Internal carotid artery (ICA) aneurysms arising from around the carotid dural ring are of considerable surgical interest due to their anatomical features and technical difficulties. With the recent refinement of microsurgical techniques, their management has changed from conservative surgery to direct neck clipping. Different authors call the ICA aneurysms arising near the dural ring by different names such as“ventral internal carotid aneurysms”,“paraclinoid aneurysms”or“infraclinoidal aneurysms.”Some of these aneurysms were considered unclippable or associated with disastrous results when surgically approached.
We report a subgroup of ICA aneurysms located around the carotid dural ring which we call Juxta-DURAL RING aneurysms. These aneurysms are classified into three types: intradural type (intradural aneurysm), carotid cave type (carotid cave aneurysm) and infraclinoid type (infraclinoid aneurysm). The intradural aneurysm arises from the ICA distal to the origin of the ophthalmic artery and correspond to so-called IC-ophthalmic aneurysms which are juxtaposed on the dural ring. The carotid cave aneurysm is located in a small dural recess (carotid cave) proximal to the origin of the ophthalmic artery and at the angiographical genu. The infraclinoid aneurysm may be included in the conventional intracavernous sinus aneurysms, and is located extradurally in the infraclinoid space close to the dural ring. From the point of view of surgical anatomy, clipping of these aneurysms requires essentially the same surgical techniques; complete removal of the anterior clinoid process, unroofing of the optic canal, complete opening of the dural ring, and exposure of the surgical genu and axilla of the ICA via the pterional approach. Utilizing these techniques they are clippable with relative ease. In this paper, our surgical technique is discussed giving explanations of surgical anatomy and clinical cases.

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We investigated serum complements (CH5O, C3, C4) after aneurysmal subarachnoid hemorrhage in 42 patients over a 2 to 3-week period. For a control, we performed the same examination on 5 patients with non-subarachnoid hemorrhage such as hypertensive intracerebral hemorrhage. There were no remarkable changes of serum complements in the control patients. Twenty-one patients who were admitted to our department after the initial pilot study were divided into two groups: Group A, who received nizofenone fumarate (Econal) which is an antivasospasmotic agent, and Group B, who did not receive the drugs. In Group A, 3 patients showed symptomatic vasospasm and in Group B, one patient showed symptomatic vasospasm. In group A, C4 levels decreased 5 days after the onset of subarachnoid hemorrhage in 8 patients; however, only 2 patients showed symptomatic vasospasm. In vitro study, nizofenone fumarate (Econal) showed anti-complement action in a dose-dependent manner.
The above findings suggest that anti-complement therapy might be useful in treating late cerebral vasospasm after subarachnoid hemorrhage.

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The present study attempts to assess the incidence of clinically significant cerebral vasospasm in subarachnoid hemorrhage (SAH), estimated through serial changes of local cerebral vasodilatory capacity (CVC) using single photon emission computed tomography (SPECT) and Nisopropyl-I-123-p-iodoamphetamine (IMP) under acetazolamide (DIAMOX) -activated conditons. One-hundred fourteen patients who underwent early surgery for ruptured aneurysm in the carotid system were postoperatively examined weekly using DIAMOX-activated IMP SPECT.
Estimating limitations in local CVC, serial changes of local CVC were “absent” in 16 patients (14%), “mild” in 52 (46%), and “moderate” in 46 (40%). The incidence of patients in the “moderate” group was significantly higher in preoperative Grades (Hunt & Kosnik) III and IV (53%-60%) than Grades I and II (23-30%)(p<0.001). The outcome of patients with limitation in local CVC was as follows: In the “mild” group, there was no morbidity and mortality due to vasospasm alone: Morbidity was mainly caused by initial brain damage. In the “moderate” group, morbidity was mainly caused by vasospasm and 4 patients (10%) died due to severe vasospasm. Therefore, moderate limitation in local CVC was clinically significant in predicting symptomatic vasospasm, because it was connected with transient or permanent neurological deteriorations.
Assessment of CVC in patients with SAH might predict potential cerebral ischemia caused by the reduction of perfusion pressure due to cerebral vasospasm, and could be a useful tool for the current management of symptomatic vasospasm.

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An early detection of vasospasm is an important factor in planning the most effective therapies for the vasospasm. The authors applied transcranial Doppler (TCD) sonography and single photon emission CT (SPECT) to 57 patients with ruptured aneurysm in the acute stage.
The degree of angiographic vasospasm was evaluated according to Fisher's classification in the operated M₁ segment at the eighth to 13th day. Mean flow velocity was serially measured by TCD in the same segment during the first two weeks. The changes in mean flow velocity were evaluated by the ratio of the change in mean flow velocity within one day to the mean velocity at each previous day (daily flow velocity change). Mean CBF was calculated in the operated middle cerebral artery (MCA) area by SPECT with Xe-133 inhalation at the eighth to 15th day.
The patients with slight to moderate or severe angiographic spasm showed a significantly higher mean flow velocity than non-spasm patients within two to four days after the onset. During the following days, the slight to moderate or severe spasm patients presented a significant increase in mean flow velocity, whereas the non-spasm patients demonstrated no change. In two severe spasm cases, no evident increase in flow velocity could be seen. The symptomatic patients showed a significantly higher flow velocity than the asymptomatic patients within two to four days after the onset. The symptomatic patients presented a significant increase whereas the asymptomatic patients showed no change during the following days. The maximum values of the daily flow velocity change in the symptomatic patients were significantly higher than those in the asymptomatic patients. Delayed ischemic symptoms developed within two days after the maximum increase of daily flow velocity change. However, in one symptomatic patient no evident increase in flow velocity could be seen. Mean CBF in the symptomatic patients was significantly lower than that in the asymptomatic patients.
TCD would be a good indicator for predicting angiographic vasospasm and the development of ischemic symptoms. Moreover, the flow velocity within a few days after the onset could suggest the severity of angiographic spasm and symptomatic spasm in this study. However, TCD also showed false negative findings in some patients with severe angiographic spasm or symptomatic spasm. On the other hand, SPECT could strongly suggest the development of ischemic symptoms. But, SPECT is too costly for daily use. Therefore, the combined application of TCD and SPECT would facilitate early diagnosis of cerebral hypoperfusion due to vasospasm.

