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Stroke. 1996;27:1524-1529

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(Stroke. 1996;27:1524-1529.)
© 1996 American Heart Association, Inc.

Articles

Streptokinase Increases Luxury Perfusion After Stroke

Bernard Infeld, MBBS, FRACP; Stephen M. Davis, MD, FRACP; Geoffrey A. Donnan, MD, FRACP; Meir Lichtenstein, MBBS, FRACP; Alison E. Baird, MBBS; David Binns, DipAppSci; Peter J. Mitchell, MBBS, FRACR John L. Hopper, PhD

the Departments of Neurology (B.I., S.M.D.), Nuclear Medicine (M.L., D.B.), and Radiology (P.J.M.), Royal Melbourne Hospital; Department of Neurology (G.A.D., A.E.B.), Austin Hospital; and the Department of Public Health and Community Medicine, University of Melbourne (J.L.H.); Melbourne, Australia.


*    Abstract
up arrowTop
 *Abstract
down arrowIntroduction
 down arrowSubjects and Methods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Background and Purpose Recent acute stroke trials have reported that intravenous streptokinase is associated with an increased risk of adverse outcomes. We aimed to study the effect of streptokinase on the nature of reperfusion and the relation between reperfusion and clinical outcome.

Methods We studied 24 patients in the Australian Streptokinase Trial with acute middle cerebral cortical infarction using 99mTc–hexamethylpropyleneamine oxime single-photon emission CT. Eleven of the 24 patients were scanned before therapy and again 24 hours later. The remaining 13 were scanned once either before therapy (1 patient) or after therapy (12 patients). All patients had outcome scans after 3 months. Infarct hypoperfusion was measured with a validated volumetric technique. Neurological impairment and functional outcome were assessed with the Canadian Neurological Scale and the Barthel Index, respectively.

Results Fifteen patients received streptokinase and 9 received placebo. There was no difference in early reperfusion between streptokinase and placebo. However, streptokinase was associated with a greater amount of nonnutritional reperfusion than was placebo (P=.04). This luxury perfusion was associated with poor functional outcome (P=.02).

Conclusions This study suggests that streptokinase augments luxury perfusion after stroke. Luxury perfusion is associated with a worse outcome, which might be due in part to reperfusion injury.


Key Words: cerebrovascular disorders • reperfusion • streptokinase • thrombolytic therapy • tomography, emission computed


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowSubjects and Methods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Recently, several large placebo-controlled, randomized trials1 2 3 4 5 aimed at evaluating the efficacy and safety of intravenous thrombolysis have concluded. Early reports indicated that streptokinase is associated with increased mortality, which led to early termination of some trials.1 2 3 The European Cooperative Acute Stroke Study suggested benefits with the use of tissue plasminogen activator within 6 hours of stroke onset in patients without major signs of early infarction on the initial CT scan.4 Both thrombolytic agents were accompanied by an increased risk of cerebral hemorrhage. The timing of thrombolysis may, however, be critical since the NINDS trial found a benefit with the use of intravenous tissue plasminogen activator when treatment was begun within 3 hours of symptom onset, without an increase in mortality.5 The ASK trial also suggested a strong tendency for improved outcome and decreased adverse events in patients treated within 3 hours.1

Imaging with HMPAO SPECT is useful for evaluating reperfusion after thrombolysis.6 7 8 9 However, the relation between reperfusion and clinical gains is controversial. We have recently suggested that acute reperfusion measured by SPECT includes both nutritional and nonnutritional components.10 Nonnutritional reperfusion may be estimated as that proportion which does not persist at the chronic phase, when regional perfusion is matched to both metabolism and anatomic infarct size.11 12 Since none of the previous studies of reperfusion after thrombolysis have analyzed cerebral perfusion during the chronic phase, the contribution of luxury perfusion has not yet been examined.

In this study we aimed to study the effect of streptokinase on both early and late perfusion changes after acute stroke in a cohort of patients with MCA cortical infarction who were enrolled in ASK. We also planned to examine the relation between the nature of reperfusion and both clinical outcome and tissue loss. Given the findings of recent clinical trials, we then intended to evaluate whether treatment delay or the severity of hypoperfusion influenced reperfusion and whether nonnutritional reperfusion was associated with hemorrhagic transformation.


