D ELAYED ischemic deterioration is an important

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1 J Neurosurg 74: , 1991 Platelet thromboxane release and delayed cerebral ischemia in patients with subarachnoid hemorrhage SEPPO JUVELA, M.D., MATH HHa~aOM, M.D., AND MARKKU KASTE, M.D. Departments ~?[' Neurosurgery and Neurology. Helsinki University Central Hosp#al, ttelsinki, Finland ~" Adenosine diphosphale-induced platelet aggregation and associated thromboxane B2 release were studied in 52 patients with subarachnoid hemorrhage (SAH) in order to detect a possible association between altered platelet function and development of cerebral ischemic complications after SAH. Compared to the values on admission, the patients showed significantly increased platelet aggregability (p < 0.05) and thromboxane release (p < 0.001) I to 2 weeks after SAH. The highest values of thromboxane release were seen in patients who deteriorated due to delayed cerebral ischemia with a permanent neurological deficit. Thromboxane release was significantly higher (p < 0.05) before the onset of severe delayed ischemia in six patients with preoperative ischernia compared to the patients without delayed ischemia. In five others, both ischemic deterioration and elevated thromboxane release occurred after operation. These patients had preoperative values similar to the values in those without ischemic symptoms. The observations suggest that increased platelet aggregability and thromboxane release are associated with delayed cerebral ischemia both before and after surgery. KEy WoRos ischemia. platelet aggregation 9 subarachnoid hemorrhage 9 lhromboxane B_, D ELAYED ischemic deterioration is an important cause of mortality and morbidity in patients suffering from an aneurysmal subarachnoid hemorrhage (SAH). The etiology and pathogenesis of delayed ischemia and decreased cerebral blood flow after SAH are unclear) 22~' Thromboxane A2 released by platelets is a potent vasoconstrictor and platelet-aggregating agent which may be associated with ischemia. Animal models of SAH have been used in order to study prostaglandins in brain tissue and the vessel wall, 2"4~6"13"16-19"25"27 but in humans only the prostaglandin concentrations of cerebrospinal fluid (CSF) after SAH have been explored. 2~ Accordingly, the role of platelet function and thromboxane release in patients with cerebral ischemia following aneurysmal SAH is unknown. We evaluated platelet aggregability, thromboxane release, and the capacity of blood to form thromboxane in subjects stricken by SAH in order to see whether any relationship exists between these platelet variables and the ischemic symptoms which frequently occur after SAH. Clinical Material and Methods Selection of Patients This prospective study included patients who were admitted to the Department of Neurosurgery, Helsinki University Central Hospital within 96 hours after the onset of SAH. Patients who had used acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs within 2 weeks before admission were excluded from analysis. Use or no use of these drugs was confirmed by the case history, by screening urine qualitatively for salicylates, and by platelet-aggregation study. None of the patients included in the study had salicylates in their urine samples on admission. Patient Characteristics The median age of the 52 patients in the study (27 men and 25 women) was 44.5 years (range 22 to 66 years). The clinical state was graded on admission and preoperatively according to the classification of Hunt and Hess. 9 The presence of SAH was verified by computerized tomography (CT) in 50 patients and by lumbar puncture and surgery in two patients. In 5 l patients CT scans were performed within 48 hours after the onset of SAH either in the primary hospital before referral or on admission. The amount of subarachnoid blood seen on the CT scan was categorized according to the method of Fisher, et al? Occurrence of intracerebral and intraventricular bleeding as well as the location of the ruptured aneurysm is shown in Table 1. The blood pressure in 17 patients (33%) exceeded 160/95 mm Hg on repeated readings before SAH, and 386 J. Neurosurg. / Volume 74/March, 1991

