Neurosurgical Clinic, University of Essen, Germany Neurosurgery 30; 877-881, 1992 ABSTRACT: Intracisternal thrombolysis with recombinant tissue plasminogen activator (rtPA) was performed in 20 patients with aneurysmal subarachnoid hemorrhage. All patients had blood accumulations in the basal cisterns according to Fisher's Grade III, thus being at a high risk for the development of posthemorrhagic delayed ischemic deficits (DID). All patients underwent an operation within 72 hours after aneurysm rupture. After the aneurysm had been excluded from the cerebral circulation, a single bolus of 10 mg of rtPA was injected into the basal cisterns. Postoperatively, serial computed tomographic examinations demonstrated radical blood clot removal in all patients. Daily transcranial Doppler examinations revealed accelerated blood flow velocities in 16 of 20 patients. The postoperative results according to the Glasgow Outcome Scale were as follows: 16 patients were Grades I and II, 2 patients were Grade III. Two patients died postoperatively, 1 because of a bowel perforation, and 1 from DID attributable to the development of a cerebral vasospasm. No postoperative bleeding complications occured. It is concluded that pharmacological removal of subarachnoid blood accumulations can be achieved in a safe and effective way by an intrathecal single bolus of 10 mg of rtPA instilled into the basal cisterns after aneurysm clipping. The acceleration of blood flow velocities in a number of patients indicated that posthemorrhagic arterial narrowing was not completely prevented by this treatment, but this remained asymptomatic in 19 of 20 patients. Although extensive blood clot removal can be achieved by a single bolus of rtPA, more radical or complete blood removal probably requires the use of higher drug concentrations or additional postoperative intracisternal or intraventricular rtPA injections, for which further studies are needed. Although the occurrence of cerebral vasospasm and DID was not completely prevented by rtPA application, the low incidence of DID in a group of patients with a high probability of perioperative vasospasm resulting from high intracisternal blood volumes is promising. KEY WORDS: Cerebral vasospasm; Intrathecal thrombolysis; Recombinant tissue plasminogen activator;

INTRODUCTION Experimental and clinical studies on the pathogenesis of posthemorrhagic arterial narrowing after aneurysmal subarachnoid hemorrhage (SAH) have clearly established the relationship between the amount of blood in the basal cisterns, the generation and release of spasmogenic metabolites, and the incidence and severity of cerebral vasospasm (6,7,15,23, 29) . The surgical removal of these subarachnoid blood accumulations has proven effective, both experimentally and clinically, in preventing the onset of vasospasm (9,17-19,26). Possible damage to vital perforating vessels, prolongation of operating time, and incomplete blood clot removal are well known, however, and are substantial drawbacks to aggressive attempts at mechanical clot removal during aneurysm surgery. Recent extensive experimental studies by two independent research groups have shown that the pharmacological removal of blood accumulation in the basal cisterns, by means of early iatrogenic thrombolysis, is possible in a safe and effective manner by the intracisternal application of the recently developed fibrinolytic substance recombinant tissue plasminogen activator (rtPA) (2,4, 5,24) . These experimental investigations have paved the way for the clinical application of rtPA in patients with aneurysmal SAH in order to prevent cerebral vasospasm. In this report, we describe our preliminary experience concerning the feasibility, safety, and efficacy of intracisternal rtPA injection in patients with aneurysm rupture, who, according to the extent of intracisternal blood accumulations (Fisher Grade III) (6), can be considered to be at a high risk for the development of cerebral vasospasm. PATIENTS AND METHODS The study consists of 20 patients with aneurysmal SAH who were randomly assigned to the following study protocol. All patients were admitted and underwent surgery within 72 hours after aneurysm rupture. Patients were examined after arrival in the hospital and were classified according to the Hunt and Hess grading scale (11). SAH was confirmed by computerized tomography (CT), and the amount of blood accumulation detectable in the basal cisterns was graded according to the Fisher scale (6). Only patients according to Fisher's Grade III were included into the study, because these patients have the highest probability for the development of cerebral vasospasm. No patients with intraparenchymal hemorrhage were included into the treatment protocol. After the diagnosis of SAH had been established, four-vessel angiography was performed and the aneurysm was clipped within 72 hours by routine microsurgical techniques. No attempts at radical mechanical intraoperative blood clot removal were undertaken. After complete exclusion of the aneurysm from the cerebral circulation, 10 mg of rtPA dissolved in an equivalent volume of physiological saline was injected into the basal cisterns before closure of the dura. During the

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AUTHOR(S): Stolke, Dietmar, M.D.; Seifert, Volker, M.D.