*    Subjects and Methods
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 *Subjects and Methods
down arrowResults
 down arrowDiscussion
 down arrowReferences
 
We prospectively studied 24 patients (15 men and 9 women; age range, 38 to 86 years; mean [SD] age, 65 [12] years) with acute MCA cortical infarction. They were enrolled in the double-blind, placebo-controlled, randomized ASK or its pilot phase. ASK involved 340 patients with anterior or posterior circulation cerebral infarction presenting within 4 hours of onset and having a score of less than or equal to 9 on the CNS (ie, moderate or severe neurological deficit).1 13 In this study we included only those with MCA cortical infarction who presented to either the Royal Melbourne Hospital or Austin Hospital and in whom it was possible to study CBF acutely and at outcome (after 3 months) with HMPAO SPECT. Hence, we have not included those patients who died before the outcome studies could be performed. This project was approved by the ethics committees of both hospitals; informed consent was obtained for all patients.

Diagnosis of MCA cortical infarction was made on the basis of (1) evidence of cortical infarction on the acute CT scan or (2) presence of cortical neurological deficits such as dysphasia, anosognosia, visual or sensory inattention, dyspraxia, or parietal sensory deficit. Exclusion criteria, in addition to those of ASK, were (1) previous cerebral pathology (infarction, hemorrhage, or tumor) interfering with assessment of CBF and (2) presence of other neurological, systemic, or psychiatric illness interfering with neurological or functional assessments.

Seventeen of the 24 received either intravenous streptokinase (1.5 million U over 1 hour) or placebo in ASK within 4 hours of symptom onset. Another 6 of the 24 patients were treated openly with intravenous streptokinase, according to the same protocol, during the pilot phase of ASK. The remaining patient received open treatment with intra-arterial streptokinase (intracarotid, 250 000 U over 30 minutes) 13 hours after stroke onset.14

Of the 23 patients treated intravenously, 11 were studied with HMPAO SPECT within 4 hours of stroke onset, before the administration of therapy (mean [SD], 3.2 [0.6] hours). Ten of these 11 were scanned again 24 hours after their first scan (24.5 [1.6] hours or 27.6 [1.6] hours after stroke onset). One of these 11 was unable to be scanned at 24 hours because she became medically unstable owing to the development of massive cerebral hemorrhage after therapy, which required neurosurgical evacuation. The single patient treated with intra-arterial streptokinase had a pretherapy SPECT scan 9 hours after stroke onset and a repeated scan 24 hours later (31 hours after onset). The remaining 12 of the 24 patients had their first SPECT scan after therapy, 30.0 (16.7) hours after stroke onset. All 24 patients had outcome SPECT scans at least 3 months after the ictus (mean, 7.7 [6.8] months, when neurological recovery had reached a plateau). None of the 24 patients suffered another stroke before follow-up. In 18 of the 24 patients, SPECT studies were acquired with a single-headed GE400AC Starcam gamma camera. In the other 6, studies were acquired with triple-headed systems, Siemens Multispect 3 in 5 and Trionix Triad in 1. For each patient, all SPECT scans were performed with the same camera.

Infarct hypoperfusion was measured with a volumetric technique, as previously described.15 This method, a modification of Mountz's technique,16 integrates both the size and severity of regional hypoperfusion and produces a volume measure (in cubic centimeters) corresponding to a hypothetical volume of tissue with zero perfusion; it has recently been validated in vitro with the use of a Hoffman brain phantom17 fitted with simulated cortical lesions. Infarct hypoperfusion analysis was performed with knowledge of the lateralization of the infarct but blinded to the clinical and radiological data.

Reperfusion was defined and calculated as follows: (1) Early perfusion change was defined as pretherapy hypoperfusion volume minus posttherapy (24 hours) hypoperfusion volume. Early reperfusion would be indicated by a decrease in hypoperfusion volume between these two stages. (2) Late perfusion change was defined as outcome (after 3 months) hypoperfusion volume minus posttherapy hypoperfusion volume. Late reperfusion would be indicated by a further decrease in hypoperfusion volume between the posttherapy and outcome stages. (3) Total perfusion change was defined as pretherapy hypoperfusion volume minus outcome hypoperfusion volume. A decrease in hypoperfusion volume between pretherapy and outcome stages would indicate overall reperfusion. According to these definitions, early perfusion change could be calculated only in those patients with both pretherapy and posttherapy SPECT scans. Late perfusion change could be calculated only in those with both posttherapy and outcome scans, whereas total reperfusion could be calculated only in those with both pretherapy and outcome scans.

