Published online before print February 20, 2003, doi: 10.1161/01.STR.0000059430.55671.56
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(Stroke. 2003;34:820.)
© 2003 American Heart Association, Inc.
Controversies in Stroke |
Early Major Ischemic Changes on Computed Tomography Should Preclude Use of Tissue Plasminogen Activator
From the Department of Neuroradiology, University of Technology, Dresden, Germany.
Correspondence to Rüdiger von Kummer, MD, Technische Universität, Department of Neuroradiology, Fetscherstr 74, Dresden D-01307, Germany. E-mail kummer-r{at}rcs.urz.tu-dresden.de
Key Words: brain ischemia • computed tomography • tissue plasminogen activator
The rationale of tissue plasminogen activator (tPA) treatment is the restoration of blood supply to ischemic brain areas by clot lysis and subsequent arterial recanalization. With view to the high vulnerability of brain tissue, early restoration of blood supply will have a better chance of regaining neurological function than delayed restoration. Brain tissue survival is, however, clearly not guaranteed for 3 hours, the currently accepted time window for thrombolysis, if cerebral blood flow falls below 10 mL per 100 g x min. Under such conditions, it survives for not more than 15 to 30 minutes.1 Time is only one condition among others for the success of thrombolysis. This treatment will work if the clot is dissolvable by tPA, (containing fibrin, not calcified, small), if reperfusion is accelerated compared with the spontaneous course, and if reperfusion of the ischemic brain tissue will result in recovery of neurological function. Fortunately, stroke can have a beneficial spontaneous course, and no treatment is necessary. Conversely, stroke in others may be caused by conditions that cannot be treated with tPA. These conditions are arterial wall dissection or inflammation, arteriosclerotic stenosis, and long-standing extracranial carotid occlusion in combination with a drop in arterial blood pressure. Again, time may play a crucial role: arterial recanalization by 0.9 mg/kg tPA may be too slow and too late. Under unfortunate circumstances (eg, embolic occlusion of the distal internal carotid artery), the major portion of the affected arterial territory is already dead, when tPA treatment is initiated and when the agent achieves recanalization. Reperfusion of severely injured brain tissue may then further enhance ischemic edema.2
Methods are available that can more specifically identify the patients who may benefit from treatment with tPA than the often unreliable assessment-of-stroke-onset method. Computed tomography (CT) detects brain tissue water content and thus ischemic edema in stroke patients. Edematous ischemic brain tissue means irreversible injury from severe hypoperfusion.3 It is logical, then, to hypothesize that hypoattenuating brain tissue on CT represents irreversible ischemic injury that may be prone to further water uptake or hemorrhagic transformation in case of reperfusion. The risk from irreversibly injured brain tissue is associated with its extent. A patient may benefit from the recanalization of the middle cerebral artery (MCA) trunk, if only the basal ganglia are irreversibly injured, but the remaining portions of the MCA territory are still viable. This patient will not benefit from tPA treatment, if the entire MCA territory or major portions are already irreversibly injured when treatment is initiated irrespective of the time point.
