Acute decrease in cerebral nitric oxide levels after subarachnoid hemorrhage.

Disturbances in the nitric oxide (NO) vasodilatory pathway have been implicated in acute vasoconstriction and ischemia after subarachnoid hemorrhage (SAH). The authors hypothesize that blood released during SAH leads to vasoconstriction by scavenging NO and limiting its availability. This was tested by measuring the major NO metabolites nitrite and nitrate in five different brain regions before and after experimental SAH. The basal NO metabolites levels were as follows (mean +/- SD, micromol/mg wet weight): brain stem, 0.14 +/- 0.07; cerebellum, 0.12 +/- 0.08; ventral convexity cortex, 0.22 +/- 0.15; dorsal convexity cortex, 0.16 +/- 0.11; and hippocampus, 0.26 +/- 0.17. In sham-operated animals, no effect of the nitric oxide synthase (NOS) inhibitor L(G)-nitro-L-arginine-methyl-ester (30 mg/kg) was found on NO metabolites 40 minutes after administration, but a significant decrease was seen after 120 minutes. The NO metabolites decreased significantly 10 minutes after SAH in all brain regions except for hippocampus, and recovered to control levels in cerebellum at 60 minutes and in brain stem and dorsal cerebral cortex 180 minutes after SAH, while remaining low in ventral convexity cortex. Nitrite recovered completely in all brain regions at 180 minutes after SAH, whereas nitrate remained decreased in brain stem and ventral convexity cortex. Our results indicate that SAH causes acute decreases in cerebral NO levels by a mechanism other than NOS inhibition and provide further support for the hypothesis that alterations in the NO vasodilatory pathway contribute directly to the ischemic insult after SAH.

Experimental models of subarachnoid hemorrhage in the rat: a refinement of the endovascular filament model.

The rat endovascular filament model has been utilized to study subarachnoid hemorrhage (SAH). Because the severity of the hemorrhage with this model has proven difficult to modulate, we attempted to vary the hemorrhage by modifying filament size, and compared this model to the blood injection method with regards to acute physiological responses and hemorrhage size. SAH was achieved using either a 3-0 or 4-0 filament, or by injecting 0.3 cc of autologous blood into the cisterna magna. Peak ICP elevations were lowest in the 4-0 filament group. CBF decreased acutely and rose from its nadir in all three models with the injection model demonstrating the earliest recovery. In the injection group, mean arterial blood pressure rose acutely and remained elevated, whereas in the 3-0 group, MABP rose transiently and in the 4-0 group it did not rise significantly. Histologically, there was less subarachnoid blood in the 4-0 group vs. the injection or 3-0 groups and a different distribution of blood in the two experimental models. Varying filament size provides a method to modulate the severity of SAH in the filament model. In addition, the rat endovascular filament and blood injection models produce different distribution of blood and physiological responses.

Resection and replacement of the superior sagittal sinus for treatment of a parasagittal meningioma: technical case report.

We report a case of the complete resection of a parasagittal meningioma, including an 8-cm length of the superior sagittal sinus and adjacent dura. Flow through the sagittal sinus was reestablished through an interposed saphenous vein graft. Intraoperative angiography confirmed immediate patency of the graft, as did delayed angiography performed at 8 days. Follow-up magnetic resonance angiography 9 months after surgery demonstrated continued patency of the graft. Sagittal sinus replacement with a vein graft can be safely performed during Simpson Grade I resection of parasagittal meningiomas.

Use of intraoperative ultrasonography to improve the diagnostic accuracy of exploratory burr holes in patients with traumatic tentorial herniation.