Neurological impairment was assessed before therapy, after therapy, and at outcome concurrently with SPECT studies with a modified CNS (scored from 0 to 11.5).18 Functional disability was measured at outcome with the BI (scored from 0 to 20).19 Posttherapy CNS was not recorded in 2 patients who received streptokinase in the open trial.

All patients except 1 had CT scans at 7 to 10 days or as clinically indicated to detect hemorrhagic transformation. Hemorrhagic transformation on the subacute CT was graded by a neuroradiologist blinded to all clinical and CBF data as follows: nil, mild (petechial hemorrhage occupying <50% of the infarct), moderate (confluent but subtotal hemorrhage occupying >50% of the infarct), or frank hematoma (confluent hemorrhage within the entire infarct). Seventeen of the 24 patients had outcome CT scans on the same day as the outcome SPECT to assess tissue loss. This was measured volumetrically (in cubic centimeters), as previously described,20 by the same neuroradiologist blinded to the clinical and CBF results.

Differences in mean hypoperfusion volumes and in means of reperfusion variables between patient groups were assessed by unpaired Student's t tests. Differences in mean hypoperfusion volumes with time were analyzed by repeated measures ANOVA. Associations between reperfusion variables, hypoperfusion volumes, tissue loss, and clinical scores were evaluated by linear regression. The regression coefficient b, its standard error, and nominal probability values are presented. Findings were considered not significant at nominal P>.05.


*    Results
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 up arrowAbstract
 up arrowIntroduction
 up arrowSubjects and Methods
 *Results
down arrowDiscussion
 down arrowReferences
 
Of the 24 patients, 15 received streptokinase and 9 received placebo. We initially compared the baseline SPECT and clinical data between patients who had three SPECT scans and those who had only two. No significant differences were found. Furthermore, there were no significant differences in mean baseline SPECT and clinical data between those who received streptokinase and those who received placebo (TableDowns 1 and 2).


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  		Table 1. Reperfusion in 11 Patients Receiving Either Streptokinase or Placebo

To test whether the 24 patients in this study were different from the entire ASK population, we compared pretherapy CNS and outcome BI scores between the two groups. In the 24 patients studied, the mean±SE pretherapy CNS score was 5.6±0.5, whereas the mean outcome BI score was 15.8±1.1. These were not significantly different from the mean pretherapy CNS score in all ASK patients (4.9±0.1) or the mean outcome BI score in ASK survivors (15.2±0.4). In ASK, 78% of those enrolled had a hemispheric syndrome.

Effect of Streptokinase on Early and Late Perfusion Changes
In the 11 patients who had three SPECT scans, mean hypoperfusion volume decreased from 80.0±14.0 cm3 before therapy to 27.7±9.8 cm3 after therapy. Mean hypoperfusion volume then increased at outcome to 64.8±17.6 cm3 (Fig 1Down). This variation with time was not consistent with chance (P=.001). Hence, mean early perfusion change indicated reperfusion over the first 24 hours, whereas mean late perfusion change indicated increasing hypoperfusion between the outcome studies at 24 hours and after 3 months. Among these 11 patients, mean late perfusion change (indicating increasing hypoperfusion volume) was significant only in streptokinase-treated patients (P=.003) and was greater (P=.04) than in those who received placebo (Table 1Up). In contrast, mean total reperfusion was significant only in placebo-treated patients (P=.008) and was greater (P=.02) than in those who received streptokinase.



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  		Figure 1. Serial changes in mean±SE hypoperfusion volume in 11 patients who had three scans.

In the 23 patients who had both posttherapy and outcome SPECT scans, mean hypoperfusion volume increased from 25.25±5.63 cm3 after therapy to 49.80±9.61 cm3 at outcome (P=.003). The mean late perfusion change was 24.56±7.43 cm3 in the group overall (P=.001). Mean late perfusion change, indicating increasing hypoperfusion, was significant only in the streptokinase group (P=.001) and was greater (P=.05) than in the placebo group (Table 2Down).


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  		Table 2. Reperfusion According to Treatment in 23 Patients With Posttherapy and Outcome Scans

Relation Between Reperfusion and Clinical Gains
We initially examined the relation between early reperfusion and the variables outcome CNS, outcome BI, and tissue loss. There were no significant associations between early reperfusion and any outcome variables.