Subarachnoid hemorrhage

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Neurosurgery 1992-98 June 1992, Volume 30, Number 6 877 Single Intracisternal Bolus of Recombinant Tissue Plasminogen Activator in Patients with Aneurysmal Subarachnoid Hemorrhage: Preliminary Assessment of Efficacy and Safety in an Open Clinical Study Experimental and Clinical Study

DISCUSSION There is now considerable material derived from experimental and clinical studies, which clearly demonstrates the relationship between the amount of blood accumulated within the basal cisterns after aneurysmal SAH and the development of DID induced by cerebral vasospasm. During posthemorrhagic lysis of erythrocytes and other blood elements located in the subarachnoid blood accumulation, complicated, and to date only partially understood, pathobiochemical changes are triggered, resulting in the generation of highly potent vasoactive substances, such as free radicals, lipid peroxides, prostaglandins, and leukotrienes, to which the cerebral vessels are exposed (8,20,22,23,27). Provided that the aneurysm has been securely excluded from the cerebral circulation, it would be most desirable to remove these intracisternal blood accumulations, and with them the mass of hemolysing erythrocytes, in order to prevent the generation and liberation of spasmogenic metabolites. Consequently, the surgical removal of intracisternal blood clots to a more or less radical

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RESULTS The ages of the patients ranged from 25 to 76 years (mean age, 49.8 yr). The group consisted of 14 women and 6 men. The locations of the 20 aneurysms were as follows: carotid artery, 10; middle cerebral artery, 4; anterior communicating artery, 2; and basilar artery, 4. The outcomes, according to the Glasgow Outcome Scale at 6 months postoperatively, were as follows. Sixteen patients were in Grades I and II, 2 patients were in Grade III, and 2 patients had died postoperatively, 1 because of a perforation of the bowel and 1 from delayed ischemic deficits (DID) attributable to the development of a cerebral vasospasm. Of the 4 patients who either had an unsatisfactory postoperative result (Grade III on the Glasgow Outcome Scale) or had died, 1 patient was preoperatively Grade II Hunt and Hess, 2 were Grade III, and 1 was Grade IV. Postoperative CT scans demonstrated extensive to complete removal of subarachnoid blood accumulation, usually within 3 days postoperatively in all patients (Figs. 1 and 2). Transcranial Doppler examinations (middle cerebral artery, depth, 55 mm; normal maximal blood flow velocity 150 cm/s, middle cerebral artery) degrees in 16 of 20 patients. In none of the patients did postoperative complications attributable to the intracisternal injection of rtPA develop.

extent has been performed routinely by most neurosurgeons during the course of aneurysm surgery. Apart from being effective for only a relatively short time, however, this procedure has distinct drawbacks including prolongation of operating time, potential injury to perforating vessels, and incomplete blood clot removal. Because of these potential hazards of intraoperative surgical blood removal, interest in alternative ways of pharmacological evacuation of intracisternal blood accumulation has been stimulated. Starting with the early work of Kennady in 1967 (14), different fibrinolytic agents including streptokinase, urokinase, and plasmin have been injected into the subarachnoid space and used successfully for the lysis of experimentally placed blood clots in animals. Investigators from Japan have used a combination of urokinase dissolved in artificial cerebrospinal fluid for posthemorrhagic blood clot removal in patients with aneurysmal SAH (1,5,26,28). Recently, the new "second generation" fibrinolytic substance rtPA has been introduced (3,10,16,21) and used successfully for the prevention of posthemorrhagic vasospasm in experimental studies performed by two independent research groups (2,4,5,24). Additional studies have proven the safety of rtPA when injected either intrathecally or intracerebral in experimental animals (5,13). On the basis of these experimental investigations, the decision was made to apply intrathecal thrombolytic therapy with rtPA in the clinical setting. In order to evaluate the efficacy of rtPA it was decided to include into the study only patients with massive intracisternal blood accumulations according to Fisher's Grade III, because these patients are the most likely to develop cerebral vasospasm and DID perioperatively. The amazing ability of rtPA to remove intracisternal blood accumulations radically, which has already been reported by us (25), was demonstrated again in this extended clinical study. After a single bolus of 10 mg of rtPA, follow-up CT scans during the postoperative period revealed radical blood clot disappearance in all patients. According to the judgment of both surgeons, the intracisternal application of rtPA did not cause any bleeding problems during the intracranial surgical procedure. Additionally, no intracerebral or extracerebral hemorrhage occurred during the postoperative period. Despite the striking blood clearing effect of the intrathecal rtPA application, accelerated blood flow velocities in the transcranial Doppler examination were demonstrable in 16 of 20 patients, although only 5 patients developed an extensive acceleration of flow velocities. In 19 patients, no clinical signs of delayed ischemic deficits occurred during the postoperative course. One patient with an anterior communicating artery aneurysm, after an apparently uncomplicated clipping procedure, developed progressive neurological deterioration within 2 days operatively, accompanied by an extensive acceleration of blood flow velocity in all basal cerebral vessels. Despite induced hypertension and hypervolemia, the patient developed severe ischemia