Seventeen head-injured patients with signs of brain stem compression at admission underwent emergency bilateral burr-hole exploration before computerized tomographic (CT) scanning. After exploration of the epidural and subdural spaces, real-time ultrasonography was performed intraoperatively to identify intraaxial hematomas. Epidural or subdural hematomas were identified surgically in 11 patients (65%) and immediately evacuated through a craniotomy; in 2 patients, bilateral subdural hematomas were removed. Ultrasonography showed no evidence of intracerebral mass lesions in 14 (82%) of the 17 patients, demonstrated extensive contusions of the temporal lobe in 2 patients (prompting partial lobectomy in both cases), and revealed a small intraparenchymal hematoma deep within the dominant hemisphere, which was not removed, in 1 patient. The sensitivity of ultrasound images for identifying intraparenchymal lesions was evaluated postoperatively by CT or autopsy. In 15 patients (88%), the results of ultrasonography were confirmed. In 2 (12%), CT scans showed small but significant lesions at the frontal pole missed by ultrasonography; one patient had a residual subdural hematoma, and the other a small intraparenchymal hemorrhage. These results confirm that patients with clinical evidence of brain stem compression soon after head injury often have extraaxial hematomas that can be readily identified by burr-hole exploration. Although intraparenchymal hematomas are rare immediately after head injury, they can usually be identified by intraoperative ultrasonography. This simple technique can reduce the risk of missing intracranial hematomas during emergency burr-hole exploration and improve intraoperative decision making in this population of severely head-injured patients.

Effects of basic fibroblast growth factor on in vivo cerebral tumorigenesis in rats.

OBJECTIVE: In vitro evidence suggests that basic fibroblast growth factor (bFGF) promotes tumor cell proliferation and angiogenesis. In this study, we evaluated the early and delayed effects of recombinant human bFGF on the early and late phases of in vivo, in situ tumorigenesis in rats. METHODS: Brain tumors were induced by transplacentally exposing fetal rats to N-nitrosoethylurea on Day 17 of pregnancy. On postnatal (PN) Day 60 or 90, N-nitrosoethylurea-exposed rats underwent stereotactic intraventricular implantation of Gelfoam saturated with bFGF (60 micrograms) or vehicle; the rats were killed 4 days (early group) or 30 days (delayed group) later. The early and delayed effects of bFGF on the early phase of tumorigenesis (PN Day 60) were evaluated in 14 and 10 rats, respectively; early and delayed effects on the late phase of tumorigenesis (PN Day 90) were evaluated in 12 rats each. RESULTS: Histological examination 30 days after implantation showed a significantly higher tumor rate in rats that had been treated with bFGF on PN Day 90, compared with vehicle-treated control rats (P < 0.05); furthermore, in the bFGF-treated animals there was significantly greater intratumoral and periventricular glial fibrillary acidic protein expression, as determined immunohistochemically. Increased vascularity in the tumor ipsilateral to the implant was found in 2 of 14 rats that had been treated with bFGF on PN Day 60. CONCLUSION: These findings support in vitro evidence that bFGF and its receptor complex are implicated in the genesis and progression of N-nitrosoethylurea-induced brain tumors in this animal model.

Direct endarterectomy of the middle cerebral artery for treatment of symptomatic stenosis: case report.

The authors report the clinical course and surgical technique used to treat a patient with a high-grade stenosis of the proximal middle cerebral artery that had caused a previous infarction and threatened the remaining dominant hemisphere. Trapping of the involved middle cerebral artery segment allowed direct exposure for excision of the atheromatous plaque and subsequent closure of the arteriotomy. Intraoperative angiography confirmed the reestablishment of flow. The patient made an uneventful postoperative recovery. Direct middle cerebral artery endarterectomy has the advantage of potentially reestablishing flow to lenticulostriate branches. The technique may also avoid the problem of occlusion at the site of maximum stenosis that can be caused by the use of an extra/intracranial bypass graft. Middle cerebral artery endarterectomy is a potentially valuable technique that deserves further investigation.

Decreased nitric oxide availability contributes to acute cerebral ischemia after subarachnoid hemorrhage.

