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(Stroke. 2002;33:1551.)
© 2002 American Heart Association, Inc.

Original Contributions

Thrombolysis-Related Hemorrhagic Infarction

A Marker of Early Reperfusion, Reduced Infarct Size, and Improved Outcome in Patients With Proximal Middle Cerebral Artery Occlusion

Carlos A. Molina, MD; José Alvarez-Sabín, MD; Joan Montaner, MD; Sonia Abilleira, MD; Juan F. Arenillas, MD; Pilar Coscojuela, MD; Francisco Romero, MD Agusti Codina, MD

From the Cerebrovascular Unit, Departments of Neurology (C.A.M., J.A.-S., J.M., S.A., J.F.A., A.C.) and Neuroradiology (P.C., 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 role of early and delayed recanalization after thrombolysis in the development of hemorrhagic transformation (HT) subtypes remains uncertain. We sought to explore the association between the timing of recanalization and HT risk in patients with proximal middle cerebral artery (MCA) occlusion treated with intravenous recombinant tissue plasminogen activator (rtPA) <3 hours of stroke onset and to investigate the relationship between HT subtypes, infarct volume, and outcome.

Methods— Thirty-two patients with acute stroke caused by proximal MCA occlusion treated with rtPA <3 hours of symptom onset were prospectively studied. Serial transcranial Doppler examinations were performed on admission and at 6, 12, 24, and 48 hours. Presence and type of HT were assessed on CT at 36 to 48 hours. Modified Rankin scale was used to assess outcome at 3 months.

Results— Early and delayed recanalization was identified in 17 patients (53.1%) and 8 patients (25%), respectively. HT was detected in 14 patients (43.7%): 4 (12.5%) with hemorrhagic infarction (HI₁), 5 (15.6%) with HI₂, 3 (9.3%) with parenchymal hematoma (PH₁), and 2 (6.8%) with PH₂. Distribution of HT subtypes differed significantly (P=0.025), depending on the time to artery reopening. Eight of 9 (89%), 1 of 5 (20%), and 8 of 18 (44.4%) with HI₁-HI₂, with PH₁-PH₂, and without HT, respectively, recanalized in <6 hours. Delayed recanalization was observed in 1 patient with HI₁-HI₂ (11%), 4 with PH₁-PH₂ (80%), and 3 without HT (16.6%). Neurological improvement was significantly (P<0.001) more frequent in patients with HI₁-HI₂ (88%) than in those without HT (39%). Infarct volume was significantly (P<0.031) lower in patients with HI₁-HI₂ (51.4±42 cm³) than in patients with PH₁-PH₂ (83.8±48 cm³) and those without HT (98.4±84 cm³, P=0.021). The modified Rankin scale score was significantly lower in HI₁-HI₂ compared with PH₁-PH₂ patients (1.9±1.1 versus 4.6±1.2, P<0.001) and with those without HT (1.9±1.1 versus 3.5±2.0, P=0.009.).

Conclusions— Thrombolysis-related HI (HI₁-HI₂) represents a marker of early successful recanalization, which leads to a reduced infarct size and improved clinical outcome.

