Intracisternal recombinant tissue plasminogen activator after aneurysmal subarachnoid hemorrhage

Transcription

1 J Neurosurg 75:181188, 1991 Intracisternal recombinant tissue plasminogen activator after aneurysmal subarachnoid hemorrhage J. MAX FINDLAY, M.D., PII.D., BRYCE K. A. WEre, M.D., NEAL F. KASSELL, M.D., I,EW B. DISNEY, M.D., AND MICltAEL G. A. GRACE, PH.D. Department of Surgery, University o/alberta, Edmonton. Alberta, Canada. and Department of Neurosurgeo'. Univo:~ity oj Virginia. Charlottesville, lffrginia ~" Fifteen patients undergoing surgery within 48 hours of aneurysm rupture were administered recombinant tissue plasminogen activator (rtpa) directly into the basal subarachnoid cisterns after minimal surgical clot removal and aneurysm clipping. Preoperatively, 13 patients had diffuse or localized thick subarachnoid blood clots on computerized tomography (CT), and two had diffuse thin clots. The rtpa was given as a single intraoperative injection of 7.5 mg (one patient), mg (nine patients), or mg (five patients). Postoperative cisternal drainage was employed in three patients. All patients except one demonstrated partial to complete cisternal clot clearance on CT scans within 24 hours after surgery. The patient who showed no clot reduction was the only patient in this series to develop symptomatic vasospasm and was the only fatality, dying 8 days after rupture. No vasospasm was seen on followup cerebral angiography in six of the 14 responding patients, and mildtomoderate arterial narrowing was seen in at least one major cerebral artery in the remaining eight patients. Severe angiographic vasospasm was not seen, although the patient who died did not undergo repeat angiography. There was one major complication early in the series which seemed clearly related to treatment, and that was a large extradural hematoma occurring within several hours of craniotomy. Intrathecal fibrinolytie treatment appears effective in clearing subarachnoid clot and reducing vasospasm, and may be associated with acceptable risks if given to patients with largevolume subarachnoid hemorrhages at high risk for severe vasospasm. KEY WORDS aneurysm subarachnoid hemorrhage vasospasm fibrinolytic therapy 9 thrombolytic therapy 9 tissue plasminogen activator E XPERIMENTAL studies have shown that the fibrinolytic agent, recombinant tissue plasminogen activator (rtpa), administered into the subarachnoid space, is able to lyse subarachnoid hematoma and prevent vasospasm."2,, In primates, rtpa given up to 72 hours after subarachnoid hemaloma placement significantly reduced vasospasm compared to control preparations. 3 This study was designed to assess the safety of intracisternal rtpa in humans after aneurysreal subarachnoid hemorrhage (SAH), and to examine the effect of rtpa on subarachnoid hematoma and vasospasm. Clinical Material and Methods Informed consent for this study was obtained from or for each of patients suffering SAH from a ruptured saccular aneurysm. Table 1 lists the clinical aspects of each patient treated. None had a history of bleeding diathesis, and baseline coagulation screening and liver function tests in all patients were normal. Surgery for aneurysm clipping was performed within 48 hours after aneurysm rupture in all patients. Although the dose of rtpa administered ranged from 7.5 to mg, the protocol for the last eight patients consisted of a single mg bolus injection directly into the basal cisterns after aneurysm clipping. The dose range of rtpa chosen for this study was based on the finding that 0.75 mg was the minimum dose of rtpa required for consistent lysis of a 5ml subarachnoid blood clot in monkeys? It was estimated that the volume of cisternal clot after aneurysm rupture in humans would be to 20 times greater than the dose required for monkeys, and the rtpa dose was multiplied accordingly. The rtpa is supplied as a lyophilized powder* that, when reconstituted with sterile water, has a concentration of I mg rtpa/ml, ph of 7.3, and osmolarity of 2 mosm. *Tissuetype plasminogen activator manufactured Genentech, inc., South San Francisco, California. by J. Neurosurg / Volume 75/August,