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As an index for estimation of cerebral vasospasm in ruptured aneurysms, systolic cerebral blood inflow rate (SCBIR) has been derived. The relationship between SCBIR and cortical CBF measured by a thermo-gradient flow meter was analyzed in 4 patients with SAH, and the relationship between them was statistically significant (CBF=0.04×SCBIR+33.7, r=0.7, p<0.05, n=10). SCBIR was reduced in all patients who seemed to have vasospasm as estimated by a reduction in CBF. On day 3, a moderate reduction in SCBIR was found in one patient even when no cortical CBF reduction was present. Shortly thereafter, however, cortical CBF started to decrease. Subsequently, SCBIR increased concomitant with the increase in cortical CBF in all surviving patients except one who eventually died one month after the onset. The total reduction in cortical CBF in the vasospasm period was-29.2±6.3% mean sd), while SCBIR at this time was-52.8±7.2% (mean±sd)(p<0.05).
In conclusion: (1) SCBIR can be calculated by the ICP pulse wave and intracranial pressure volume relationship (PVI). (2) Generally, SCBIR was correlated with cortical CBF in the early stage of vasospasm and its recovery. However, the statistical test indicated that SCBIR was more sensitive than cortical CBF to the change in cerebral hemodynamics, especially, in the early phase of vasospasm. Thus, there is a possibility of early detection of cerebral vasospasm by analyzing the ICP pulse wave and pressure volume relationship.

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Although vasospasm is still a serious problem for aneurysmal subarachnoid hemorrhage patients, it seems that the incidence has recently decreased. We analyzed the occurrence of vasospasm after acute aneurysm surgery in 270 patients, and compared the incidence and outcome between the first and the latter halves of the 1980's. The occurrence of vasospasm was evaluated by the appearance of ischemic symptoms, with or without CT evidence of infarcts. The overall incidence of vasospasm was 38.3%and 33.6%in the first and the latter periods, respectively. In patients with preoperative Glasgow Coma Scale Scores between 7 and 12, a lower incidence of vasospasm was seen in the latter years, as compared to the first years. On the other hand, the incidence of vasospasm in patients with Glasgow Coma Scale Scores above 13 showed no difference between the two periods. However, the latter period showed significantly lower incidence of infarction in patients of this group. These results proved to be reflected in the decreased mortality and in the increased rate of good outcome in the latter period. In order to confirm whether the results obtained in our clinic is universal, we applied the same analysis to control groups of four cooperative double-blind clinical trials performed during this period in Japan. The study again showed that the rate of infarction as well as the overall incidence of vasospasm have decreased, resulting in the improved surgical outcome. The present study shows that the incidence and severity of vasospasm have decreased, and that the occurrence of infarction has significantly diminished over the decade. In consequence, the rate of poor outcome due to vasospasm after acute surgery is now under 10%

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Over the past 5 years, we have experienced 101 cases (38.8%) of aneurysmal SAH with Fisher 3 on CT scan, out of a total of 260 cases of aneurysmal SAH. We have analyzed these cases.
There were 37 males and 4 females whose ages ranged from 19 to 81 years (mean: 58.3 years). All cases received cerebral angiography and cerebral aneurysms were detected. Intensive delayed operation was carried out on an average of 14 days after onset.
Location of the aneurysms were A.com 38 cases, ICA. 27 cases, MCA 22 cases, AC. distal 1 case, BA. 5 cases, and unknown 3 cases. 47 cases (46.5%) had symptomatic vasospasm (transient 26 cases, permanent 21 cases) on mean Day 8.6. 9 cases took rebleeding and almost on ranged Day 16 to 19. 92 cases (90.2%) acquired operation and others couldn't acquire due to preoperative death. Outcome were good recovery in 50 cases (49.5%), moderate disability in 28 cases (27.7%), severe disability in 2 cases (2.0%), vegetative in 5 cases (5.0%), and death in 16 cases (15.8%). In 21 cases with permanent deficits, only 4 cases were caused by vasospasm only, and other cases took some occasions in vasospasm period

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The indication for, efficacy of and limitations to transluminal balloon angioplasty (TA) for vasospasm following subarachnoid hemorrhage (SAH) are discussed from the viewpoint of our experience with 24 cases (22 of ruptured aneurysm, two of other causes). TA was indicated when the patient showed definite neurological decline in spite of intensive supportive therapy. Prophylactic TA was performed in 2 cases after detection of decreased cerebral blood flow (CBF) without symptoms. Fifty one vascular systems (ICA14, MCA32, ACA5) were successfully dilated with various types of angioplastic balloon catheter. Improvement of clinical symptoms were accomplished in 15 cases among 22 cases of symptomatic vasospasm shortly after TA and no symptom was evoked after prophylactic TA in 2 cases. The outcome at the time of discharge was excellent in 13 cases, good in 3, and fair in 4. Four patients died. Earlier TA (within 6 hours after onset of symptomatic vasospasm) resulted in a more favorable outcome. Follow-up angiography showed no evidence of re-stenosis and/or any arterial wall damage at the site of angioplasty. Single photon emission tomography (SPECT) in 4 cases showed significant improvement in CBF after TA.
Emergent TA may play an important role in the treatment of severe symptomatic vasospasm, especially when the condition of the patient may not allow intensive conservative therapy.