2 Platelet thromboxane release and ischemia in SAH TABLE 1 Baseline characteristics of 52 patients with SA H* Characteristics Cases No. % clinical grade on admission 52 1 O0 I III IV 7 13 V 2 4 before surgery I II 6 15 III V 1 2 V 3 7 amount of blood in cisterns 5It 100 on entry CT scan no blood 1 2 thin layer thick layer intraeerebral hematoma:~ 5 It 100 no yes intraventricular bleeding 51-~ 100 no yes location of ruptured aneurysm internal carotid artery anterior communicating artery pericallosal artery 2 4 middle cerebral artcry vcrtebrobasilar artery 5 10 none foundw 4 8 * Clinical grade according to Hunt and Hess. 9 Amount of blood in fissures and vertical cisterns on enid, computerized tomography (CT) scan according to Fisher, et al 5 All CT scans were performed within 48 hours after subarachnoid hemorrhage (SAH). ~ One patient is missing due to lack of CT scan on admission. :~ At least 10 mm in diameter. w Only carotid angiograms were performed: SAH verified by CT in all four; delayed cerebral ischemia in one. in eight of them antihypertensive medication was prescribed. None had any other chronic disease, including diabetes mellitus. Thirty-three patients (63%) were current smokers and eight (15%) were known to be heavy drinkers. Treatment Forty-one patients were operated on. The median time from SAH (Day 0) to surgery was 5 days (range 0 to 23 days). Fifty percent of these operations were performed within 3 to 8 days after SAH. Patients who were operated on received intramuscular betamethasone routinely, 4 mg every 6 hours, starting the day before surgery and continuing to the 6th postoperative day with diminishing doses. Severe hypertension was treated by vasodilator or. diuretic agents. None of the patients received betaadrenergic blocking agents before or during the sam- pling. Headache was treated by narcotic analgesic and sedative drugs. Nonsteroidal anti-inflammatory drugs were not administered to the patients during their hospital stay. Clinical Monitoring ACT scan was performed on admission, after clinical deterioration, and at discharge. Patients were determined to have delayed cerebral ischemia with a fixed neurological deficit if there was a gradual development of totally or partially irreversible focal signs of cerebral ischemia and/or deterioration in level of consciousness not due to intracerebral hematoma, rebleed, hydrocephalus, clipping of an arterial branch together with the aneurysm, infection, serum electrolyte disorders, or any other known reason. These causes of deterioration were excluded by a CT scan and a routine postoperative angiogram, at autopsy, and/or by laboratory investigation. Outcome was assessed at 1 year according to the Glasgow Outcome Scale (GOS). j~ Patients were categorized into three groups: independent state (good recovery or moderate disability); dependent state (severe disability or persistent vegetative); and death. Blood Sampling Blood samples were collected both pre- and postoperatively, and grouped into early- and late-phase samples according to the time obtained. Three patients were sampled only during the late phase and 11 patients died or were discharged to another hospital before the latephase sampling. Therefore, only 38 patients had samples for both phases. The mean timing of the first sample (early phase) in 49 patients was 2.7 days (range 1 to 5 days) after SAH, and that of the second sample (late phase) in 41 patients was 8.8 days (7 to 14 days). The first sample in each phase was included in the analysis of platelet aggregability. Because thromboxane is released from platelets during the later (irreversible) phase of aggregation, the thromboxane level was determined only from samples showing irreversible platelet aggregation. Accordingly, in some cases different samples from the same patient were used in the analysis of aggregability and thromboxane release. Laboratory Procedures To study the release of thromboxane from platelets (measured as the concentration of the stable metabolite thromboxane B2), we applied the method of adenosine diphosphate (ADP)-induced platelet aggregation- described in detail elsewhere ~ (ADP is believed to be a physiological inducer of platelet aggregation J). For this study 8 um ADP was used on the basis of our earlier observations. TM Thromboxane B2 formation in 1 liter of blood was calculated as the product of thromboxane B2 release and the blood platelet count. This variable reflects the capacity of blood to release thromboxane. Thromboxane B2 samples were analyzed after all the follow-up and radiologieal data had been recorded. J. Neurosurg. / Volume 74~March,