2 J. M. Findlay, et al. TABLE 1 ("[illica/ MItllIHClr.FOf [5 l~ol[tvll~wilt) rr162 Age Case (yrs), Aneurysm No. Sex Location Admission Grade'l 241 t r Vasospasm Subarachnoid SAH to rtpa ('lot Treatment Outcom@ Blood on Surgery Dose Admission CT (hrs) (rag) Clearance Complications Clinical Angiographic~c on CT , F 23, M 44. F 66, F 27, M ItICA 2 IVb Ill Ill II1 111 diffuse,tllick localized,thick diffuse, thick dill'use,thin l0 6 45, M rt PCoA II diffuse, thin l0 I , F 48, M 63, M 42, F 69, M 69, F rt PCoA rt MCA It MCA x 2, rt MCA rt MCA rt ICA ItMCA IVb IVb IVa Ill lva IVb localized,thick l0 l0 V lvb lva diffuse, thick F 14 70, F 56, F i~llrclci.~'lert?a]rlj~4* thin extradural hematoma large extradural hematoma mild. diffuse not done mild, focal mild, focal died moderate disability moderate, focal mild, focal mild, focal moderate, focal severe disability moderate, diffuse * npa = recombinant tissue plasminogen activator; CT = computerized tomography; SAH = subarachnoid hemorrhage; = anterior communicating artery" ICA = internal carotid artery', PCoA = posterior communicating arteu; MCA = middle cerebral artery. = positive; = none. t Classification according to the World Federation of Neurological Surgeons SAH scale.l Mild = 0% to 25% luminal narrowing: moderate = 25% to 50% luminal narrowing: focal = one major cerebral artery, diffuse = two or more major cerebral arteries. wclassification according to the Glasgow Outcome Scale.s O n l y e n o u g h blood clot necessary' for exposure a n d clipping o f the a n e u r y s m was r e m o v e d surgically. In the last eight p a t i e n t s in this series, m i n u t e s was allowed to pass after rtpa a d m i n i s t r a t i o n, followed by vigorous irrigation o f the s u b a r a c h n o i d space with 1 or 2 liters o f w a r m e d saline. M o d i f i c a t i o n of the p r o c e d u r e allowed for dilution a n d d i s p e r s e m e n t o f e n z y m e t h r o u g h o u t the s u b a r a c h n o i d cisterns a n d served to reduce the c o n c e n t r a t i o n o f n o n f i b r i n b o u n d rtpa from the w o u n d prior to closure. After microscopic inspection o f the operative site a n d pial b a n k s for bleeding, the dura a n d w o u n d were closed securely. A l t h o u g h a t e m p o r a r y cisternal drain was used early in the series, the last n i n e patients did not u n d e r g o postoperative cisternal drainage. O n e patient (Case 11), w h o had a large i n t r a v e n tricular h e m o r r h a g e from r u p t u r e o f a n a n t e r i o r c o m m u n i c a t i n g artery a n e u r y s m, received additional intrav e n t r i c u l a r injections o f 5 m g rtpa via a v e n t r i c u l a r c a t h e t e r at 24 a n d 48 h o u r s after a n e u r y s m clipping. This was c o m b i n e d with extensive v e n t r i c u l a r d r a i n a g e in o r d e r to p r o m o t e clearance o f the i n t r a v e n t r i c u l a r clot. All patients h a d at least o n e c o m p u t e r i z e d t o m o g r a phy (CT) scan p e r f o r m e d within 24 h o u r s of surgery, a n d s c a n n i n g was repeated thereafter as necessary. Vasospasm was m o n i t o r e d clinically a n d with repeat cerebral a n g i o g r a p h y o n or near Day 7 following SAH and, w h e n possible, by daily transcranial D o p p l e r ultra182 s o u n d ( T C D ) e x a m i n a t i o n (seven cases). All patients received n i m o d i p i n e, 60 m g every, 4 h o u r s by m o u t h or t h r o u g h a nasogastric tube, for 14 to 21 days after surgery. E n o u g h i n t r a v e n o u s fluids were a d m i n i s t e r e d in each p a t i e n t to m a i n t a i n m o d e s t hypervolemia, a n d o n e p a t i e n t (Case 3) was