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The effects of hyperdynamic therapy using dobutamine and clinical significance of stroke-CBF, on patients with cerebral vasospasm are here reported. Twenty-six out of 75 (35%) patients developed delayed neurological deficits. The ischemic symptoms of 24 of these patients disappeared after treatment with dobutamine, while the CBF, heart rate and cardiac output increased, although there were no significant elevations in arterial pressure and stroke-SVRI (meaning the systemic vascular resistance index for every pulse beat). This can be done with little difficulty. All clinical results to date are satisfactory. The CBF of symptomatic vasospasm patients increased well, depending on the increase of the cardiac output, not on arterial pressure. However, CT scans on 3 of the 26 patients who had marked tachycardia, showed multiple ischemic lesions, and 1 patient died due to severe brain swelling. In these 3 patients, CBF and stroke-CBF (CBF divided by the heart rate, meaning the CBF for every pulse beat) decreased markedly. The decrease of stroke-CBF may have contributed to the decrease in both the intravascular blood volume and the inside pressure of the spastic arteries for every pulse beat, causing impairment of cerebral circulation.
In the post-operative management for vasospasm, hyperdynamic therapy with dobutamine was effective, and caused no side effects. It is important to control dehydration and marked tachycardia, and thereby prevent a stroke volume and stroke-CBF decrease. Patients with vasospasm should be treated in conjunction with the monitoring of cardiac functions. A value of systemic arterial pressure would not be available to evaluate cerebral circulation.

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Sixty eight consecutive patients with subarachnoid hemorrhage were managed according to the protocol of prophylactic isovolemic hemodilution therapy (PIH) using the Swan-Ganz catheter (S-G) for spasm between November 1988 and September 1990. Aneurysm surgery was performed on fifty five patients between day 0 and 3; 7 were operated on after day 4 and 6 were not operated on. All patients underwent placement of an S-G as soon as possible and were treated until day 14 with PIH. Pulmonary artery wedge pressure (PWP) of 10mmHg and right atrial pressure (RA) of 5mmHg were presumed as isovolemia, and optimal hemodilution was determined to be 32%of hematocrit (Ht). Isovolemic hemodilution (IH) was induced just after the first hemodynamic study and maintained by administration of hemodiluting agents such as fresh frozen plasma (FFP) or low molecular weight dextran. According to early experience with symptomatic spasm (SS), the protocol was slightly changed. Rather than PWP and RA, the cardiac index (CI) was thought to be more important and was maintained above 51/min/m2 by administration of Dobutamine (Hyperdynamic therapy: HD) or/and Nicardipine (Vasodilatation therapy: VD) in reference to systemic vascular resistance index, when it was inadequately elevated by those of IH alone.
Results showed that most of the postoperative patients were in a hypovolemic state, few patients showed low CI even without cardiac disease and PIH combined with HD or/and VD resulted in low incidence of SS and cerebral infarction following spasm. Especially in patients younger than 70 years old with Fisher group 3 SAH, PIH combined with HD or/and VD reduced SS and cerebral infarction in half of IH using a central venous pressure catheter with which patients had been managed before October 1988 (SS: 32.1%vs 62.9%, infarction: 14.3%vs 31.4%).
Several complications occurred, which were divided into those of S-G and IH. The former were pneumothorax, hemothorax at the insertion, which did not occur after changing the insertion site from the subclavian vein to the internal jugular vein, and arryhthmia at the insertion and while the catheter was in place. The latter, which might become serious, were pulmonary emboli (1 case, which improved with medical therapy) and non-A non-B hepatitis (4/54 cases which we were able to follow for 3 months; 3 patients improved, 1 is still in therapy).
This study shows that although hemodynamic management using S-G is effective for preventing SS, serious-but low rate-complications related to S-G and FFP may occur. Protocol have to be changed in selection of patients, placing of S-G, hemodiluting agents and duration of catheterization

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The contribution of hematocrit (Hct) values on symptomatic vasospasm is still controversial. In the present study, effects of Hct variations on symptomatic vasospasm were investigated in patients with subarachnoid hemorrhage (SAH). These patients had ruptured intracranial aneurysms and underwent aneurysmal neck clipping within 2 days after SAH. The 45 patients (Jan. 1. 1987-Dec. 31. 1987, 17 male, 28 female, age: 59.3±10.9yrs) were treated without special attention to blood transfusion and their Hct values were between 30 and 40% (group A). The remaining 39 patients (Jan. 1. 1988-Jun. 30. 1989, 13 male, 26 female, age: 57.3±10.9yrs) were managed with aggressive maintenance of high Hct values with blood transfusion, and their Hct values were maintained at a level of 40 to 45% (group B). The Hct values were 35.2±2.6% in group A and 41.6±1.8% in group B. The outcome after six months was significantly better in group B than in group A (p<0.05). The incidence of symptomatic vasospasm was higher in group B, but with no statistical significance; however, the incidence of permanent neurological deficits due to vasospasm (ND) was significantly lower in group B than in group A (p<0.05).
Central venous pressure (CVP) was an important factor in group B, especially in grade III and IV patients; namely, those with CVP values higher than 5 cmH2O had lower incidence of symptomatic vasospasm (p<0.05) and lower incidence of ND (p<0.01). On the contrary, however, those with CVP values less than 5 cmH₂O had higher incidence of vasospasm in group B (p<0.05). Systolic blood pressure (BPmax) was also important in grade III and IV patients of group B; namely, those with BPmax higher than 140 mmHg showed lower incidence of vasospasm (p<0.05). In conclusion, aggressive maintenance of high Hct values could provide good results in patients with SAH, especially in cases of grade III and IV patients. But hypovolemia should be avoided to keep CVP values higher than 5 cmH₂O; and a rather hypertensive state should be maintained for about two weeks postoperatively.