OBJECTIVE: Disturbances of the L-arginine-nitric oxide (NO) vasodilatory pathway have been implicated as a cause of acute vasoconstriction and ischemia after subarachnoid hemorrhage (SAH). Because NO-dependent vasodilatory mechanisms are still intact in this setting, acute vasoconstriction may be the result of limited NO availability after SAH. The present study examines this hypothesis by administration of the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). METHODS: SAH was induced by the endovascular suture method in anesthetized rats. L-NAME (30 mg/kg intravenously) was injected 20 minutes before or 15, 30, or 60 minutes after SAH. Control rats received normal saline. Arterial and intracranial pressure and cerebral blood flow (CBF) were measured continuously for 60 minutes after SAH. RESULTS: L-NAME administration 20 minutes before SAH produced a significant decrease in resting CBF (29.4 +/- 3.4%; P < 0.05), but it had no effect on the acute decrease in CBF after SAH or on its early recovery up to 30 minutes after SAH. However, a significant decrease in CBF recovery was found in animals receiving L-NAME injections (28.7 +/- 9.4%; P < 0.05 versus controls) 60 minutes after SAH. Administration of L-NAME 15 or 30 minutes after SAH had no effect on CBF recovery, as compared with controls. However, when administered 60 minutes after SAH, L-NAME decreased CBF significantly (45.4 +/- 8.8%; P < 0.05 versus controls). CONCLUSION: These results indicate a biphasic pattern of NO availability after SAH. NO-mediated vasodilation is limited during the first 30 minutes of SAH and is restored 60 minutes after SAH.

Conservative treatment of patients with acoustic tumors.

Seventy of 178 patients with acoustic tumors initially were treated conservatively and have been followed up for an average of 26 +/- 2 months. The tumor size was determined by the mean maximum anteroposterior and mediolateral diameters, using computed tomographic or magnetic resonance imaging scans obtained sequentially throughout the follow-up period. The average tumor growth was 1.6 +/- 0.4 mm the 1st year, and 1.9 +/- 1.0 mm the 2nd year (range, -2 to 17 mm/y): 4 tumors showed apparent regression, 28 (40%) had no detectable growth, and 37 (53%) exhibited growth (average, 3.8 +/- 1.2 mm/y). Within individual patients, the tumor growth rate determined during the 1st year of follow-up was predictive of tumor growth rate determined during the following year. Rapid tumor growth or clinical deterioration in 9 of the 70 patients (13%) who initially were treated conservatively necessitated subsequent surgery an average of 14 +/- 5 months after the patient was initially seen. This group had a larger initial tumor size (27.0 +/- 3.4 mm vs. 21.3 +/- 0.9 mm, P less than 0.05), and a faster 1-year growth rate (7.9 +/- 2.3 mm/y vs. 1.3 +/- 0.3 mm/y, P less than 0.05) than the 61 patients who did not require surgery. Two patients, however, experienced neurological deterioration that required surgery, even though there was no tumor growth. The high incidence of acoustic tumors with no detectable growth or apparent spontaneous regression must be taken into account when evaluating the indications for surgery and the efficacy of radiotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Intracranial venous hypertension and the effects of venous outflow obstruction in a rat model of arteriovenous fistula.

A model of rat arteriovenous fistula (AVF) was created using a proximal common carotid artery to distal external jugular vein anastomosis. Anatomical dissections revealed that the external jugular vein is the primary vessel draining intracranial venous blood. Physiological measurements were made with the AVF open and closed, and during venous outflow occlusion of the contralateral external jugular vein. Opening the AVF increased torcular pressure from 6.5 +/- 0.6 to 13.5 +/- 1.1 mm Hg and decreased mean arterial pressure from 82.7 +/- 1.8 to 62.8 +/- 1.8 mm Hg (both P less than .05), decreasing cerebral perfusion pressure from 76.2 +/- 1.7 to 49.3 +/- 2.2 mm Hg (P less than .05). Middle cerebral artery blood flow velocity (MCA BFV) decreased from 6.8 +/- 1.1 to 4.2 +/- 0.7 cm/s (P less than 0.05). In rats with an AVF, occlusion of venous outflow increased torcular pressure to 34.8 +/- 3.1 mm Hg (P less than 0.05), MCA BFV decreased to 1.8 +/- 0.5 cm/s (P less than 0.05), and severe ischemic changes were seen on the electroencephalogram. Under this condition, torcular pressure and systemic arterial pressure had a positive linear relationship (P less than 0.05), whereas in control rats torcular pressure and arterial pressure had no relationship. Restoration of cerebral perfusion pressure by release of venous outflow occlusion and AVF closure transiently increased MCA BFV to 69% above baseline (P less than 0.05). Histological examination 1 week after permanent venous outflow occlusion revealed venous infarction, subarachnoid hemorrhage, and severe brain edema in rats with an AVF but not in control rats without an AVF. This model of cerebrovascular steal with venous hypertension reproduces both hemodynamic and hemorrhagic complications of human AVF and emphasizes the importance of venous outflow obstruction and venous hypertension in the pathophysiology of these lesions.