treated with i n d u c e d hypertension. Renal, hepatic, a n d coagulation testing was performed pre a n d postoperatively in all patients. In addition, systemic fibrinogenolysis was m o n i t o r e d with o n e or two s e r u m fibrinogen level assays d u r i n g the first 2 postoperative days in the last six patients. S e r u m assays for D d i m e r, a crosslinked fibrin d e g r a d a t i o n product, were p e r f o r m e d pre a n d postoperatively in seven o f the last eight patients treated. Results Patient Presentation T a b l e I provides d e m o g r a p h i c, clinical, a n d o u t c o m e data for each patient treated. T h e r e were six m e n a n d nine w o m e n, with ages ranging from 23 to 76 years (average age s t a n d a r d deviation 52.3 _ 16.4 years). A n e u r y s m location s h o w e d t h a t seven patients had a n t e r i o r c o m m u n i c a t i n g artery () aneurysms, two h a d internal carotid artery (ICA) aneurysms, two h a d posterior c o m m u n i c a t i n g artery (PCoA) aneurysms, a n d four had m i d d l e cerebral artery ( M C A ) aneurysms. T h i r t e e n p a t i e n t s had o n e a n e u r y s m, o n e patient h a d J. Neurosurg. / Volume 75 / A ugusl, 19 91

3 Intracisternal rtpa after subarachnoid hemorrhage two aneurysms, and another had three aneurysms. The patient with two adjacent ICA ancurysms (Case 3) underwent repair of both prior to rtpa administration. The patient with three ancurysms had a large left MCA aneurysm that was clearly the source of bleeding based upon CT and surgical findings. This aneurvsm and a smaller proximal left MCA aneurs, sm were clipped prior to rtpa administration, and a small contralateral MCA aneurysm was not repaired. On admission, the patients were classified according to their SAH as follows: one Grade It, five Grade III, three Grade lva, five Grade IVb, and one Grade V (World Federation of Neurological Surgeons Scaler). Only one patient was alert preoperatively (Case 6). Admission CT scans classified subarachnoid blood as diffuse and thick in 11 cases, localized and thick in two, and diffuse and thin in two. Mean time to surge~' was 22.5 _ 11.4 hours, with a range from 8 to 48 hours. There were no significant differences between sexes, time to surge~' (< 24 hours vs. _> 24 hours), or in aneurysm location. Complications There was one major complication that seemed clearly related to rtpa treatment. This 45yearold man (Case 6) underwent uneventful clipping of a large right PCoA aneurysm 16 hours postrupture, after which mg of rtpa was instilled into the basal cisterns. The cisterns were not irrigated, but both ventricular and cisternal drains were inserted. Postoperatively, the patient did not awaken, and an immediate CT scan demonstrated a large right frontal extradural hematoma (Fig. 1). This was evacuated, and the following morning the patient underwent removal of residual right subdural and temporal hematomas. He had a prolonged convalescence and, although he eventually returned home and became partially independent, he remained with significant left hemiparesis and neglect. In another patient (Case 5), a thin asymptomatic epidural hematoma was noted beneath the craniotomy and was partially aspirated on the day following surgery'. Dosages of rtpa used in this study did not result in systemic fibrinogenolysis. No patient had a prolongation in thrombin or partial thromboplastin time postoperatively. In the six patients in whom it was measured, the plasma fibronogen level did not decrease postoperatively. Ddimers were detected in plasma preoperatively in two patients and postoperatively in six of eight patients tested (a positive Ddimer indicates a level > 1.0 ug/ml). The presence of fibrin degradation products in serum has previously been observed following SAH) and appears to be the result of subarachnoid fibrinolysis. Clot Clearance All patients except one (Case 3) demonstrated clot clearance on CT scans within 24 hours after surgery' (Fig. 2). Two patients (Cases 13 and ) underwent immediate postoperative CT scanning (under anesthe Ih(;. 