Key Words: hemorrhage • reperfusion • thrombolysis • ultrasonography

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The National Institutes of Neurological Disorders (NINDS) trial¹ clearly demonstrated a beneficial effect of intravenous tissue plasminogen activator (rtPA) when given <3 hours after symptom onset. However, the beneficial effect obtained by thrombolysis-induced recanalization may be counteracted by an increased risk of hemorrhagic transformation (HT). The extent of radiologically defined HT varies widely, ranging from petechial hemorrhagic infarction (HI) to large parenchymal hematoma (PH) with mass effect. Prognostic implications of thrombolysis-related HT subtypes have previously been evaluated in nonselected stroke patients.^2–5 A posthoc analysis of the European Cooperative Acute Stroke Study (ECASS) I and II trials^3,4 confirmed the clinical observation that PHs were associated with early neurological deterioration and mortality. Conversely, a trend toward good neurological recovery at 24 hours was seen in patients showing HI,⁴ which suggests that HI may be a marker of early successful reperfusion. However, these studies were based on a heterogeneous group of patients with various stroke subtypes and different patterns of arterial occlusion and did not monitor recanalization at different times after stroke. In addition, the role of early and delayed reperfusion after thrombolysis in the development of HT subtypes has not yet been systematically evaluated. Therefore, we sought to explore the association between the timing of recanalization and HT risk in patients with proximal middle cerebral artery (MCA) occlusion treated with intravenous rtPA <3 hours after stroke onset and to investigate the relationship between HT subtypes, infarct volume, and long-term clinical outcome.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Our target group consisted of patients with acute ischemic stroke admitted within 3 hours of 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 with a nonlacunar stroke involving the vascular territory of the MCA were evaluated between March 2000 and October 2001. Of these, 138 (94.5%) underwent urgent carotid ultrasound and transcranial Doppler (TCD) examinations. Fifty-three patients (36.3%) had proximal MCA occlusion on TCD. We excluded those patients who were taking anticoagulants (n=4), those >85 years of age (n=8), those who experienced a dramatic spontaneous neurological improvement (n=1), and those who showed early signs of infarction of >33% of the MCA territory on baseline CT (n=8). Finally, 32 patients (21.9%) with acute stroke caused by proximal MCA occlusion received intravenous rtPA in a standard 0.9-mg/kg dose within 3 hours of symptom onset and 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. In patients with suspected cardioembolic stroke, anticoagulant therapy was started in the absence of HT on the second CT performed at 36 to 48 hours. 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 (<3 hours). To assess recanalization, follow-up recordings were also performed 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 with Multidopx4 equipment with a hand-held probe in a range-gated, pulsed-wave mode at a frequency of 2 MHz. Flow velocities of the MCAs, anterior cerebral arteries, and posterior cerebral arteries were bilaterally recorded with 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 anterior cerebral artery 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 posterior cerebral artery was detected at 65 mm as a signal directed toward the probe and traced from a depth of 60 to 70 mm. Doppler shifts from all arteries were recorded at 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 anterior cerebral and posterior cerebral arteries.⁶ Recanalization on follow-up TCD recordings was diagnosed when a dampened flow appeared in a previously demonstrated proximal MCA occlusion (partial recanalization) or when a previous absent, minimal, or dampened flow came within the normal range (complete recanalization).^6,7 The appearance of a low-resistance stenotic signal on follow-up was also considered complete recanalization.⁷ No change in the abnormal waveforms indicated that no recanalization had occurred.

CT Studies
On admission, all patients underwent a CT within the first 3 hours of stroke onset, which was repeated after 36 to 48 hours (or earlier when a rapid neurological deterioration occurred) and again between days 5 and 7. The presence of hyperdense MCA sign, early focal hypodensity, or swelling as a result of developing infarction on baseline CT was assessed according to ECASS criteria.^2,8 The extent of hypodensity or swelling resulting from acute ischemic edema on baseline CT was categorized as normal, <33% of the MCA territory, and >33% of the MCA territory.

The presence and type of HT were defined according to previously published criteria.^2,9,10 HI was defined as a petechial infarction without space-occupying effect, and PH was defined as hemorrhage with mass effect. HIs were categorized as HI₁ (small petechiae) or HI₂ (more confluent petechiae). PHs were also categorized as PH₁ when hematoma involved 30% of the infarcted area with some mild space-occupying effect and as PH₂ when hematoma involved >30% of the infarcted area with significant mass effect or clot remote from the infarcted area. Total infarct volume was measured by CT at day 5 to 7. We measured the ischemic lesion with and without HT using the formula for irregular volumes. In patients who died before day 5 to 7, the last available CT was used to measure infarct volume. CT scans were reviewed by a neuroradiologist with extensive experience in acute stroke who was blinded to the clinical and TCD details.

Clinical Assessment
We assessed clinical status at baseline and 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 video trained and certified for application of the NIHSS.¹¹ 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.¹ Complete recovery was defined as a decrease in the total NIHSS score to <3 at 48 hours.^1,12 An intracranial hemorrhage was considered as symptomatic (SICH) if the patient had clinical deterioration causing an increase of 4 points on the NIHSS and if the hemorrhage was likely to be the cause of neurological deterioration. Modified Rankin scale¹³ (MRS) was used to assess clinical outcome at 90 days. We defined good outcome as MRS score 2.