3 S. Juvela, M. Hillbom, and M. Kaste Platelet studies were performed by a laboratory technician who was blinded to the case history of the patients. Statistical Analysis The data were analyzed by BMDP statistical programs? Fisher's exact two-tail test and the sign test were used for comparison of aggregability between and within groups. The results of thromboxane B2 release and formation capacity were subjected to logarithmic transformation because the distribution was skewed. Thromboxane values are expressed as the median _+ standard error of the median. The differences, according to the presence of delayed cerebral ischemia, amounl of blood in vertical cisterns, timing of surgery, clinical state on admission, and outcome were compared by Student's or Welch's t-test, or analysis of variance with Welch's statistic and multiple pairwise comparisons using the Bonferroni method at different phases. In patients without missing data, the effect of time after SAH and different grouping variables were compared by repeated measures analysis of variance and covariance. Results Occurrence of Delayed Cerebral lschemia Eleven patients (21%) had delayed ischemia with fixed neurological deficit. Six of them had preoperative symptoms and, for this reason, three were not operated on. In one patient the operation was delayed until the 4th week after SAH. Two other patients with preoperative ischemia were operated on as planned; however, their ischemic symptoms worsened after surgery. In five patients, ischemic symptoms developed following surgery. The median time from SAH to the onset of the ischemic symptoms was 6.0 days (range 2 to 13 days). Delayed lschemia and Blood in Cerebral Cisterns All primary CT scans were performed within 48 hours after SAH. There was a good association between the amount of blood in the fissures and vertical cisterns and the occurrence of delayed cerebral ischemia. Ten (32%) of 31 patients with a thick layer or localized clots in the cisterns suffered from delayed ischemia compared to only one (5%) of the 20 with a thin layer or no blood (p = 0.034). Platelet Aggregability and Thromboxane Release vs. Time i!fter SAH and Blood Amount Platelet aggregability increased significantly in relation to time after SAH (sign test, p = 0.002). In the early phase, 29% of the aggregations were reversible, whereas nearly all aggregations in the late phase (98%) were irreversible. The amount of blood in the fissures and vertical cisterns was not associated with platelet aggregability. During the early phase, 29% of aggregations were reversible in the groups with thin and thick layers of blood on CT scans. Thirty-two patients had both early- and late-phase TABLE 2 Platelet thromboxane B2 (TxB2) release and TxBeformation capacit), of blood vs. time a['ter SAH and CT blood* Early Phase Severity of Bleed Late Phase Group I Group II Group I Group II no. of cases sampling from SAH (day, mean + SD) _+_ 1.4 _+ 1.6 _+ 1.7 _ 2.1 TxBz release (fmol/lo 7 platelets) median SE TxB2 formation capacity (nmol/liter) median SE * Early phase = samples obtained 1 to 5 days after subarachnoid hemorrhage (SAH); late phase = samples obtained 7 to 14 days after SAH Group I = no blood or thin layer in fissures or vertical cisterns; Group II = thick layer or clots in fissures or vertical cisterns. CT = computerized tomography; SD = standard deviation; SE = standard error of the median. Patients with reversible aggregations were excluded from this analysis. Patients in Group II had higher values than in Group I in both the phases (p < 0.05); values in the late phase were higher than in the early phase (p < 0.001). There was no interaction of time after SAH and severity of bleeding on TxBz values. samples with irreversible aggregation available for the measurement of thromboxane B2 release (one patient did not have a CT scan on admission). Thromboxane release was significantly higher (F~,3o = 4.24, p < 0.05) in the patients with a thick layer or clot in the fissures or vertical cisterns on CT scans than in the patients with a thin blood layer. Thromboxane release also increased very significantly according to time after SAH (Fi,3o = 17.06, p < 0.001). The interaction of severity of hemorrhage and time on thromboxane values was insignificant, so thromboxane release increased similarly over time in both blood density