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Delayed neurologic deterioration from vasospasm remains the greatest cause of death and major disability following subarachnoid hemorrhage. The authors assess the incidence and clinical course of symptomatic vasospasm following aneurysmal subarachnoid hemorrhage using a uniform management. One hundred seventy two consecutive patients were admitted to the neurosurgery service within 2 weeks of subarachnoid hemorrhage not attributed to vascular malformation, tumor or head injury. Four vessels study was performed in 155 patients (149 patients had aneurysms). Hypervolemic hemodilution therapy was instituted at the first sign of clinical vasospasm. Sixty nine patients (40.1%) developed characteristic signs and symptoms of clinical vasospasm with angiographic verification of spasm in all cases. All patients with clinical vasospasm received hypervolemic hemodilution therapy aiming for a hematocrit of 30-35%, pulmonary wedge pressure of 12-18 mmHg (or a central venous pressure 7-10 mmHg), and systolic pressure of 160-200 mmHg for clipped aneurysm (120-150 mmHg for unclipped aneurysm) for the duration of clinical vasospasm. Neurologic grades of 69 patients on admission: 7 patients were Hunt & Kosnik grade I, 25 were grade II, 32 were grade III, 6 were grade IV, and 1 was grade V. At the onset of clinical vasospasm, 3 were grade II, 58 were grade III, 6 were grade IV, 2 were grade V.
At the end of hypervolemic hemodilution therapy, thirty one patients (44.9%) had become neurologically normal, eighteen patients (26.1%) had mild or moderate disability, and twenty patients (29.0%) had severe disability or death. There were 3 instances of pulmonary edema, and all were resolved with appropriate diuresis. Four patients rebled and died while on hypervolemic hemodilution therapy. Death or severe disability from clinical vasospasm occurred in 7.5% of all patients with subarachnoid hemorrhage. This compares favorably with the mortality and morbidity attributed to vasospasm in recent reports. Similar results have been reported for patients treated with hypervolemic hemodilution and arterial hypertension. The authors conclude that early surgery and aggressive managements of clinical vasospasm with volume expansion therapy can be accomplished with minimal morbidity.

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Effect of high doses of nicardipine on cerebral vasospasm was studied in patients with ruptured aneurysms. Twenty patients were treated with nicardipine (Group A), whereas 21 patients did not receive the drug (Group B). Intravenous infusion of nicardipine started within 24 hours after subarachnoid hemorrhage (SAH) in 18 cases, and on Day 4 and Day 5 in 2 cases, respectively. The dosage was 3mg/hr in 3 cases, 5mg/hr in 4, 7mg/hr in 7, and 10mg/hr in 6, for 9 to 21 days. Early surgery was performed within 72 hours after SAH in 15 cases in Group A and 16 cases in Group B, and other cases in both groups had delayed operation. Postoperative angiography was carried out 8 to 16 days after SAH in 15 cases in Group A and 16 cases in Group B. The flow velocity in middle cerebral artery was recorded with transcranial Doppler sonography every other day in 18 cases in Group A and all cases in Group B.
No patients in Group A demonstrated ischemic symptoms and low-density areas on CT scans, while high incidences of brain ischemia (48%) and low-density areas on CT scans (43%) were noted in Group B patients. Severe angiographic vasospasm was shown in 7 of 16 patients in Group B, but was not found in any patients in Group A. Statistically significant increase in mean blood flow velocity in the M₁ segment was noted by transcranial Doppler sonography on Day 6, Day 8, and Day 10 in Group B.
The present study demonstrated that intravenous infusion of high doses of nicardipine had significantly beneficial effects on development of brain ischemia and angiographic vasospasm after aneurysmal SAH. Early treatment with nicardipine might be essential to prevent delayed cerebral vasospasm.

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A cerebral Ca²⁺ overload blocker-flunarizine hydrochloride (F)-was used with excellent results for prevention of delayed ischemic neurologic deficits (DIND) in severe SAH.
Of the consecutive 108 patients (62 Fisher's group III) including 28 FET (F plus Vit. E and Trifluoperazine-calmodulin antagonist-) treated orally with this drug, only one in Fisher's group, III developed DIND. The cause of the DIND was attributable to administration failure of flunarizine. The association of severe angiographic vasospasm was less frequent (18%) in flunarizine treatment and even much less frequent (6%) with FET treatment. There were no side-effects from flunarizine.
The results are much superior to those obtained in studies with nimodipine reporting that 10-30% of patients in Fisher's group III developed DIND and some of them died.
These highly benefical effects on delayed vasospasm might be attributable to better cerebral affinity and the strong cerebral protective effect of flunarizine, in combination with the antivasoconstrictive effect of trifluoperazine.