1. Postoperative computerized tomography (CT) scans in Case 6. a: A large right frontotemporal extradural hematoma occurred within hours after craniotomy for clipping o1" a right posterior communicating artery aneurysm and administration of mg of rtpa into the basal cisterns, b: The hcmatoma was evacuated but the patient has remained moderately disabled due to an infarction in the right posterior cerebral artery distribution, seen on this CT scan obtained 3 days after subarachnoid hemorrhage. sia), and neither study showed significant change in the amount of diffuse thick subarachnoid hematoma compared to their preoperative CT scans; however, scans from both patients 12 hours later showed almost complete resolution of cisternal blood clot. These results suggest that clot lysis mediated by intraoperative rtpa is not immediate, but occurs over 24 hours. In Cases 1, 4, 7, and 9 to, the overnight reduction in cisternal blood clot was remarkable. One patient with hematocephalus (Case 1 I) had complete resolution of his intraventricular clot within several days after direct ventricular injections of rtpa (Fig. 3). VasmT) a.~m Clinical vasospasm was seen in a single patient (Case 3), who failed to demonstrate clot clearance. This patient deteriorated from renal, pulmonary, and cardiac failure and became comatose with evidence of severe brain swelling. Although repeat cerebral angiography was not obtained, TCD examinations revealed increased cerebral blood velocities in both MCA's beginning on Day 3 after SAH, reaching values as high as 220 cm/sec (mean value in the left MCA) on Day 5. This patient was declared braindead on Day 7 following SAH and died the following day. Thirteen patients underwent repeat cerebral angiography between 5 and 8 days postsah; of these studies were carried out on Day 7 after hemorrhage. There was no evidence of angiographic asospasm in five of these patients, mild vasospasm (_< 25% reduction in luminal caliber compared to the preoperative caliber) was seen in five, and three had moderate vasospasm (25% to 50% reduction in luminal caliber) (Figs. 4 and 5). Severe angiographic vasospasm was not observed. The two patients who did not undergo angiography J. Neurosurg. / Volume 75/August

4 J. M. Findlay, el al. FI{;. 2. Serial compl~leri~ed tomography (CT) scans ira all paticms except Case 6 (shown in Fig. 1). Preoperative CT scans x~erc obtained within 24 hours after subarachnoid hemorrhage (SAH), the lstday postoperative CT scans were obtained within 24 hours after surgery and ripa administration, and the followup CT scans were obtained on the days shown. All patients show paltial to complete subarachnoid clot Issis within 24 hours after surgery except Case 3 where there was no clot reduction on the 1st postoperative day. This was the only patient in the series to develop sexere vasospasm, and she died 8 days after SAH and 6 days after surgery. during the interval of peak vasospasm included the patient who died (Case 3) and the patient with a large postoperative extradural hemorrhage (Case 6). This latter patient underwent repeat angiography on Day 2 to 184 check the aneurysm clipping, and further angiography was not performed; however, daily T C D studies did not demonstrate increased flow velocities indicative of vasospasm. J. Neurosut~. / I'olume 75/August, I991