groups (Table 2). Thromboxane release and formation capacity per liter of blood were also analyzed separately in the early and late phases both before and after surgery. This was done because not all the patients had samples with irreversible aggregation in both the phases and also in order to take surgery and possible surgical stress into account. Thromboxane variables were significantly (p < 0.05) higher preoperatively during the early phase and postoperatively during the late phase in patients with a thick layer of blood on CT scans (Table 3). Postoperative thromboxane release was also significantly (p < 0.05) higher than preoperative release during the 2nd week after SAH. The presence of intraventricular or intracerebral hemorrhage had no significant effect on platelet aggregation or associated thromboxane release. Platelet Aggregability and Thromboxane Release vs. Delayed Cerebral Ischemia Platelet aggregability tended to be increased in pa- 388 J. Neurosurg. / Volume 74/March, 1991

4 Platelet thromboxane release and ischemia in SAH TABLE 3 Platelet thromboxane B2 (TxB2) release and TxB2formation capacity of blood vs. surgery and surgical clot profile* Early Phase Severity of Bleed Late Phase Group I Group II Group I Group II preop samples no. of cases sampling from SAH (day, mean _+ SD) _+ 1.6 _ _+ 2.1 TxBz release (fmol/107 platelets) median t SE TxB2 formation capacity (nmol/liter) median SE postop samples no. of cases sampling from SAH (day, mean _+ SD) _+ 1.2 _+ 1.0 _ TxB2 release (fmol/107 platelets) median t SE TxB2 formation capacity (nmol/liter) median SE * Surgical clot profile: amount of blood in the fissures or vertical cisterns. For definitions of early phase, late phase, and severity of bleeding, see Table 2. Reversible aggregations were excluded from this analysis. SAH = subarachnoid hemorrhage; SD = standard deviation; SE = standard error of the median. t A significant (p < 0.05) difference compared to Group 1 in the same phase. tients with delayed ischemia compared to those without ischemia during the early phase (p = 0.10). Nine percent of the patients developing delayed ischemia (one of 11 cases) and 34% of those without ischemia (13 of 38 cases) showed reversible platelet aggregation during the early phase. In the late phase nearly all aggregations were irreversible regardless of presence of ischemia (100% for the ischemic patients and 97% for those without ischemia). One to 5 days after SAH, the preoperative thromboxane B2 release of those patients who later suffered from postoperative ischemic deterioration did not differ from that seen in subjects who developed no ischemic symptoms (Table 4). On the other hand, the preoperative thromboxane B2 release measured in patients who deteriorated due to preoperative cerebral ischemia was significantly higher (p < 0.05), even before the onset of ischemic symptoms when compared to patients without ischemia (Table 4). This difference remained significant after adjustment by clinical grade and the amount of blood in the subarachnoid space. The thromboxane release measured in two patients with severe preopera- TABLE 4 Preoperative thromboxane B2 (TxB2) release and TxB2 formation capacity of blood vs. occurrence of delayed cerebral ischemia* No Preop Postop Ischemia Ischemiat lschemia no. of cases sampling from SAH (day, _ _+ 1.8 mean + SD) YxB2 release (fmol/107 platelets) median ~c SE TxB2 formation capacity (nmol/liter) median ~: 162 SE * Measurements taken during irreversible platelet aggregation in the early phase (1 to 5 days) after subarachnoid hemorrhage (SAH). SD = standard deviation; SE = standard error of the median. t All samples in patients with preoperative ischemia were taken before delayed cerebral ischemia. :~ Significant (p < 0.05) difference compared to no ischemia. TABLE 5 Postoperative thromboxane B2 (TxB2) release and TxB2 formation capacity of blood vs. occurrence of postoperative delayed cerebral isckemia* No lschemia Delayed Ischemiat no. of cases 27 7 sampling from SAH (day, mean + SD) 9.8 _ TxBz release (fmol/107 platelets) median :~ SE TxB: formation capacity (nmol/liter) median :~ SE ,8 * Measurements taken during irreversible platelet aggregation in the late phase (7 to 14 days) after subarachnoid hemorrhage (SAH). SD = standard deviation; SE = standard error of the median. i" In two patients the ischemic symptoms started before surgery