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The purpose of the present study is to clarified the preventive effects of GTN and Ca⁺⁺-antagonist combination therapy for symptomatic vasospasm following ruptured cerebral aneurysm.
It is a well known fact that Ca⁺⁺-antagonist has a depressive effect on the contraction of vascular smooth muscle induced by spasmogenics as a Ca⁺⁺-entry blocker, and that GTN also has a strong relaxant effect on these contractions as an activator of intracellulary G-kinase. We have applied this combination therapy to 13 patients and obtained good clinical results. Only one patient (8%) showed a symptomatic vasospasm.
1. EXPERIMENTAL STUDY
Using helical strips of the bovine middle cerebral arteries, changes in vascular tension were measured during isometric contractions induced by 5HT, PGF_2α and Oxy-Hb. A helical strip was hung in a small perfusing chamber (1.5ml) and perfused with a modified Tyrode solution with 95% O₂ and 5% CO₂.
The occurrence of contractions induced by 5HT, PGF_2a and Oxy-Hb were depressed by 50-60% of each control in 10^-8M nicardipine (NC). GTN had not depressed the occurrence of these contractions. However, vascular tension on the plateau of these contractions was strongly relaxed by 10^-5-10^-4M GTN. GTN had also strongly relaxed the tension of vascular muscle at the resting tension dose-dependently. GTN caused dose-dependent relaxations in 10^-6M Oxy-Hb-,-10^-6M PGF_2a and 10^-7M 5HT-induced contractions in the presence of 10^-8M nicardipine. The above results suggested that Ca⁺⁺-antagonists would be effective drugs for prevention of cerebral vasospasm, and GTN would be an effective drug for relaxation of the cerebral vasospasm.
II. CLINICAL STUDY
142 patients with SAH who underwent early and/or late surgery, were divided into four groups. 80 patients underwent early surgery and were treated without Ca⁺⁺-antagonist and/or GTN, as a control group. 36 patients were treated with NC after early surgery. 13 patients were treated with diltiazem (Dil) until late surgery. 13 patients were treated with GTN (0.05 mg-0.10 mg/kg/hr) intravenously until the 14th day after SAH {4 patients of early surgery were treated with intrathecal injections of NC (4 mg 2×1/day-10 day), 9 patients of late surgery were treated with intravenously injections of Dil (0.2 mg-0.3 mg/kg/hr-14 day)}
RESULTS: Symptomatic vasospasm occured in 1 (7%) out of 13 patients treated with GTN combined Ca⁺⁺-antagonists, whereas the occurrence in the control group was 41 (51%) out of 80 (early surgery and NC), 5 (38%) out of 13 (late surgery and Dil). The recovery rate was 100% in the 4 patients (early surgery) treated with GTN combined NC, 78% in the late surgery and GTN combined Dil. The recovery rate in the control group was 73% (early surgery only), 86% (early surgery and NC), 60% (late surgery and Dil).
III. CONCLUSION
The intrathecal administration of nicardipine is very effective for prevention of symptomatic vasospasm, however we have sometimes experienced the development of a severe clinical stage due to vasospasm. It is expected for GTN to improve such a permanent symptom. These results depend on the coexistence of the preventive effects of Ca⁺⁺-antagonist and relaxing effects of GTN for vasocontraction after subarachnoid hemorrhage.

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The pathogenesis of symptomatic vasospasm following subarachnoid hemorrhage is still unclear. To clarify this, we analyzed changes of blood coagulation activities between 65 poor risk aneurysmal patients treated by a combination with ticlopidine, albumin and nicardipine (so called TAN therapy) and in 52 untreated patients with symptomatic vasospasm. The hypercoagulable state was scored according to the Disseminated Intravascular Coagulation (DIC) scoring system. Our clinical studies showed that severe SAH following aneurysmal rupture caused the hypercoagulable state. There were good correlations between the degree of hypercoagulation and the severity of the symptomatic vasospasm. TAN therapy reduced the DIC scores by antiplatelet agent and prevented the occurrence of the symptomatic vasospasm in severe SAH. These facts support the beneficial effects of TAN therapy in prevention of symptomatic vasospasm in severe SAH.

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Effect of thromboxane A2 synthetase inhibitor (sodium ozagrel) on development of symptomatic vasospasm and on discharge outcome was studied in 16 patients with ruptured aneurysm (sodium ozagrel group) in comparison with another 46 patients without the drug (control group). Cerebral blood flow (CBF) was also measured sequentially in 6 patients of the former group. In the first group, six patients were classified group 1 or 2 of Fisher's CT scan classification of subarachnoid hematoma volume and 10 patients were classified group 3 or 4; 19 patients were classified group 1 or 2 and 27 patients were classified group 3 or 4 in the latter group. All these patients were surgically treated within 72 hours of onset. In the patients of group 1 or 2, no one of the sodium ozagrel group developed a symptomatic vasospasm and all of them had an excellent outcome on discharge. Six of 19 patients of the control group developed a symptomatic vasospasm, and 17 patients had an excellent outcome and 2 patients had a good outcome. In the patients of group 3 or 4, 6 out of 10 patients of the sodium ozagrel group developed a symptomatic vasospasm, and 7 patients had an excellent or good outcome on discharge and 3 patients had a fair or poor outcome. No patient died. Seventeen of 27 patients of the control group developed a symptomatic vasospasm, and 16 patients had an excellent or good outcome, 9 patients had a fair or poor outcome and 2 patients died. CBF was reduced temporarily in the area of the parent artery of the aneurysm in the patients who had an excellent clinical course. On the contrary, CBF reduction was diffuse and long-standing in the patient who developed a symptomatic vasospasm and subsequently a normal pressure hydrocephalus. From these findings, it is concluded that sodium ozagrel is effective in mild cases of subarachnoid hemorrhage, but its efficacy is limited in severe cases. The drug is to improve a microcirculatory disturbance secondary to vasospasm.