Intracerebral hemorrhage occurring remote from the craniotomy site.

OBJECTIVE: The purpose of this study was to analyze the available clinical data on postoperative intracerebral hemorrhages that occur in locations remote from the sites of craniotomy. METHODS: The findings of 37 cases of postoperative intracerebral hemorrhages occurring remote from the craniotomy sites were reviewed (5 from our records and 32 from the literature). RESULTS: Remote postoperative intracerebral hemorrhages presented within the first few hours postoperatively in 78% of the patients and were not related to the types of lesions for which the craniotomies were performed. Supratentorial procedures that produced infratentorial hemorrhages involved operations in the deep sylvian fissure and paraclinoid region in 81% of the patients and hemorrhages in the cerebellar vermis in 67% of the patients. Infratentorial procedures that produced supratentorial hemorrhages were performed with the patient in the sitting position for 87% of the patients. The remote supratentorial hemorrhages that occurred were superficial and lobar in 84% of the patients, as opposed to deep and basal ganglionic, which are classic locations for hypertensive hemorrhages. Remote intracerebral hemorrhages occurring after craniotomies were not associated with hypertension, coagulopathy, cerebrospinal fluid drainage, or underlying occult lesions. These hemorrhages commonly led to significant complications; 5 of 37 patients (14%) were left severely disabled, and 12 of 37 patients (32%) died. CONCLUSIONS: Remote intracerebral hemorrhage is a rare complication of craniotomy with significant morbidity and mortality. Such hemorrhages likely develop at or soon after surgery, tend to occur preferentially in certain locations, and can be related to the craniotomy site, operative positioning, and nonspecific mechanical factors. They do not seem to be related to hypertension, coagulopathy, cerebrospinal fluid drainage, or underlying pathological abnormalities.

Acute vasoconstriction after subarachnoid hemorrhage.

OBJECTIVE: Decreased cerebral blood flow (CBF) and cerebral ischemia occurring immediately after subarachnoid hemorrhage (SAH) may be caused by acute microvascular constriction. However, CBF can also be influenced by changes in intracranial pressure (ICP) and cerebral perfusion pressure (CPP). The goal of these experiments was to assess the significance of acute vasoconstriction after SAH and its relationship to changes in CBF, ICP, CPP, and extracellular glutamate concentrations. METHODS: Three experiments were performed using the endovascular filament technique to produce SAH. In the first experiment, CBF, ICP, and CPP were measured for 60 minutes after SAH (n = 21) and were correlated with the 24-hour mortality rate. In the second experiment, rats undergoing SAH (n = 23) or a sham procedure (n = 7) were perfused 60 minutes after SAH for measurement of the circumference and wall thickness of the internal carotid and anterior cerebral arteries and correlation with CBF, ICP, and CPP. In the third experiment (n = 11), extracellular glutamate concentrations determined by hippocampal and cortical microdialysis and high performance liquid chromatography were correlated with physiological changes. RESULTS: CBF reductions to less than 40% of baseline for 60 minutes after SAH predicted 24-hour mortality with 100% accuracy and were used to define "lethal" SAH. In contrast, ICP and CPP 60 minutes after SAH were not correlated with the mortality rate. The vascular circumference was significantly smaller in lethal than in sublethal SAH or sham-operated rats (P < 0.001). Vessel measurements were correlated with both CBF and hemorrhage size (P < 0.01). Extracellular glutamate concentration increased to 600% of baseline after lethal SAH in both hippocampus and cortex and was inversely correlated with CBF (r = 0.9, P < 0.001) but did not increase after sublethal SAH. CONCLUSION: Acute vasoconstriction after SAH occurs independently of changes in ICP and CPP and is associated with decreased CBF, larger hemorrhage size, persistent elevations of extracellular glutamate, and poor outcome. Acute vasoconstriction seems to contribute directly to ischemic brain injury after SAH. Further evaluations of pharmacological agents with the potential to reverse acute vasoconstriction may increase CBF and improve outcome.