We then analyzed the relation between late perfusion change and each of the outcome variables. Late perfusion change correlated with poor outcome. It was associated negatively with outcome BI (b=-0.072±0.029, P=.02), positively with tissue loss (b=1.00±0.40, P=.02), and negatively, but only marginally, with outcome CNS (b=-0.032±0.016, P=.06) (Fig 2Down).



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  		Figure 2. Linear regression of each of the outcome variables BI (top), CNS (middle), and tissue loss (bottom) as a function of nonnutritional reperfusion.

Total reperfusion was associated with favorable clinical outcome. It was associated positively with outcome BI (b=0.11±0.05, P=.04), marginally with outcome CNS (b=0.053±0.028, P=.08), but not with tissue loss.

Effect of Hemorrhagic Transformation, Infarct Size, and Treatment Delay on Reperfusion
There were 8 patients who had any degree of hemorrhagic transformation detected on the subacute CT scan. Patients with hemorrhagic transformation had more late perfusion change (52.47±19.38 cm3) than those without any hemorrhagic transformation (12.01±4.52 cm3, P=.01). In addition, patients with hemorrhagic transformation had less total reperfusion (-8.69±5.62 cm3) than those without any hemorrhagic transformation (36.61±12.84 cm3, P=.009).

We examined the relation between pretherapy hypoperfusion volume and late perfusion change and found a strong association for all patients (b=0.51±0.11, P=.001). This positive effect of pretherapy hypoperfusion volume on late perfusion change was even stronger in streptokinase-treated patients (b=0.70±0.11, P<.001).

We next analyzed the effect of treatment delay on total reperfusion in patients treated with streptokinase. After allowing for variations in pretherapy hypoperfusion volume and early reperfusion, we found that earlier treatment correlated with improved total reperfusion (b=-31.12±5.89, P=.03).


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowSubjects and Methods
 up arrowResults
 *Discussion
down arrowReferences
 
The serial perfusion changes seen in our study of ischemic stroke are consistent with previous serial studies of perfusion and metabolism with positron emission tomography.11 12 21 22 These demonstrate that regional perfusion is initially reduced to a greater extent than regional metabolism. This is followed, within 12 to 24 hours, by a period of overabundant perfusion relative to metabolic needs, consistent with Lassen's luxury perfusion syndrome.23 In the chronic phase, regional perfusion decreases again, while regional oxygen extraction ratio returns to normal.

This study demonstrated significant early reperfusion after ischemic stroke. The late perfusion change, however, indicated a significant increase in hypoperfusion rather than further reperfusion. This is best explained by nonnutritional reperfusion, or luxury perfusion, present during early reperfusion but not maintained at outcome. Conversely, the proportion of early reperfusion that is maintained (total reperfusion) reflects nutritional reperfusion (Fig 3Down). Therefore, early reperfusion on SPECT consists of nutritional and nonnutritional components that can only be distinguished retrospectively. Previous SPECT studies by our group10 15 and others24 25 26 27 28 29 have demonstrated a trend to reperfusion over the first 72 hours after stroke without accompanying clinical gains, which is not maintained at the chronic stage. Furthermore, outcome hypoperfusion matches anatomic infarct size, indicating that the observed increase in hypoperfusion at outcome is not due to either diaschisis or ischemia.11 12 Examples of nonnutritional and nutritional reperfusion are shown in Figs 4 and 5DownDown, respectively.



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  		Figure 3. Hypoperfusion volumes at pretherapy, posttherapy, and outcome stages. The proportion of acute reperfusion that is maintained at outcome is nutritional, whereas the proportion that is not maintained is largely nonnutritional.



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  		Figure 4. Nonnutritional reperfusion. Serial SPECT scans of a patient with right MCA cortical infarction showing reperfusion after therapy that is not accompanied by clinical gains or maintained at the outcome stage. This reperfusion is therefore nonnutritional in nature.



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  		Figure 5. Nutritional reperfusion. Serial SPECT scans of a patient with right MCA cortical infarction showing reperfusion after therapy, accompanied by clinical improvement and maintained at outcome. This reperfusion is therefore nutritional in nature.