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postoperative period, all patients were examined neurologically on a daily basis. Additional daily transcranial Doppler examinations were performed. CT scans were performed on Days 1, 2, 5, and 10 postoperatively. All surviving patients were examined at the time of discharge and at 3 months postoperatively and were categorized according to the Glasgow Outcome Scale (12).

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Received for publication, July 17, 1991; accepted, final form, November 15, 1991. Reprint requests: Dietmar Stolke, M.D., Neurochirurgische Klinik, Universitätsklinikum, Hufelandstraβe 55 D-4300 Essen, Germany. REFERENCES: (1-29) 1.

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ADDENDUM Since the submission of the manuscript, the following articles on the topic of intrathecal rtPA application have appeared. Findlay JM, Weir BKA, Kassell NF, Disney LB, Grace MGA: Intracisternal recombinant tissue plasminogen activator after aneurysmal subarachnoid hemorrhage. J Neurosurg 75:181-188, 1991. Öhman J, Servo A, Heiskanen O: Effect of intrathecal fibrinolytic therapy on clot lysis and vasospasm in patients with aneurysmal subarachnoid hemorrhage. J Neurosurg 75:197-201, 1991. Zabramski JM, Spetzler RF, Lee KS, Papadopoulos SM, Bovill E, Zimmerman RS, Bederson JB: Phase I trial of tissue plasminogen activator for the prevention of vasospasm in patients with aneurysmal subarachnoid hemorrhage. J Neurosurg 75:189-196, 1991.

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jugular vein model as efficient as continuous infusion. J Cell Biochem 11 [Suppl]:184, 1987. Findlay JM, Weir BKA, Steinke D, Tanabe T, Gordon P, Grace P: Effect of intrathecal thrombolytic therapy on subarachnoid clot and chronic vasospasm in a primate model of SAH. J Neurosurg 69:723-735, 1988. Findlay JM, Weir BKA, Kanamaru K, Grace M, Gordon P, Baughman R, Howarth A: Intrathecal fibrinolytic therapy after subarachnoid hemorrhage: Dosage study in a primate model and review of the literature. Can J Neurol Sci 16:28-40, 1989. Fisher CM, Kistler JP, Davis JM: Relation of cerebral vasospasm to subarachnoid hemorrhage visualized by computerized tomographic scanning. Neurosurgery 6:1-9, 1980. Fraser J, Johnson S, Ray M, Robertson JT: Prediction of cerebral vasospasm with subarachnoid hemorrhage due to ruptured intracranial aneurysm by computerized tomography. Neurosurgery 6:686-687, 1980. Fujii S, Fujitsu K: Experimental vasospasm in cultured arterial smooth-muscle cells. Part 1: Contractile and ultrastructural changes caused by oxyhemoglobin. J Neurosurg 69:92-97, 1988. Handa Y, Weir BKA, Nosko M, Mosewich R, Tsuji T, Grace M: The effect of timing of clot removal on chronic vasospasm in a primate model. J Neurosurg 67:558-564, 1987. Hoylaerts M, Rijken DC, Lijnen HR, Collen D: Kinetics of activation of plasminogen by human plasminogen activator. Role of fibrin. J Biol Chem 257:2912-2919, 1982. Hunt WE, Hess RM: Surgical risk as related to time of intervention in the repair of intracranial aneurysm. J Neurosurg 28:14-19, 1968. Jennett B, Bond M: Assessment of outcome after severe brain damage. Lancet 1:480-484, 1975. Kaufman HH, Schochet S, Koss W, Herschberger RN, Bernstein D: Efficacy and safety of tissue plasminogen activator. Neurosurgery 20:403-407, 1986. Kennady JC: Investigations of the early fate and removal of subarachnoid blood. Pacif Med Surg 75:163-168, 1967. Kistler JP, Crowell RM, Davis KR, Heros R, Ojemann RG, Zervas T, Fisher CM: The realtion of cerebral vasospasm to the extent and location of subarachnoid blood visualized by CT-scan. A prospective study. Neurology 33:424-436, 1983. Korniger C, Collen D: Studies on the specific fibrinolytic effect of human extrinsic (tissuetype) plasminogen activator in the plasma of various primate species. Thromb Haemost 52:308-310, 1981. Mizukami M, Kawase T, Usami T, Tazawa T: Prevention of vasospasm by early operation