Statistical Analysis
Analyses were performed with SPSS 9.0 software (SPSS Inc). Statistical significance for intergroup differences was assessed by the 2-tailed Fisher’s exact test and ² test for categorical variables and the Kruskal-Wallis test and Student’s t test for continuous variables. Pearson’s coefficient was applied to verify correlation between examined variables. A receiver-operator characteristic curve was applied to determine a cut point of infarct volume that better distinguishes between favorable and unfavorable outcome. The probability of good outcome and independence 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

 
We studied a total of 32 patients (12 men, 20 women) with acute stroke resulting from proximal MCA occlusion treated with intravenous rtPA <3 hours of stroke onset. Demographic data, risk factor profile, and baseline clinical findings are shown in Table 1. The mean age was 68.4±10.1 years (range, 31 to 85 years). Fifty percent of patients were hypertensive, and 25% had a history of diabetes mellitus. The NIHSS score of the series on admission was 18.11±3.5 (range, 14 to 22). The time elapsed between symptom onset and drug administration was 157±34.1 minutes (range, 85 to 182 minutes). The door-to-needle time was 79.2±27.4 minutes (range, 51 to 123 minutes).

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 43 to 177 minutes (mean, 131.7±63.1 minutes). On baseline TCD assessment, proximal MCA occlusion was detected at a mean insonation depth of 54±5.2 mm. In 2 patients, carotid ultrasound also revealed a cervical carotid artery occlusion. Recanalization within 48 hours occurred in 25 patient (78.1%): 11 complete and 14 partial recanalizations. Early recanalization (at 6 hours) was identified in 17 patients (53.1%): 8 complete and 9 partial recanalizations. Delayed recanalization (>6 hours) occurred in 8 patients (25%): 3 complete and 5 partial recanalization. Five patients (15.6%) recanalized between 6 and 12 hours, 3 (9.3%) between 12 and 24 hours, and 0 between 24 to 48 hours after stroke onset. In 7 patients (21.8%), the MCA remained occluded at 48 hours.

The second CT was performed 39.4±6.5 hours after stroke onset. HT on CT was detected in 14 patients (43.7%). Distribution of HT subtypes occurring within the first 48 hours was as follows: HI₁ was identified in 4 patients (12.5%), HI₂ in 5 (15.6%), PH₁ in 3 (9.3%), and PH₂ in 2 (6.8%). HT was considered symptomatic (SICH) in 3 patients (9.3%; 1 PH₁ and 2 PH₂). HT was located in the deep MCA territory in 13 patients: 9 early and 4 delayed reperfused patients. In the remaining delayed-reperfusion patient, HT involved the superficial MCA territory. Figure 1 illustrates the time course of rtPA-induced recanalization according to the presence of HT within the first 48 hours. Nine patients (52.9%) who recanalized in <6 hours had HT. Moreover, 3 of 5 patients (60%) and 2 of 3 patients (66.6%) who recanalized between 6 and 12 hours and 12 and 24 hours, respectively, experienced HT. Although the presence of HT was unrelated to the time to reperfusion, distribution of HT subtypes differed significantly (P=0.025), depending on the time to artery reopening (Figure 2). Eight of 9 patients (89%), 1 of 5 (20%), and 8 of 18 (44.4%) with HI₁-HI₂, with PH₁-PH₂, and without HT, respectively, successfully recanalized <6 hours of stroke onset. Delayed recanalization was observed in 1 HI₁-HI₂ patient (11%), 4 PH₁-PH₂ patients (80%), and 3 patients without HT (16.6%). The 2 PH₂ instances occurred in a patients who recanalized between 6 and 12 hours. The presence of early signs of infarction on baseline CT (P=0.011) and recanalization achieved <24 hours of stroke onset (P=0.009) were significantly associated with the presence of HT on CT at 48 hours (Table 1).

View larger version (35K): [in this window] [in a new window]   Figure 1. Relationship between timing of recanalization and HT. Overall rate of HT appeared unrelated to time point of recanalization. NR indicates no recanalization.

View larger version (38K): [in this window] [in a new window]   Figure 2. Distribution of HT subtypes at 36 to 48 hours according to time to recanalization.

Clinical assessment revealed that 8 patients (25%) worsened, 16 (50%) improved, and 8 (25%) remained stable during the first 48 hours of admission. Neurological improvement was significantly (P<0.001) more frequent in patients with HI₁-HI₂ (88%) than in those without HT (39%). Figure 3 illustrates the changes in NIHSS score at 48 hours according to the presence and type of HT. Detection of HI₁-HI₂ on CT at 48 hours was significantly associated with a greater decrease (P=0.005, Kruskal-Wallis test) in NIHSS score compared with each of the other categories. Complete recovery was seen in 4 patients (12.5%). Two HI₁-HI₂ patients (22%) and 2 of 18 without HT (11%) completely recovered at 48 hours.