and in five others after surgery. :~ Significant (p < 0.05) difference compared to the group with no ischemia. tive or postoperative ischemia is illustrated in Fig. 1 in order to characterize the time course and extent of the observed effects. Seven patients with cerebral ischemia, having either spontaneous (two cases) or postoperative ischemia (five cases), were pooled into one group in order to analyze postoperative thromboxane B2 release during the 2nd week after SAH. (Three patients not operated on and one operated on 3 weeks after SAH were not analyzed.) All seven patients had marked cerebral ischemia due to surgery. Thromboxane release was on a significantly (p < 0.05) higher level after operation in samples of patients with cerebral ischemia than in samples of nonischemic patients (Table 5). This difference did not reach significance after adjustment for the amount of blood in the subarachnoid space. The effect of the postoper- J. Neurosurg. / Volume 74/March,

5 S. Juvela, M. Hillbom, and M. Kaste FI~;. 1. Changes in thromboxane B2 release (fmol/10 7 platelets) after the onset of subarachnoid hemorrhage (SAH) in a patient with severe preoperative delayed cerebral ischemia (A) and in another with severe postoperative ischemia (B). Op = operation: DID = onset of dclayed ischemic deterioration symptoms. ative grade of the patient on these high tbromboxane values during the 2nd week after SAH cannot be ruled out because the patients with cerebral ischemia were in a poorer state after surgery than those without ischemia and because the number of patients who deteriorated after surgery for reasons other than ischemia was small (one due to permanent clipping of the pericallosal artery for an anterior communicating artery aneurysm and one due to pneumonia). The thromboxane B2 formation capacity and thromboxane B2 release yielded similar results (Tables 4 and 5). Outcome and Other Observations At I year 36 patients were independent, eight were dependent, and eight were dead. The causes of death were as follows: primary bleed in one patient; rebleed in four; and cerebral ischemia in three. Three of 11 patients with delayed ischemia died, four became severely disabled, and tbur were moderately disabled. There were no significant associations between the measured hemostatic parameters and outcome (according to a three-point GOS), grade on admission, preoperative grade, timing of surgery,, hypertension, antihypertensive medications, sex, location of the aneurysm, or age. Deterioration due to the primary bleed, the rebleed, and temporary or permanent clipping of a major arterial branch at operation had no significant augmenting effect on thromboxane release. Discussion Thromboxane Release and Delayed Ischemia Delayed ischemic deterioration and rebleeding are the most important causes of mortality and morbidity in patients surviving a primary aneurysmal SAH. The t)athogenesis of delayed ischemia in patients with SAH is unknown and could be due to many factors? 2 We observed the highest values for thromboxane release in the patients with delayed ischemia. ]~hromboxane is a potent vasoconstrictor and platelet-aggregating agent, while prostacyclin exerts the opposite effects. ~5 The balance between thromboxane and prostacyclin production is of interest, but its role in cerebral ischemia after SAH is still unknown.12 Bleeding into the subarachnoid space is considered to be the primary event which possibly leads to endothelial injury, with disturbance of the blood-arterial wall barrier. Destruction of the endothelial cells of the vessel wall may lead to decreased production of many endothelial mediators among which are the potent vasodilators, prostacyclin and endothelial-derived relaxing factor? 2 On the other hand, platelets may adhere to the damaged endothelium and denuded subendothelium, and release vasoconstrictor substances such as serotonin and thromboxane A2 which further promote platelet aggregation and vasoconstriction and might finally cause local thrombus formation with accompanying ischemia.'5 Some reports are available of the prophylactic treatment of ischemia with thromboxane synthetase inhibitors, -'2-24 but the therapeutic effect of these agents needs to be confirmed. There are also a few studies of prostaglandins in CSF after aneurysmal SAH? ~ Elevated concentrations of thromboxane have been found in the CSF during the first few days after SAH; that is, at a time when we found platelet thromboxane B2 release to be at lowest levels. It probably reflects liberation of thromboxane from platelets in the subarachnoid blood clot. Thromboxane derived from circulating platelets was 390 J. Neurosurg. / Volume 74/March, 1991