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One hundred twenty six patients with subarachnoid hemorrhage due to ruptured intracranial aneurysm were admitted to our service between June 1988 and November 1989. Of these, 79 patients were treated with sodium ozagrel, thromboxane A₂ synthetase inhibitor, or nizofenone, cerebral protector for ischemic cerebral damage. The effects were evaluated by the outcome of patients, incidence of symptomatic vasospasm and fatal vasospasm. Sodium ozagrel improved the outcome of patients and reduced the incidence of fatal vasospasm; however, it did not reduce the incidence of symptomatic vasospasm. Nizofenone was effective as well, but less so than sodium ozagrel. These results suggested that both drugs were effective in the treatment of delayed ischemic neurological deficits (DIND) due to cerebral vasospasm after subarachnoid hemorrhage.

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The effect of combined therapy of Ozagrel Na and Nizofenone on delayed ischemic neurological deficits (DIND) following subarachnoid hemorrhage (SAH) due to aneurysmal rupture was investigated.
A consecutive series of 50 individuals with SAH subjected to early operation (within 72 hours after the recent attack) were categorized in 3 treatment groups.
All patients were admitted to one institution and operated on by the senior author (T. T.) between January, 1987, and September, 1989. Patients were divided into three groups according to treatment protocol: treated by ordinary therapeutic method (20 cases=group A), treated with intravenous administration of Ozagrel Na, 80mg/day for 14 days after the clipping operation (13 cases=group B) and treated with same dosage of Ozagrel Na and Nizofenone, 30mg/day for 14 days after the operation (17 cases=group C).
Location of ruptured aneurysm, neurological grade and CT classification of the patients on admission were the same in all three groups. Overall outcome by Glagow Outcome Scale at discharge was as follows: in 20 cases of group A, Good Recovery (GR): 13 cases (65.0%), Moderately Disabled (MD): 5 cases (25.0%), Dead (D): 2 cases (10.0%), in 13 cases of group B, GR: 4 cases (30.8%), MD: 3 cases (23.1%), Severely Disabled (SD): 2 cases (15.4%), D: 4 cases (30.8%) and in 17 cases of group C, GR: 12 cases (70.6%), MD: 3 cases (17.6%), SD: 1 case (5.9%), Vegetative Survival (VS): 1 case (5.9%).
Among 41 patients who were in Hunt and Kosnik grade I through III, 9 cases (50%) of group A, 4 cases (40%) of group B and 5 cases (38.5%) of group C showed DIND in the postoperative course. In those patients DIND remained as a permanent neurological dysfunction in 5 cases (27.8%) of group A, 3 cases (30.0%) of group B and 2 cases (15.4%) of group C consequently. Thus group C patients treated with Ozagrel Na and Nizofenone showed better outcome.
Nizofenone, a protective agent for the brain, may be useful as a therapy for delayed neurological deficits following SAH.

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The clinical effects of thromboxane synthetase inhibitor and Nizofenone were examined. The subjects were 33 patients on whom clipping of cerebral aneurysm was done within three days of onset of subarachnoid hemorrhage (SAH) and on whom angiography and CT were performed at a stage of acme of vasospasm. They were divided into the thromboxane synthetase inhibitor monotherapy group (7 patients), the Nizofenone monotherapy group (4 patients), the combination therapy group of both drugs (7 patients), and a control group of 15 patients. The effects of thromboxane synthetase inhibitor were measured by the degree of angiographical vasospasm. As for the SAH in Fisher groups 3 and 4, the degree of vasospasm was significantly milder in the thromboxame synthetase inhibitor use group than in the group which did not use this inhibitor (p<0.05). On the other hand, the effects of Nizofenone were measured by the degree of low density on CT. In patients with a mild vasospasm, the Nizofenone-use group showed less tendency to exhibit low density than the group which did not use Nizofenone (p<0.01). Also, the outcome was evaluated with the Glasgw outcome scale (GOS), and the effects of thromboxane synthetase inhibitor and Nizofenone on such outcome were examined. Relating to the SAH in the Fisher groups 1 and 2, the thromboxane synthetase inhibitor and/or Nizofenone therapy groups showed favorable outcome in every case. On the other hand, with respect to the SAH in Fisher groups 3 and 4, no difference was observed in the outcome between the thromboxane synthetase inhibitor and/or Nizofenone therapy groups and the control group.
Thromboxane synthetase inhibitor and Nizofenone seem to have some clinical utility even though there may be a limit to their effect.

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Continuous cisternal drainage (CCD) was performed in 47 of 205 patients with ruptured cerebral aneurysms who underwent CT scan, cerebral angiography and surgical obliteration of the aneurysms within 72 hours after subarachnoid hemorrhage. Patients were included in the vasospasm (VS) group only when they suffered from neurological deterioration which remained until the time of discharge, or resulted in death during the post-operative period.
CCD was more frequently performed in Hunt and Kosnik's grades III and IV patients and in Fisher's CT groups 3 and 4 patients. VS was observed in 26 out of 205 patients (13%). Incidence of VS was significantly higher in Hunt and Kosnik's grade III + IV than in grade I + II. It was also significantly higher in Fisher's CT group 3 + 4 than in group 1 + 2.
The effect of CCD on the prevention of VS was evident in Fisher's groups 3 and 3 + 4. In these groups, the incidence of VS was significantly lower with CCD than without. Although the use of CCD tended to reduce the incidence of VS in all cases, statistical significance was not available. VS occured in 3 (6%) out of 47 cases with CCD, and in 23 (15%) out of 158 cases without CCD.
In this study we conclude that CCD can reduce the incidence of VS in patients with diffuse and severe subarachnoid hemorrhage on preoperative CT scan, but its effect is still not satisfactory for the complete prevention of VS.