View larger version (14K): [in this window] [in a new window]   Figure 3. Changes in NIHSS score between baseline and 48-hour assessment according to presence and type of HT. Hemorrhagic infarction (H1-H2) was significantly associated with a greater decrease (P=0.005 by Kruskal-Wallis test) in NIHSS score compared with each of the other categories.

The mean infarct volume as measured on CT at day 5 to 7 was 83.5±72.3 cm³. The infarct volume was significantly (P<0.031) lower in patients who showed HI₁-HI₂ (51.4±42 cm³) than in patients with PH₁-PH₂ (83.8±48 cm³) and those without HT (98.4±84 cm³, P=0.021). Infarct volume was 33.1±28.4 cm³ in patients who completely recanalized at 6 hours, 40.6±38.1 cm³ in those who partially recanalized, and 129±72.2 cm³ in patients with persisting MCA occlusion at 6 hours (P=0.002, Kruskal-Wallis test).

The MRS score at 3 months was 3.2±1.81. The MRS score was significantly lower in HI₁-HI₂ patients than PH₁-PH₂ patients (1.9±1.1 versus 4.6±1.2, P<0.001) and those without HT (1.9±1.1 versus 3.5±2.0, P=0.009.). Seven of 9 patients (77.7%), 0 of 5, and 6 of 18 (33.3%) with HI₁-HI₂, with PH₁-PH₂, and without HT, respectively, became functionally independent (MRS 2) at 3 months (P=0.011). Among patients who recanalized in <6 hours, a trend (P=0.086) toward a better long-term outcome was found in patients showing HI₁-HI₂ (MRS score, 1.7±0.7) compared with patients without HT (MRS score, 2.6±2.1). Furthermore, there was good correlation between infarct volume and MRS at 3 months (r=0.64, P<0.001, Pearson’s coefficient). A receiver-operator characteristic curve provided a cut point of 38.6 cm³ (sensitivity, 73%; specificity, 72%) as the value of infarct volume that better distinguishes between favorable and unfavorable outcome. The relative contribution of different variables for good outcome and independence at 3 months in univariate analysis is shown in Table 2. Absence of coronary heart disease (P=0.039), infarct volume <38 cm³ (P=0.025), HI on CT at 36 to 48 hours (P=0.029), and early (<6 hours) recanalization (P<0.004) were significantly associated with good outcome and independence. Of these, only early recanalization (odds ratio, 10.9; 95% confidence interval, 1.7 to 69.9; P=0.001) emerged as an independent predictor of good outcome and independence at 3 months through the use of a multiple logistic regression model.

View this table: [in this window] [in a new window]   Table 2. Relative Contribution of Different Variables for Good Outcome and Independence (MRS 2) at 3 Months

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The present study demonstrates in highly selected and homogeneous stroke patients with proximal MCA occlusion that although the occurrence of HT of any type is unrelated to the time point of recanalization, distribution of HT subtypes differs significantly, depending on the time to reperfusion. HI₁-HI₂ represents a marker of early successful recanalization, which leads to a reduced infarct size and improved clinical outcome. Conversely, delayed recanalization (>6 hours) was associated with an increased risk of PH.

HT of cerebral infarction is considered a drawback and generally assumed to be a major concern after thrombolytic therapy for acute stroke. Risk factors for HT after thrombolysis include increased age, the presence of early signs of infarction on baseline CT, severity of neurological deficit, and hyperglycemia and high blood pressure at baseline.^14–16 However, the contribution of early and delayed recanalization after thrombolysis to the risk of HT remains uncertain.

The phenomenon of reperfusion hemorrhage as a result of clot lysis and recirculation into an ischemic and abnormally permeable vascular bed has been thought to be one of the mechanisms of HT after brain embolism.¹⁷ The timing of arterial recanalization has been shown to be an important determinant of the risk of HT in animal models of acute stroke,^18,19 in which delayed recanalization has been associated with the presence of HT at 24 hours. Recently, delayed spontaneous recanalization occurring >6 hours of stroke onset has been shown to be associated with an increased risk of HT.²⁰ In contrast, in the present study, the occurrence of HT of any type in patients receiving rtPA <3 hours was unrelated to the time point of recanalization. These results may be explained in part by differences in the timing of spontaneous or rtPA-induced recanalization. Unlike spontaneous recanalization,²⁰ early reperfusion is a common event after thrombolysis, occurring in up to 66% of rtPA-treated patients,^21,22 which eventually leads to reperfusion hemorrhage into areas of irreversible damage. This is supported by recent diffusion-weighted and perfusion-weighted imaging studies in which thrombolysis-induced HT appeared earlier than that which occurs spontaneously.^23,24