Use of an acellular dermal allograft for dural replacement: an experimental study.

OBJECTIVE: In this study, a nonimmunogenic, acellular, dermal collagen matrix termed XenoDerm (LifeCell Corp., The Woodlands, TX) was examined for use as a dural replacement material in a porcine model. This model was used to investigate whether AlloDerm (LifeCell), an almost identical material made from human dermis, could be safely used in neurological surgery. METHODS: Bilateral temporoparietal dural defects were surgically created in 12 Yucatan minipigs. One side was repaired with autologous pericranium, and the other was repaired with XenoDerm. The pigs were killed after 1, 3, or 6 months, and the areas of dural repair were collected and examined macroscopically and histologically. XenoDerm is derived from porcine skin collected in thin sheets. It is processed so that the epidermis and all dermal cells are removed without disruption of the collagen matrix, rendering the material immunogenically inert and resistant to calcification. It is packaged as a freeze-dried sheet and is easily rehydrated at the time of surgery. RESULTS: There were no postoperative complications, and all pigs survived. Both grafts performed well as dural replacements in all cases. There was no macroscopic evidence of inflammation or cerebrospinal fluid leakage. The XenoDerm grafts were intact, retained their original dimensions, and resembled the surrounding dura. The autologous pericranial grafts, in contrast, were thicker than when implanted and had bony excrescences firmly adhering to their surfaces. Again, however, there was no evidence of cerebrospinal fluid fistulae. There was no gross adherence to the underlying meninges or brain tissue in any specimen. Repopulation by fibroblasts and neovascularization were evident in the XenoDerm grafts as early as 1 month after surgery; by 3 months, the XenoDerm had been remodeled to assume the connective tissue appearance of the surrounding dura. CONCLUSION: In this porcine model, an allograft of acellular dermis is a nearly ideal dural replacement. AlloDerm, the human equivalent of XenoDerm, would be an allograft of acellular dermis after implantation in human subjects. On the basis of this study and previous work with AlloDerm in other reconstructive applications, it is proposed that this material could be similarly used for duraplasty in human subjects.

Evaluation of microvascular decompression and partial sensory rhizotomy in 252 cases of trigeminal neuralgia.

Outcome after 252 posterior fossa explorations for the treatment of trigeminal neuralgia was determined by a retrospective review. Patients with distortion of the fifth nerve root caused by extrinsic vascular compression underwent microvascular decompression, those with no compression underwent partial sensory rhizotomy, and those with vascular contact but no distortion of the nerve root underwent decompression and rhizotomy. The mean follow-up period was 5.1 years. An excellent (75%) or good (8%) clinical outcome was achieved in 208 patients; 13 patients (5%) experienced little or no pain relief. Thirty-one patients (12%) suffered recurrent trigeminal neuralgia an average of 1.9 pain-free years after operation; recurrence continued at a rate of approximately 2% per year thereafter. Reoperation for recurrent or persistent pain provided excellent or good results in 85% of reoperated patients, but partial sensory rhizotomy was required in most of these patients. Outcome was affected by previous surgical procedures. A previous percutaneous radiofrequency lesion was associated with a significantly greater incidence of fifth nerve complications and a worse outcome after posterior fossa exploration. Because of this finding, the authors recommend that percutaneous radiofrequency rhizolysis be reserved for patients who have failed posterior fossa exploration or who are not candidates for surgery. Patients with compressive nerve root distortion and a short duration of symptoms before surgery had a significantly better outcome than patients with a longer duration of symptoms. In contrast, there was no relationship between the duration of symptoms and outcome of patients without nerve root distortion. Vascular decompression may cause dysfunction of the trigeminal system in tic douloureux, but in patients who remain untreated for long periods an intrinsic abnormality develops that may perpetuate pain even after microvascular decompression. Posterior fossa exploration is recommended as the procedure of choice for patients with trigeminal neuralgia who are surgical candidates.