Other CT findings such as brain tissue swelling or hyperdense segments of arteries indicating occlusion are not closely associated with brain tissue damage. From a pathophysiological point of view, it makes no sense to mix these findings with tissue hypoattenuation, then measure the extent of this mixture of early "CT changes" or "CT signs" and study whether the extent is associated with the response to tPA treatment.4
The hypothesis that the extent of hypoattenuating ischemic brain tissue is associated with poor prognosis and lack of benefit from tPA was first used for a careful selection of patients in ECASS and is now supported by clinical evidence: patients with MCA trunk occlusions and hypoattenuation of more than one half of the MCA territory had a mortality of 85%.5 Patients with hypoattenuating brain tissue in more than one third of the MCA territory did not benefit from tPA in ECASS I.6 In ECASS II, the extent of hypoattenuating brain tissue on baseline CT was identified as an independent risk factor for parenchymal hematoma.7 The quantitative grading of early CT findings in tPA treated patients showed a threshold beyond which the clinical outcome of patients was considerably impaired.8 A study of 1205 tPA-treated stroke patients identified "early ischemic CT changes, in particular if exceeding one third of the MCA territory" as an independent risk factor for symptomatic brain hemorrhage.9 In a recent analysis with re-evaluation of CT scans by a single observer, the risk for symptomatic hemorrhage was odds ratio (OR, 95% CI)=2.9 (0.3 to 32.4) in patients with hypodensity in >33% of the MCA territory and OR=1.5 (0.3 to 7.2) in patients with hypodensity in 
33% of the MCA compared with patients with normal early CT.4 These data demonstrate a low statistical power because only a few patients with hypodensity were identified. The CT reader in this study had a sensitivity of only 31% for early ischemic changes in contrast to a sensitivity of 75% in a comparable study.8
In summary, based on pathophysiological considerations and increasing evidence from clinical trials, "early major ischemic changes on CT" should preclude the use of tPA. Patients with ischemic edema as detected by CT as hypoattenuating brain tissue in the major portion of an arterial territory, or presenting >33% of the MCA territory, or >100 mL, or an ASPECTS <8, should not be treated with tPA, because a benefit of this treatment is not proven for these patients.
Footnotes
Section Editors: Geoffrey A. Donnan, MD, FRACP and Stephen M. Davis, MD, FRACP
The opinions expressed in this editorial are not necessarily those of the editors or of the American Stroke Association.
References
1. Heiss W, Rosner G. Functional recovery of cortical neurons as related to degree and duration of ischemia. Ann Neurol. 1983; 14: 294–301.[CrossRef][Medline] [Order article via Infotrieve]
2. Ito U, Ohno K, Nakamura R, Suganuma F, Inaba Y. Brain edema during ischemia and after restoration of blood flow: measurement of water, sodium, potassium content and plasma protein permeability. Stroke. 1979; 10: 542–547.
3. von Kummer R, Bourquain H, Bastianello S, Bozzao L, Manelfe C, Meier D, Hacke W. Early prediction of irreversible brain damage after ischemic stroke by computed tomography. Radiology. 2001; 219: 95–100.
4. Patel S, Levine S, Tilley B, Grotta J, Lu M, Frankel M, Haley E, Brott T, Broderick J, Horowitz S, et al. Lack of clinical significance of early ischemic changes on computed tomography in acute stroke. JAMA. 2001; 286: 2830–2838.
5. von Kummer R, Meyding-Lamadé U, Forsting M, Rosin L, Rieke K, Hacke W, Sartor K. Sensitivity and prognostic value of early computed tomography in middle cerebral artery trunk occlusion. AJNR Am J Neuroradiol. 1994; 15: 9–15.[Abstract]
6. von Kummer R, Allen K, Holle R, Bozzao L, Bastianello S, Manelfe C, Bluhmki E, Ringleb P, Meier D, Hacke W. Acute stroke: usefulness of early CT findings before thrombolytic therapy. Radiology. 1997; 205: 327–333.
7. Larrue V, von Kummer R, Müller A, Bluhmki E. Risk factors for severe hemorrhagic transformation in ischemic stroke patients treated with recombinant tissue plasminogen activator: a secondary analysis of the European-Australasian Acute Stroke Study (ECASS II). Stroke. 2001; 32: 438–441.
8. Barber P, Demchuk A, Zhang J, Buchan A. Validity and reliability of a quantitative computed tomography score in predicting outcome of hyperacute stroke before thrombolytic therapy. Lancet. 2000; 355: 1670–1674.[CrossRef][Medline] [Order article via Infotrieve]
9. Tanne D, Kasner S, Demchuk A, Koren-Morag N, Hanson S, Grond M, Levine S. Markers of increased risk of intracerebral hemorrhage after intravenous recombinant tissue plasminogen activator therapy for acute ischemic stroke in clinical practice. Circulation. 2002; 105: 1679–1685.
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