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In order to prevent vasospasm, removal of thick subarachnoid clot is carried out in acute aneurysm surgery. Sufficient prevention, however cannot be achieved with this maneuver only. Therefore, we added two other methods; that is, to dissolve and eliminate the remaining subarachnoid clot with the cisternal irrigation of Urokinase (UK) and to change Oxy-Hb, one of the spasmogenic substances, into something harmless with ascorbic acid (AsA).
Cisternal irrigation therapy with UK and AsA has been applied in ruptured aneurysm cases operated upon in the acute stage since 1984. Preoperative CT scan was all in Group 3 according to Fisher's CT classification and the CT number of the clot was over 60, which suggested a great possibility of vasospasm. The total number of cases was 106. After clipping, the subarachnoid clot was removed and then irrigation tubes were inserted deep in to one or both sylvian fissures (inlet) and into the prechiasmal or prepontine cistern (outlet). Twelve hours after the operation, lactate Ringer's solution with UK and AsA (pH 7.2-7.4, osmotic pressure 280-300 mOsm/Kg) was infused at the rate of 20 to 60ml/hr. The concentration of UK was 60-120IU/ml and that of AsA was 2-4mg/ml. The duration of this therapy was between 4 and 15 days (mean: 9.9 days). Among these 106 cases, symptomatic vasospasm was observed in three cases at the rate of 2.8%. Two of them developed a slight hemiparesis immediately after removal of the irrigation tube, but were discharged with no deficit. One patient had a permanent hemiparesis. During irrigation, one case developed meningitis and slight bleeding occurred in two cases, but they recovered completely.
In order to prove the effectiveness of this therapy, we compared these result of the irrigation group with that of the control group, in which irrigation was not performed. The degree of SAH, age, sex, operation timing, preoperative grade by Hunt and Kosnik and distribution of the site of aneurysm are almost the same as the irrigation group. In the control group, symptomatic vasospasm occurred in 37 cases out of 96 cases at the rate of 38.5%.
Considering the outcome, cisternal irrigation therapy with UK and AsA is effective in preventing symptomatic vasospasm after SAH.

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Urokinase cisternal irrigation was performed in patients with thick subarachnoid hemorrhage due to rupture of cerebral aneurysm, and, the effects on clearance of subarachnoid clots and prevention of vasospasm were assessed in comparison with patients who underwent cisternal drainage.
Within 24-48 hours after start of urokinase cisternal irrigation, an extreme amount of hemoglobin derived from the subarachnoid clot was withdrawn. CT number of cerebral cisterns decreased immediately in cases of urokinase cisternal irrigation while the reduction of CT number was slower in cases with cisternal drainage. Cerebral vasodilatory capacity assessed by DIAMOX^® activated ¹²³IIMP SPECT during the first and second week after subarachnoid hemorrhage showed less limitation in cases with urokinase cisternal irrigation than with cisternal drainage. Angiographical and symptomatic vasospasm were also expressed less severely in cases of urokinase cisternal irrigation than with cisternal drainage, and subsequently, no low density area in CT due to ischemia from vasospasm appeared with urokinase cisternal irrigation. In conclusion, urokinase cisternal irrigation accelerated clearance of subarachnoid clots, followed by reduction of severity of vasospasm and cerebral ischemia.

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We analyzed the usefulness of cisternal irrigation with urokinase (UKI) and intravenous injection of Ca²⁺ antagonist (TA-3090) for treatment of vasospasm after subarachnoid hemorrhage (SAH) with a ruptured aneurysm. Twelve patients were operated on 24 hours after SAH. Seven patients were treated with UKI, and five with combined UKI and Ca²⁺ antagonist. Nine were operated on 48 hours after SAH; five were treated with UKI and four with combined treatment. Nine were operated on 72 hours after SAH; five were treated with UKI and four with combined treatment. Seven were operated on 96 hours after SAH; four were treated with UKI and three with combined treatment. The clinical grading (Hunt & Kosnik) was II to IV in this series, and the CT grading (Fisher classification) was all III.
Symptomatic vasospasm (SV) was recognized in four of the twelve patients treated with UKI and one of the eight treated with combined therapy within 48 hours. On the other hand, in the patients who were operated on 48 hours after SAH, SV increased.
On the ADL, excellent and good results were obtained in all cases except one in the UKI treated group and the combined therapy group within 48 hours. But, in the UKI treated group after 48 hours ADL was worse. However, in the combined therapy group after 48 hours ADL was better.
In patients treated with UKI within 48 hours, CT showed that perimesencephalic cisternal clots were dissolved within three days after SAH but in the cases with UKI after 48 hours cisternal clots was not dissolved within three days.
We consider that UKI is an effective therapy in prevention of SV and that it is important that UKI be carried out within 48 hours after SAH, and that in the cases where treatment is started after 48 hours after SAH, combined therapy of Ca²⁺ antagonist is a beneficial method of protecting against delayed ischemia.