Anastomosis of the anterior temporal artery to a secondary trunk of the middle cerebral artery for treatment of a giant M1 segment aneurysm. Case report.

The clinical course, operative technique, and angiographic outcome are reported for a patient with a giant intracranial aneurysm of the proximal middle cerebral artery (MCA) who presented with symptoms of ischemia. Treatment of the aneurysm required bypassing the involved MCA bifurcation, but the patient lacked a suitable donor superficial temporal artery. The involved arterial segment was therefore bypassed with a side-to-side anastomosis of the anterior temporal artery to one of the secondary trunks of the MCA. This bypass eliminated the need to harvest a vein graft and re-established flow using in situ intracranial vessels of similar diameter, minimal arterial dissection, and only one suture line.

A new microclip for vascular occlusion. Technical note.

A new microclip for use on blood vessels 300 mu to 1 mm in diameter is described. This clip is suitable for either temporary or permanent occlusion and has been used in experimental applications. Potential clinical applications are described.

Treatment of fusiform intracranial aneurysms by circumferential wrapping with clip reinforcement. Technical note.

The authors describe a new technique for treating unclippable aneurysms. The method involves a modification of the traditional wrapping technique, including a clip-reinforced cotton sling. The results of this method in four patients are presented.

Genesis of a dural arteriovenous malformation in a rat model.

A rat model was developed to determine the role of sinus thrombosis and elevated sinus pressures in the pathogenesis of dural arteriovenous malformations (AVMs). Five protocols were tested to compare various sinus pressures and thrombosis of a sinus: 1) Control I, sham operation (five animals); 2) Control II, occlusion of the right common carotid artery, the right external jugular vein, and the vein draining the left transverse sinus, as well as thrombosis of the sagittal sinus (10 animals); 3) arteriovenous fistula (AVF) I, anastomosis of the right common carotid artery to the external jugular vein causing retrograde flow through the transverse sinus (10 animals); 4) AVF II, anastomosis (as described in AVF I) and thrombosis of the sagittal sinus (12 animals); 5) AVF III, anastomosis (as described in AVF I) as well as thrombosis of the sagittal sinus and occlusion of the vein draining the transverse sinus on the left (12 animals). Mean arterial and sagittal sinus pressures were monitored and cerebral angiograms were obtained intraoperatively and again 90 days later. Afterward, the animals were sacrificed and their brains and dura were examined histologically. Formation of a fistula resulted in a significant (p < 0.05) threefold increase in sagittal sinus pressure in the AVF II group and a significant (p < 0.05) sixfold increase in the AVF III group. Seven dural AVMs (three in the AVF II group and four in the AVF III group) were demonstrated angiographically and histologically. The seven malformations were located adjacent to a thrombosed sagittal sinus. All lesions were within the dura and sinus wall with direct thrombus-sinus wall connections demonstrated in four of the malformations. The other three lesions displayed arteriovenous connections within the sinus wall and dura. These data suggest the importance of not only sinus thrombosis but also sinus hypertension in the development of a dural AVM.

Radiation-induced bilateral cystic temporal lobe necrosis: reversal of memory deficit after fenestration and internal shunting. Case report.