Our study demonstrates that distribution of HT subtypes differs markedly, depending on the time to artery reopening. It has been hypothesized that the difference between symptomatic and asymptomatic hemorrhage may be related more to the degree of bleeding than to differences in pathophysiology.^25,26 The amount of hemorrhage after reperfusion may reflect the degree of blood-brain barrier breakdown. We hypothesize that early successful recanalization reestablishes brain perfusion and may rescue still viable ischemic tissue despite the development of some petechial hemorrhages into a relatively small core of irreversible brain damage. Conversely, after several hours of persistent occlusion, the severity and extent of blood-brain barrier disruption yield to a large hemorrhage after reperfusion, which grows enough to counteract the beneficial effect of reperfusion, leading to clinical worsening. This may explain the observation that delayed treatment (>5 hours) is associated with the highest risk of SICH.²⁷ Furthermore, in the Prolyse in Acute Cerebral Thromboembolism (PROACT) II trial,²⁸ the mean time to the onset of intracranial hemorrhage symptoms was 10 hours, suggesting that delayed recanalization may play an important role in the pathogenesis of SICH in patients with MCA occlusion receiving thrombolytic therapy.

The present study underscores the importance of early CT signs of infarction in predicting the risk of HT in patients receiving intravenous rtPA. Several thrombolytic studies have reported that regions of early hypodensity and cerebral edema on CT and lack of metabolic recovery on single-photon emission CT are associated with an increased hemorrhagic risk.^29–32 In patients with angiographically proven MCA trunk occlusion, early CT signs in deep MCA territories have been reported as early as 1 hour after stroke onset, increasing up to 100% during the first 2 hours.³³ Thus, reperfusion therapy for patients with MCA trunk occlusion may be associated with a high risk of bleeding.^34,35 In our study, early CT signs were detected in 68% of patients, and all but 1 HT occurred in the areas of preceding ischemic changes. Moreover, among patients with early CT signs, HT was present in all patients who recanalized in <24 hours, suggesting that the relevance of early CT changes in predicting HT risk may be linked to the occurrence of recanalization. Therefore, a multimodal approach by combining information on both early CT signs and time to reperfusion may better estimate HT risk in patients receiving thrombolytic therapy.

Prognostic implications of HT may depend on the extent of bleeding seen on CT. Both experimental³⁶ and clinical^1–3,16 data indicate that hemorrhage volume significantly increases after rtPA treatment. The ECASS I and II trials^4,5 demonstrated that only the presence PH₂ independently modifies the risk of a worse outcome and that PH₁ increases the risk of early deterioration but not of a worse long-term outcome. Conversely, among patients receiving rtPA, HI tended to be associated with early neurological improvement.⁵ Furthermore, among patients with HI, those receiving placebo had a higher risk of poor outcome than those treated with rtPA,¹⁶ suggesting that rtPA may benefit some patients despite minor degrees of HT. Our results support these observations and add that HI (HI₁-HI₂) represents a surrogate marker of early successful reperfusion and good clinical outcome in patients receiving rtPA.

Our study shows results that are diametrically opposed to those of previous studies,^37,38 which concluded that HI is often a proxy for large infarction and poor outcome. The underlying mechanism and clinical meaning of HI may differ, depending on whether it appears within the first few days or later after stroke. Early (<48 hours) HI may indicate that recanalization occurred when the ischemic tissue was still at least partially viable. In contrast, HI detected later but not in the early stage may reflect persisting arterial occlusion with reperfusion via collateral flow or very delayed recanalization, both of which have been associated with larger infarction and worse clinical outcome.^21,39

In conclusion, in patients with proximal MCA occlusion treated with intravenous rtPA, the distribution of HT subtypes differs significantly, depending on the time to reperfusion. HI₁-HI₂ represents a marker of early successful recanalization, which leads to a reduced infarct size and improved clinical outcome. Treatment with rtPA may benefit some severe stroke patients despite minor degrees of HT. Larger studies are required to confirm the association between delayed recanalization (>6 hours) and increased risk of PH after thrombolytic therapy.

Received January 30, 2002; revision received February 19, 2002; accepted February 20, 2002.

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