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We have originated cisternal irrigation combined with head shaking in order to remove subarachnoid clots rapidly and extensively. Eighteen patients with subarachnoid hemorrhage (SAH) due to ruptured intracranial aneurysms of the anterior part of the circle of Willis were studied. The degree of SAH as shown by CT was Group 3 on the Fisher's grading scale. Clipping was performed within 72 hours after the last bleeding. Continuous ventriculo-cisternal irrigation was carried out from 12 hours after the surgery, using solution with or without urokinase. The head was intermittently shaken (amplitude 4 cm, frequency 1.0-2.0 c/s) by a head-shaking device of our own making. The effect of head shaking on clot removal was evaluated by neurological examination, CT, and the volume of sedimentary clots in the draining fluid. Postoperative angiography was usually performed about 10 days after SAH.
Although the number of patients was small for statistical analysis, the effect of head shaking on clot removal as shown by CT was remarkable. The subarachnoid clots with CT attenuation values of more than 60 in the basal and sylvian cisterns were usually washed out to the range (10-15) of normal cerebrospinal fluid within 48 hours. No delayed ischemic neurological deficits (DIND) occurred, and no low-density areas due to vasospasm were observed on computed tomography. Angiographic vasospasms were observed in only 2 cases, in which the diameter of the artery was less than 75% of that in the acute phase. But these vasospasms were limited to the area adjacent to the ruptured aneurysm.

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T-PA is expected to be used for cisternal drainage in subarachnoidal hemorrhage, because rapid and safe liquefaction and removal of clots are very important. We performed a pharmacological experimental study on the efficacy, administration method, and toxicity of various hematolytic agents, especially tissue-plasminogen activator (t-PA).
The hematolysis rate following a single administration was 88.9% with t-PA+Elase (Fibrinolysin+Deoxyribonuclease), 85.4% with t-PA, 84.6% with t-PA+urokinase, 80.2% with t-PA+urokinase+Elase, 27.5% with Elase+urokinase, 24.6% with Elase+urokinase+heparin, 17.2% with heparin+urokinase, 16.4% with urokinase, 12.6% with Elase, and 10.1% with the control (saline). Locally administered t-PA had remarkably greater hematolytic effects than urokinase on the hematoma (p<0.001). The effect of the local administration of t-PA seemed to reach a plateau at a dosage of 10×10⁴ IU/ml. The local effects of each hematolytic agent continued for about 4-8 hours but markedly decreased thereafter.
Because of the low dose-dependency, frequent administrations of divided doses were more effective than a few administrations at a large dosage when the total dosage was the same (p<0.01). Intermittent repeated administration was also more effective than continuous administration (p<0.01).
A brain surface attachment test (patch test) of t-PA was negative, and light or scanning electron micrography after the intrathecal t-PA administration (10×10⁴ IU/ml) showed no neurotoxicity, cell infiltration or arachnoid damage.
The pH of the t-PA general-purpose solution (for intravenous injection) is maintained at 4.6 to 4.8 because of its solubility and stability, and the osmotic pressure is also increased with an increase in concentration of t-PA. When the concentration of t-PA is 750×10⁴ IU/ml, the osmotic ratio is 30 and the pH is 4.82. These features suggest that a locally administered t-PA solution at high concentration may induce meningeal irritations such as headache and vomiting, and exacerbation of the symptomatic cerebral vasospasm when it is used for cisternal drainage.
The pH and osmotic pressure of t-PA saline solution (10×10⁴ IU/ml) were corrected to 7.23±0.072 and 1.45-1.48, respectively, with 6.0μl of Meylon, and those of t-PA Hartmann's pH: 8 solution (10×10⁴ IU/ml) were corrected to 7.28±0.023 and 1.44-1.46, respectively, with 4.0μl of Meylon.
Therefore, the dosage and method of administration of the t-PA for cisternal drainage should be determined by taking into consideration not merely its histotoxicity but also its pH and osmotic pressure.

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A drug delivery system for fibrinolysis of the residual subarachnoid clot has been developed. Tissue plasminogen activator contained within the biodegradable polyer (polylactic acid) was more effective for the experimental clot lysis than was a placebo. In 3 patients with subarachnoid hemorrhage (WFNS Grade 3) TPA-PLA complex was administrated within the basal cistern after the aneurysmal neck clipping. The sequential changes of the concentration of FDP and of Hb in the cerebrospinal fluid drained through the cisternal drainage tube were monitored. The concentrations of both lowered more quickly in those patients treated with TPA-PLA complex than in those given a placebo. This DDS enables cisternal fibrinolytic therapy easily in comparison with the cisternal irrigation therapy, which requires careful observation of the water balance between irrigation and drainage.

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Efficacy of single intracisternal bolus injection of tissue plasminogen activator (t-PA) for cerebral vasospasm were studied using double hemorrhage canine model. Each doses of 250μg, 25μg of t-PA, and 25μg of t-PA with 50 CU of plasminogen were injected into cisterna magna 3 hours after the second hemorrhage on Day 2. In the treated dogs with t-PA, clot lysis were facilitated, and significant inhibition of angiographical vasospasm were observed. Hb and FDP in cerebrospinal fluid decreased earlier in treated group. Intracisternal bolus injection of t-PA is highly efficacious for preventing cerebral vasospasm following subarachnoid hemorrhage (SAH).

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The effect of intrathecal tissue plasminogen activator administered after subarachnoid hemorrhage on the development of cerebral vasospasm was examined. Fourteen cases with severe subarachnoid hemorrhage (Group 3 as defined by Fisher's computed tomography criteria) underwent early surgery for aneurysm neck clipping within 2 days of subarachnoid hemorrhage and were treated with t-PA after the operation. The subarachnoid clot was eliminated dramatically after t-PA introduction in all cases. None of the patients showed symptomatic vasospasm. Eight cases (57%) showed angiographical narrowing, but this was very mild and only the distal portion of the anterior cerebral or middle cerebral artery where the subarachnoid clot had remained until late was involved. Intrathecal t-PA administration was effective in early elimination of subarachnoid clots and in preventing cerebral vasospasm after subarachnoid hemorrhage.

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