The authors report a case in which bilateral cystic temporal lobe necrosis developed after treatment of nasopharyngeal lymphoepithelioma with 7000 cGy of external beam radiation. The patient presented with an isolated memory deficit that was documented by neuropsychological testing. After fenestration and internal shunting of both cysts, there was striking resolution of the lesions and of the memory deficit.

Nuclear magnetic resonance imaging and spectroscopy in experimental brain edema in a rat model.

Many aspects of the use of high-resolution nuclear magnetic resonance (NMR) imaging in the examination of brain edema have not been fully explored. These include the quantitation of edema fluid, the ability to distinguish between various types of edema, and the extent to which tissue changes other than a change in water content can affect NMR relaxation times. The authors have compared NMR relaxation times obtained by both in vivo magnetic resonance imaging (MRI) and in vitro NMR spectroscopy of brain-tissue samples from young adult rats with cold lesions, fluid-percussion injury, hypoxic-ischemic injury, bacterial cerebritis, and cerebral tumor. Changes in relaxation times were compared with changes in brain water content, cerebral blood volume, and the results of histological examination. In general, both in vivo and in vitro longitudinal relaxation times (T1) and transverse relaxation times (T2) were prolonged in the injured hemispheres of all experimental groups. Water content of tissue from the injured hemispheres was increased in all groups. A linear correlation between T2 (but not T1) and water content was found. Changes in the values of T1 and T2 could be used to distinguish tumor from cold-injured tissue. Cerebral blood volume was reduced in the injured hemispheres and correlated inversely with prolongation of T1 and T2. The results of this study suggest that, in a clinical setting, prolongation of T2 is a better indicator of increased water content than prolongation of T1, yet quantitation of cerebral edema based solely upon prolongation of in vivo or in vitro T1 and T2 should be undertaken with caution.

Phase I trial of tissue plasminogen activator for the prevention of vasospasm in patients with aneurysmal subarachnoid hemorrhage.

Recent laboratory studies have demonstrated that intracisternal administration of recombinant tissue plasminogen activator (rt-PA) can facilitate the normal clearing of blood from the subarachnoid space and prevent or ameliorate delayed arterial spasm. The results of a preliminary Phase I trial of intracisternal rt-PA in 10 patients are reported with documented aneurysmal subarachnoid hemorrhage (SAH). All patients enrolled were classified as clinical Grade III or IV (according to Hunt and Hess) with thick clots or layers of blood in the basal cisterns and major cerebral fissures (Fisher Grade 3). Ventriculostomy and surgery for clipping of the aneurysms were performed within 48 hours of hemorrhage. In one patient, 10 mg rt-PA was instilled into the subarachnoid cisterns prior to closing the dura. In the remaining nine patients, a small silicone catheter was left in the subarachnoid space and rt-PA (5 mg in four cases or 1.5 mg (0.5 mg every 8 hours for three infusions) in five cases) was instilled 12 to 24 hours after surgery. Minor local bleeding complications were noted in all patients receiving 5 or 10 mg rt-PA. Oozing was noted at the operative incision site in four of five patients and at the ventriculostomy site in two patients. One patient developed a small epidural hematoma that was treated by delayed drainage. No bleeding complications were noted in the patients receiving the lower regimen of rt-PA (three infusions of 0.5 mg each). Serial coagulation studies demonstrated no evidence of systemic fibrinolysis. Analysis of cisternal cerebrospinal fluid samples revealed thrombolytic tissue plasminogen activator (t-PA) levels for 24 to 48 hours. Follow-up cerebral angiography 7 to 8 days after rupture disclosed mild to moderate spasm in nine patients, while one patient with hemorrhage from a posterior inferior cerebellar artery aneurysm had severe focal spasm of the vertebral arteries that was not symptomatic. These results suggest that postoperative treatment with rt-PA may be effective in reducing the severity of delayed cerebral vasospasm. The results of serial t-PA levels suggest that the lower dosage regimen with divided dosages at 8-hour intervals is well tolerated and that even lower dosages may be effective. Further studies are clearly indicated.