6 Platelet thromboxane release and ischemia in SAH found to be associated with delayed cerebral ischemia in the present study. In fact, the increased aggregability and thromboxane release of platelets either preceded or developed concomitantly with the ischemic symptoms. It is associated with delayed ischemic deterioration irrespective of whether it occurred before or after surgery. Patients who deteriorated due to cerebral ischemia preoperatively already had higher thromboxane release than other patients before the onset of the symptoms of delayed ischemia. The reason for the elevated thromboxane values in these patients was unknown and could not be attributed to clinical state or the amount of subarachnoid blood. On the other hand, the patients who developed postoperative cerebral ischemia had preoperative values similar to those of patients who did not suffer from ischemic symptoms. The patients deteriorating due to postoperative ischemia also had high values for thromboxane release, but only after operation. The reasons for these very high thromboxane values in the patients with postoperative ischemia during the 2nd week after SAH were obscure. Part of this can be attributed to time after SAH and part to surgery, because thromboxane release was higher during the 2nd week after SAH than during the 1 st week and because postoperative values were greater than preoperative values during the 2nd week after SAH. The effects of factors like postoperative grade or the amount of subarachnoid blood on the results cannot be ruled out on the basis of these data. The patients with postoperative ischemia may have been more effective thromboxane producers than the others and prone to thromboxanemediated cerebral ischemia which could have been triggered by surgical stress, while those patients who suffered spontaneous ischemia before surgery may have been the most effective producers of all as suggested by their high thromboxane B2 release before the onset of isehemic symptoms. The process must be triggered by some mechanism which stimulates platelet function. However, we do not know the mechanism by which platelet thromboxane release is increased after SAH. All the patients showed increased platelet aggregability, but only a portion of them had markedly increased thromboxane release. Those with highest thromboxane release developed delayed ischemia. Accordingly, patients with sticky platelets might not deteriorate if their thromboxane release is not high enough. Thromboxane Release and Rebleeding Increased platelet aggregation and thromboxane release probably contribute to enhanced hemostasis after SAH and might be one of the mechanisms involved in the prevention of rebleeds. In our previous study, there was a tendency of increased risk of rebleeding in patients with decreased thromboxane release. Patients with rebleeding also had a significantly lower thromboxane release after rebleeding.l~ Platelet aggregability and thromboxane release correlate differently to delayed ischemia and rebleeding, the two most important causes of deterioration after SAH; delayed ischemia is associated with increased thromboxane release while rebleeding is associated with decreased platelet thromboxane release compared to the values of the patients without deterioration. Thromboxane Release and Blood on CT Scan Thromboxane B2 release from platelets was also observed to correlate with the amount of blood in the basal cisterns, which is known to predict the risk of delayed ischemia. It is well known that the primary CT scan is most valuable in predicting the risk of cerebral ischemia. The greater the amount of blood in the basal cisterns around the great arteries on CT scan, the more likely the patient is to suffer later from ischemic symptoms The primary cause and the significance of increased thromboxane release in delayed cerebral ischemia remain to be elucidated. Acknowledgment We thank Mrs. Saija Heinonen for technical assistance. References I. Carter A J, Heptinstall S: Platelet aggregation in whole blood: the role of thromboxane A2 and adenosine diphosphate. Thromh