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of the anterior cerebral artery territory with consequent bilateral frontal infarction from which he did not recover. From our still limited experience with the intracisternal application of rtPA, the following conclusions can be drawn. The pharmacological removal of subarachnoid blood accumulations can be achieved in a safe and effective way by an intrathecal single bolus of 10 mg of rtPA instilled into the basal cisterns after aneurysm clipping. The acceleration of blood flow velocities in a number of patients indicated that posthemorrhagic arterial narrowing was not completely prevented by this treatment but 19 of 20 patients remained asymptomatic. Although extensive blood clot removal can be achieved by a single bolus of rtPA, more radical or complete blood removal probably requires the use of higher concentrations of drugs or additional postoperative intracisternal or intraventricular rtPA injections, for which further studies are needed. Although the occurrence of cerebral vasospasm and DID was not completely prevented by rtPA application, the low incidence of DID in a group of patients with a high probability of perioperative vasospasm due to high intracisternal blood volumes is promising.

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COMMENT This study by Stolke and Seifert is part of the flurry of recent clinical activity regarding the safety and

Bryce Weir J. Max Findlay Edmonton, Alberta, Canada REFERENCES: (1-5) 1.

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Findlay JM, Weir BKA, Kassell NF, Disney LB, Grace MGA: Intracisternal recombinant tissue plasminogen activator after aneurysmal subarachnoid hemorrhage. J Neurosurg 75:181-188, 1991. Mizoi K, Yoshimoto T, Fujiwara S, Sugawara T, Takahashi A, Koshu K: Prevention of vasospasm by clot removal and intrathecal bolus injection of tissue-type plasminogen activator: Preliminary report. Neurosurgery 28:807-813, 1991. Öhman J, Servo A, Heiskanen O: Effect of intrathecal fibrinolytic therapy on clot lysis and vasospasm in patients with aneurysmal subarachnoid hemorrhage. J Neurosurg 75:197-201, 1991. Tanabe T, Arimitsu M, Morimoto M, Kurisaka M, Mori K: The effect of intracranial thrombolytic therapy with tissue-type plasminogen activator on subarachnoid clot and chronic cerebral vasospasm, in Sano K, Takakura K, Kassell NF, Sasaki T (eds): Cerebral Vasospasm. Proceedings of the IVth International Conference on Cerebral Vasospasm. Tokyo, University of Tokyo

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efficacy of intrathecal recombinant tissue plasminogen activator for patients with large-volume aneurysmal subarachnoid hemorrhage. In their 20 patients with large-volume subarachnoid clot on the initial computed tomographic scan who underwent operations within 72 hours, 1 patient had delayed ischemic deficits attributable to cerebral vasospasm and died. There were no postoperative bleeding complications. The authors used an intrathecal single bolus of 10 mg of recombinant tissue plasminogen activator instilled into the basal cisterns after aneurysmal clipping. These results are similar to those of others just recently published (1-5). The conclusions of all of the authors so far have been remarkably similar in that there is apparently rapid dissolution of the subarachnoid clot and a remarkably low incidence of delayed ischemic deficits and infarction attributable to vasospasm as seen on computed tomographic scan. The rate of postoperative bleeding complications has been well within what would be anticipated for a group of aneurysmal patients having craniotomies. These results are from open studies, and what is required now are randomized, placebo-controlled trials to demonstrate that there is clinical benefit from the use of this potentially dangerous drug. We would discourage its widespread clinical introduction before having definitive evidence of both safety and efficacy. Notwithstanding this, however, the excellent study of Stolke and Seifert contributes to our optimism that a significant advance in the treatment of vasospasm may be in the offing.