5 Intracisternal rtpa after subarachnoid h e m o r r h a g e due to the initial effects of rupture from which she did not recover, and 12 patients had results (Glasgow Outcome Scale% Discussion FIG. 3. Computerized tomography scans in Case 11. Upper: Scans obtained at admission showing large intraventri cular blood clots from rupture of an anterior communicating artery aneurysm. These were treated with two separate intraventricular injections of 5 mg rtpa 24 and 48 hours after aneurysm clipping through a ventficulostomy catheter. Combined with ventricular drainage, this resulted in rapid and complete clot clearance. Center and Lower: Scans obtained on Days 4 and 12 after rupture showing resolution of the clots. Outcome The patients in this series have been followed for periods from 1 to 14 months. There has been one death (Case 3), one patient (Case 6) suffered moderate disability due to effects of a postoperative extradural hematoma, one patient (Case 12) had severe disability J. Neurosurg, / Vohtme 75/August, 1991 Although hypertensive hypervolemic therapy and the calcium antagonist nimodipine significantly ameliorate the ischemic consequences of vasospasm, individuals with largevolume SAH's remain al substantial risk from severe diffuse vasospasm. Although operative clot removal at the time of aneurysm repair has been suggested to prevent vasospasm,7~'" an aggressive surgical effort to empty the subarachnoid spaces is both hazardous and frequently incomplete after extensive subarachnoid bleeding. Experimentally, rtpa was effective in clearing diffuse subarachnoid clot and preventing vasospasm in primates up until 72 hours after induction of SAH) In this study, the safety and efficacy of rtpa were tested in patients after SAH from rupture of a saccular aneury.sin. Thirteen of the patients had thick SAH's on CT scans. The protocol developed in this series consisted of an intraoperative injection of mg rtpa (in ml) directly into the basal cisterns following aneurysm clipping. After waiting minutes, the subarachnoid space was irrigated with l or 2 liters of saline to dilute and disperse the enzyme throughout the basal cisterns and to partially remove nonfibrinbound rtpa. Cisternal drainage was used only in three patients early in the series, but ventficular drainage for acute hydrocephalus was employed in nine patients. It is essential that the ruptured aneurysm be repaired prior to rtpa administration. The one patient who had an unclipped contralateral aneurysm remaining at the time of treatment (Case 12) had unequivocal radiological and operative evidence that the ruptured aneurysm was indeed one of two aneu~'sms repaired before rtpa was given. This study demonstrates that intraoperative intracisternal administration of rtpa promotes rapid clearance of clot from basal subarachnoid cisterns, including cisterns distant from the operative exposure. In a recent Canadian trial of nimodipine in poorgrade aneurysm patients, 42 patients with thick subarachnoid clot on admission CT underwent another scan between 5 and I0 days following SAH; "~persistent basal subarachnoid clot was evident within this 5 to day interval in 24 (57%) of these patients. In comparison, only one of the patients treated with rtpa in this series had subarachnoid clot persisting beyond 5 days. Large reductions in diffuse subarachnoid clot were generally apparent on CT obtained on the 1st postoperative day. In addition, postoperative intraventricular injections of rtpa were effective in rapidly [ysing biventricular hematomas resulting from rupture of an aneurysm. Rapid clearance of subarachnoid hematoma appeared to be associated with a reduced incidence of 185

6 J. M. Findlay, et al. FIG. 4. Preoperative and followup cerebral angiograms in the first eight patients treated in the series, excluding Case 3 in which postoperative angiography was not performed. Areas of mildtomoderate vasospasm (< 50% luminal narrowing) are indicated by arrows. Day 0 (do) = day of hemorrhage. 186 J. Neurosurg. / Volume 75/AugTcst, 1991

7 Intracisternal rtpa after subarachnoid hemorrhage FIG, 5. Preoperative and followup cerebral angiograms in the last seven patients treated in the series. Areas of mildtomoderate vasospasm (< 50% luminal narrowing) are indicated by arrows. Day 0 (do) = day of hemorrhage. J. Neurosurg, / Volume 75/August,