Haemost 54: , Chan RC, Durity FA, Thompson GB, et al: The role of the prostacyclin-thromboxane system in cerebral vasospasm following induced subarachnoid hemorrhage in the rabbit. J Neurosnrg 61: , Dixon W J, Brown MB, Engelman L, et al (eds): BMDP Statistical Software. Berkeley, Calif.' University of California Press, DuBoulay GH, Hughes JT, Aitken V, et al: Platelets in the subarachnoid space. A cause of acute and delayed arterial spasm, intimal damage and cerebral infarction. Acta Neuroehir 89:64-70, Fisher CM, Kistler JP, Davis JM: Relation of cerebral vasospasm to subarachnoid hemorrhage visualized by computerized tomographic scanning. Neurosurgery 6: 1-9, Fukumori T, Tani E, Maeda Y, et ah Effect of selective inhibitor of thromboxane A2 synthetase on experimental cerebral vasospasm. Stroke 15: , Gurusinghe NT, Richardson AE: The value of computerized tomography in aneurysmal subarachnoid hemorrhage. The concept of the CT score. J Neurosurg 60: , Hillbom M, Kangasaho M, Kaste M, et al: Acute ethanol ingestion increases platelet reactivity: is there a relationship to stroke? Stroke 16:19-23, Hunt WE, Hess RM: Surgical risk as related to time of intervention in the repair of intracranial aneurysms. J Neurosurg 28:14-20, Jennett B, Bond M: Assessment of outcome after severe brain damage. A practical scale. Lancet 1: , Juvela S, Kaste M: Reduced platelet aggregability and thromboxane release after rebleeding in patients with subarachnoid hemorrhage. J Neurosurg 74:21-26, Kassell NF, Sasaki T, Colohan ART, et al: Cerebral vasospasm following aneurysmal subarachnoid hemorrhage. Stroke 16: , 1985 J. Neurosurg. / Volume 74/March,

7 S. Juvela, M. Hillbom, and M. Kaste 13. Maeda Y, Tani E, Miyamoto T: Prostaglandin metabolism in experimental cerebral vasospasm. J Neurosurg 55: , Mohsen F, Pomonis S, lllingworth R: Prediction of delayed cerebral ischaemia after subarachnoid haemorrhage by computed tomography. J Neurol Neurosurg Psychiatry 47: , Moncada S, Vane JR: Arachidonic acid metabolites and the interactions between platelets and blood-vessel walls. N Engl J Med 300: , Nosko M, Schulz R, Weir B, et al: Effects of vasospasm on levels of prostacyclin and thromboxane A2 in cerebral arteries of the monkey. Neurosurgery 22:45-50, Roy MW, Dempsey RJ, Cowen DE, et al: Thromboxane synthetase inhibition with imidazole increases blood flow in ischemic penumbra. Neurosurgery 22: , Sasaki T, Murota S, Wakai S, et al: Evaluation of prostaglandin biosynthetic activity in canine basilar artery following subarachnoid injection of blood. J Neurosurg 55: , Sasaki T, Wakai S, Asano T, et al: Prevention of cerebral vasospasm after SAH with a thromboxane synthetase inhibitor, OKY J Neurosurg 57:74-82, Seifert V, Stolke D, Kaever V, el al: Arachidonic acid metabolism following aneurysm rupture. Evaluation of cerebrospinal fluid and serum concentration of 6-ketoprostaglandin F~, and thromboxane B2 in patients with subarachnoid hemorrhage. Surg Neurol 27: , Siess W, Roth P, Weber PC: Stimulated platelet aggrega- tion, thromboxane B2 formation and platelet sensitivity to prostacyclin. A critical evaluation. Thromb Haemos! 45: , Suzuki S, lwabuchi T, Tanaka T, et al: Prevention of cerebral vasospasm with OKY-046 an imidazole derivative and a lhrombo synthetase inhibitor. A preliminary co-operative clinical study. Acta Neurochir 77: , Suzuki S, Sobata E, lwabuchi T: Prevention of cerebral ischemic symptoms in cerebral vasospasm with trapidil, an antagonist and selective synlhesis inhibitor of thromboxane A2. Neurosurgery 9: , Tani E, Maeda Y, Fukumori T, et al: Effect of selective inhibitor of thromboxane A2 synthetase on cerebral vasospasm after early surgery. J Neurosurg 61:24-29, Walker V, Pickard JD, Smythe P, et al: Effects of subarachnoid haemorrhage on intracranial prostaglandins. J Neurol Neurosurg Psychiatry 46: , Wilkins RH: Attempts at prevention or treatment of intracranial arterial spasm: an update. Neurosurgery 18: , Zuccarello M, Sasaki T, Kassell NF, et al: Effect of intracislernal thromboxane A2 analogue on cerebral artery permeability. Aeta Neurochir 90: , 1988 Manuscript received February 15, Accepted in final form September 4, Address reprint requests lo." Seppo Juvela, M.D., Department of Neurosurgery, Helsinki University Central Hospital, Topeliuksenkatu 5, SF Helsinki 26, Finland. 392 J. Neurosurg. / Volume 74/March, 1991