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with removal of subarachnoid blood. Neurosurgery 10:301-307, 1981. Nosko M, Weir BKA, Lunt A, Grace M, Allen P, Miehlke B: Effect of clot removal at 24 hours on chronic vasospasm after SAH in a primate model. J Neurosurg 66:416-422, 1987. Ohta H, Ito Z, Yasui N: Extensive evacuation of subarachnoid clot for prevention of vasospasm--effective or not? Acta Neurochir 67:394-398, 1982. Osaka K: Prolonged vasospasm produced by breakdown products of erythrocytes. J Neurosurg 47:403-411, 1977. Pennica D, Holmes WE, Kohr WJ: Cloning and expression of human tissue-type plasminogen activator cDNA in E. coli. Nature 301:214-221, 1983. Seifert V, Stolke D, Kaever V, Dietz H: Arachidonic acid metabolism after aneurysm rupture--evaluation of 6-keto PGF1alpha and TXB2 in patients with subarachnoid hemorrhage. Surg Neurol 27:243-252, 1987. Seifert V, Stolke D, Kunz U, Resch K: Influence of blood volume on cerebrospinal fluid levels of arachidonic acid metabolites after subarachnoid hemorrhage: Experimental study on the pathogenesis of cerebral vasospasm. No Title Available 23:313-321, 1988. Seifert V, Eisert WG, Stolke D, Goetz CH: Efficacy of single intracisternal bolus injection of recombinant tissue plasminogen activator to prevent delayed cerebral vasospasm after experimental subarachnoid hemorrhage. Neurosurgery 25:590-598, 1989. Seifert V, Stolke D: Injection of tissue plasminogen activator (reply to letter) Neurosurgery 26:549-550, 1990. Shiobara R, Kawase T, Toya S, Ebato K, Miyahara Y: "Scavenger surgery" for subarachnoid hemorrhage. II. Continuous ventriculocisternal perfusion using artificial cerebrospinal fluid with urokinase, in Auer LM (ed): Timing of Aneurysm Surgery. Berlin, Walter de Gruyter, 1985, pp 365-372. White RP, Robertson JT: Pharmacodynamic evaluation of human cerebral arteries in the genesis of vasospasm. Neurosurgery 21:523531, 1987. Yoshida Y, Ueki S, Takahashi A: Intrathecal irrigation with urokinase in ruptured cerebral aneurysm cases. Basic studies and clinical application. Neurol Med Chir 24:987-997, 1985. Zabramski JM, Spetzler RF, Bonstelle C: Chronic cerebral vasospasm: Effect of volume and timing of hemorrhage in a canine model. Neurosurgery 18:1-6, 1986.

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Press, 1990, pp 321-323. Zambramski JM, Spetzler RF, Lee KS, Papadopoulos SM, Bovill E, Zimmerman RS, Bederson JB: Phase I trial of tissue plasminogen activator for the prevention of vasospasm in patients with aneurysmal subarachnoid hemorrhage. J Neurosurg 75:189-196, 1991.

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Figure 1. A, digital angiography of Patient S. D., a 27year-old woman, demonstrates an aneurysm of the internal carotid artery. B, CT scan performed on the day of surgery. Extensive SAH with tamponade of the basal cisterns. C through E, follow-up CT scans performed on postoperative Days 2, 5, and 10 demonstrate radical removal of intracisternal blood accumulations.

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Figure 2. A, digital angiography of Patient G. S., a 31year-old woman, demonstrates an aneurysm of the basilar artery at the origin of the superior cerebellar artery. B, CT scan performed on the day of surgery. Severe SAH, predominantly in the interpeduncular cistern, additional widening of both temporal horns. C through E, postoperative CT scans of Days 2, 3, and 10. Radical removal of intracisternal blood clots. Small right frontal hemorrhage results from intraoperative puncture of the right ventricle, but the patient remained asymptomatic.

Single intracisternal bolus of recombinant tissue plasminogen activator in patients with aneurysmal subarachnoid hemorrhage: preliminary assessment of efficacy and safety in an open clinical study.

Intracisternal thrombolysis with recombinant tissue plasminogen activator (rtPA) was performed in 20 patients with aneurysmal subarachnoid hemorrhage...
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