage in patients receiving thrombolytics or anticoagulants requires further investigation. Although the overall rate of HT observed in our study appeared unrelated to clinical deterioration and outcome, the degree of neurological deterioration was significantly higher in patients with PH2. This finding is in agreement with a recent report³⁴ in which PH2 was the only subtype of HT that correlated with early neurological worsening and death and disability at 3 months. Therefore, clinical and experimental research should be focused on the prevention of this type of hemorrhage.

Compared with previous TCD studies,^{11 12 35} we performed TCD examinations at shorter time intervals to accurately identify when recanalization occurred. Our study supports a previous observation³⁶ that spontaneous recanalization in cardioembolic stroke occurs in the majority of patients within 48 hours (72% in our series) and mainly occurs between 6 and 12 hours (35.8%) after symptom onset. Moreover, two thirds of all delayed recanalizations occurred at 6 to 12 hours and 11 of 17 early HT (65%) occurred in patients who recanalized during the same time frame. These observations may reflect a type 2 error in view of the small number of patients who recanalized after 12 hours. Larger studies are needed to determine whether recanalization occurring at 6 to 12 hours represent a critical time interval that promotes HT.

Our study shows that clinical course and outcome are determined mainly by early CT findings and clinical status at baseline, respectively, and that delayed recanalization appears unrelated to early clinical course and long-term prognosis. This may be explained by no reperfusion after recanalization or by the observation that arterial recanalization can be more easily achieved in patients with occlusion of smaller arteries and better spontaneous prognosis³⁷

In conclusion, in patients with acute cardioembolic stroke, delayed spontaneous recanalization achieved beyond the 6-hour time window significantly increased the risk of hemorrhage. HT, with the exception of PH2, neither increased the proportion of patients with early deterioration nor affected clinical outcome at 3 months. Further studies are required to determine whether delayed recanalization increases the risk of clinically relevant HT in patients who receive thrombolytic therapy.

Received October 12, 2000; revision received November 29, 2000; accepted January 5, 2001.

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