8 J. M. Findlay, et al. vasospasm in this series of patients. Among 1 patients with thick SAH's in the Canadian trial of nimodipine in poorgrade patients, 77 underwent repeat cerebral angiography during the peak vasospastic interval 5 to days following SAH. ~~ Vasospasm was seen in 72 (94%) of these patients, and in 47 (61%) it was severe and diffuse. In the present series of patients, 13 with thick SAH's, mild or no vasospasm was seen in 11, and moderate vasospasm (25% to 50% luminal narrowing) was seen in three. The only patient with symptomatic vasospasm in this series did not have repeat angiography but, on the basis of TCD examination, likely had severe diffuse vasospasm. This was the only patient who had no evidence of clot lysis on postoperative CT, and the only incidence of a poor outcome (death) due to vasospasm. The major risk of intraeisternal rtpa is postoperative bleeding; among the patients presented here, one patient had a large extradural hematoma resulting in a poor outcome. The results of this preliminary investigation of rtpa suggest that this risk may be acceptable if treatment is restricted to patients with large SAH's at high risk for severe vasospasm. A randomized trial of intracisternal rtpa in such patients would seem appropriate. Addendum Since this paper was submitted for publication, six additional patients with diffuse, thick SAH's have been treated with mg of intracisternal rtpa. All have demonstrated overnight basal clot clearance without complication and only one patient developed angiographic vasospasm, which was localized, moderate in degree, and asymptomatic. Acknowledgments The authors thank Ms. Arlene MacLean, Peter Jeremy, and Karen Popowieh for their help in preparing this manuscript. References I. Drake CG: Report of World Federation of Neurological Surgeons Committee on a universal subarachnoid hem orrhage grading scale. J Neurosurg 68:985986, 1988 (Letter) 2. Findlay JM, Weir BKA, Gordon P, et ah Safety and efficacy of intrathecal thrombolytic therapy in a primate model of cerebral vasospasm. Neurosurgery 24:491498, Findlay JM, Weir BKA, Kanamaru K, et al: The effect of timing of intrathecal fibrinolytic therapy on cerebral vasospasm in a primate model of subarachnoid hemorrhage. Neurosurgery 26:201206, Findlay JM, Weir BKA, Kanamaru K, et al: Intrathecal fibrinolytic therapy after subarachnoid hemorrhage: dosage study in a primate model and review of the literature. Can d Neurol Set 16:2840, Findlay JM, Weir BKA, Steinke D, et al: Effect of intrathecal thrombolytic therapy on subarachnoid clot and chronic vasospasm in a primate model of SAH. d Neurosurg 69:723735, Fodstad H, Nilsson IM: Coagulation and fibrinolysis in blood and cerebrospinal fluid after aneurysmal subarachnoid haemorrhage: effect of tranexamic acid (AMCA). Aeta Neuroehir 56:2538, lnagawa T, Yamamoto M, Kamiya K: Effect of clot removal on cerebral vasospasm, d Neurosurg 72: , Jennett B, Bond M: Assessment of outcome after severe brain damage. A practical scale. Lancet 1:480484, Mizukami M, Kawase T, Usami T, et al: Prevention of vasospasm by early operation with removal of subarachnoid blood. Neurosurgery :301307, Petruk KC, West M, Mohr G, et al: Nimodipine treatment in poorgrade aneurysm patients. Results of a multicenter doubleblind placebocontrolled trial. J Neurosurg 68: , I. Seifert V, Eisert WG, Stolke D, et al: Efficacy of single intracisternal bolus injection of recombinant tissue plasminogen activator to prevent delayed cerebral vasospasm after experimental subarachnoid hemorrhage. Neurosurgery 25:590598, Taneda M: Effect of early operation for ruptured aneurysms on prevention of delayed ischemic symptoms. J Neurosurg 57:622628, 1982 Manuscript received December 19, Address reprint requests to." J. Max Findlay, M.D., Ph.D., FR.C.S.(C)., 2DI.02 W.C. Mackenzie Health Sciences Centre, Street, Edmonton, Alberta T6G 2B7, Canada. 188 J. Neurosurg. / Volume 75/August, 1991