Another possible explanation for the perfusion changes observed in our study could be early arterial recanalization and nutritional reperfusion followed by arterial reocclusion. Angiographic studies have reported that recanalization of occluded arteries with intravenous thrombolytic therapy occurs in only approximately one third of treated patients.30 31 32 33 Little is known, however, about the rate of subsequent reocclusion.31 Early reperfusion after thrombolysis was not accompanied by clinical gains in the present study. In addition, none of our patients had a clinical deterioration after therapy, except for the one patient who had a massive cerebral hemorrhage. This suggests that nonnutritional reperfusion or luxury perfusion is a more likely explanation.

Nonnutritional reperfusion appears to explain the differing results regarding the relation between reperfusion and clinical outcome after thrombolysis in previous studies with HMPAO SPECT.6 7 8 9 Although streptokinase was associated with increased nonnutritional reperfusion in this study, the nutritional component correlated with improved outcome. This study demonstrates the importance of outcome studies when HMPAO SPECT is used to evaluate reperfusion after therapy.

We were only able to study a small number of patients in ASK owing to early termination of the trial. Only patients with MCA cortical infarction were included in the present study because this stroke subtype is readily visualized with SPECT.34 35 36 37 Furthermore, we restricted the present analysis to surviving patients so that we could test our hypothesis that acute reperfusion could be retrospectively divided into nutritional and nonnutritional components. In fact, based on initial clinical severity and final outcome, the patients in this study were no different from the overall ASK population. Hence, we believe that our results pertain to the overall trial and do not reflect any selection bias.

This study sheds light on important conclusions reached by the recent intravenous thrombolytic stroke trials. First, in this study streptokinase did not increase early reperfusion after stroke in comparison to control patients. Streptokinase was, however, associated with increased nonnutritional reperfusion, which in turn correlated with poor outcome. Hence, the increased risk of hemorrhagic transformation and cerebral edema associated with intravenous thrombolysis1 2 3 4 may in part reflect reperfusion injury. Neuronal death after cerebral ischemia is due not only to the direct effects of energy failure but also to multiple postischemic metabolic processes.38 39 40 Reperfusion can further exacerbate ischemic injury by augmenting these metabolic derangements.39 40 41 Luxury perfusion, observed in this study, was associated with hemorrhagic transformation and therefore may signify reperfusion injury.

Second, in the present study there was a linear relation between the severity of pretherapy hypoperfusion and nonnutritional reperfusion, especially in those patients who received streptokinase. Reperfusion injury might also explain why patients with established or large infarcts have a tendency to develop cerebral edema or hemorrhage after thrombolysis, resulting in poor outcome.4 8 42 43 44

Third, this study suggests that earlier treatment with streptokinase was associated with a greater degree of nutritional reperfusion, which correlated with better outcome. This observation supports the concept of the "therapeutic window" and the dynamic penumbra, which has the potential for recovery but which is progressively recruited into the core of irreversible infarction.38 39 45 This might explain why both the ASK and NINDS trials found improved outcome in patients who received thrombolysis within 3 hours of stroke onset.1 5 This study suggests that the efficacy and adverse effects of thrombolysis relate to the balance between nutritional and nonnutritional reperfusion. This balance in turn relates to the timing of thrombolysis and initial stroke severity.


*    Selected Abbreviations and Acronyms
 
ASK = Australian Streptokinase Trial
BI = Barthel Index
CBF = cerebral blood flow
CNS = Canadian Neurological Scale
HMPAO = 99mTc–hexamethylpropyleneamine oxime
MCA = middle cerebral artery
NINDS = National Institute of Neurological Disorders and Stroke
SPECT = single-photon emission computed tomography


*    Acknowledgments
 
This study was supported by the National Health and Medical Research Council and the Australian Stroke and Neuroscience Institute.


*    Footnotes
 
Reprint requests to Stephen M. Davis, MD, FRACP, Department of Neurology, Royal Melbourne Hospital, Victoria 3050, Australia. E-mail bernardi@neuro.medrmh.unimelb.edu.au.

Presented in part at the Third International Conference on Stroke, Prague, Czech Republic, October 18-21, 1995, and at the Annual Scientific Meeting of the Stroke Society of Australasia, Melbourne, Australia, October 4-6, 1995.

Received January 18, 1996; revision received May 15, 1996; accepted May 15, 1996.


*    References
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowSubjects and Methods
 up arrowResults
 up arrowDiscussion
 *References
 

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