Use of epsilon aminocaproic acid (EACA) in the preoperative management of ruptured intracranial aneurysms

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1 Use of epsilon aminocaproic acid (EACA) in the preoperative management of ruptured intracranial aneurysms RAM P. SENGUPTA, M.B., B.S., F.R.C.S., F.R.C.S.E., $1Nr C. So, M.B., B.S., F.R.A.C.S., AND FRANCISCO J. VILLAREJO-.ORTEGA, M.D. Department of Neurosurgery, Newcastle General Hospital, Newcastle upon Tyne, England The author s report their experience with the use of epsilon aminocaproic acid (EACA) in the preoperative management of a series of patients with ruptured intracranial aneurysms. A similar series of patients was taken as control. They found that EACA is of definite value in preventing recurrent hemorrhage in the preoperative period. The significance of antifibrinolytic therapy in ruptured intracranial aneurysms is discussed. KEY WORDS EACA 9 ruptured intracraniai aneurysm 9 preoperative management 9 antifibrinolytic therapy I NTRACRANIAL aneurysms have a high tendency for recurrent hemorrhage once they have ruptured and second hemorrhages often cause increased mortality and morbidity. Despite improvements in anesthesia, surgical facilities, and techniques during the past 20 years, early surgery irrespective of clinical condition has proven to be disastrous. It is now acknowledged that if rebleeding is prevented during the first few weeks the brain has a chance to recover from the original assault and the outcome of surgery is rewarding? a4 Various means of conservative management, including bed rest, sedation, and hypotensive therapy, have been advocated but they have not been shown to be of value. The following report is a study of the value of epsilon aminocaproic acid (EACA) in preventing recurrent hemorrhage in two con- current series of patients who suffered from ruptured intracranial aneurysm, one of which received EACA after a diagnosis of subarachnoid hemorrhage was confirmed by lumbar puncture. Clinical Material We reviewed the case histories of 142 patients with subarachnoid hemorrhage (SAH) and angiographic demonstration of intracranial aneurysms admitted under two surgical teams on alternate weeks during the period from July 1971 to June Of these patients, 76 admitted under one team were managed by means of bed rest and sedation immediately after admission, and 66 under the other team received EACA in addition. The institution of EACA was not later than the third day after the initial hemorrhage. The dose used was 3 gm/3 hr (24 gm/day), J. Neurosurg. / Volume 44 / April,

2 R. P. Sengupta, et al. mostly orally but occasionally by intravenous administration. This dose has been demonstrated to provide an effective therapeutic blood level of 13 mg/100 ml sufficient to inhibit fibrinolysis? ',~2 Lumbar puncture was carried out in all cases to establish the diagnosis of subarachnoid hemorrhage. Cases were suspected of a recurrent hemorrhage (SAH) if they showed two or more of the following signs: 1. Sudden deterioration in consciousness level 2. Increase in the degree of neck rigidity 3. Increase in severity of headache 4. Sudden appearance of fresh neurological deficits or further progression of neurological signs. Lumbar puncture was not repeated in cases when clinical evidence of a recurrent hemorrhage was convincing enough in a very ill patient. Lumbar puncture was carried out to confirm the presence of a recurrent hemorrhage only in cases when clinical signs were doubtful. In eight such cases, lumbar puncture confirmed recurrent hemorrhage. For the purposes of this report, however, the remaining nine cases without a lumbar puncture were presumed to have recurrent bleeding. Results There were 30 male and 36 female patients in the group receiving EACA and 45 male and 31 female patients in the control group. In the EACA treated group the ages ranged from 16 to 65 years; in the control group from 16 to 63 years. The age distribution of the two groups of patients is expressed in Table 1. The site of the intracranial aneurysm is illustrated in Table 2. Each group of patients at the time of admission to the neurosurgical unit was graded clinically according to Botterelrs classification 2 (Table 3). There was no recurrent hemorrhage in the preoperative period in the EACA-treated group (Table 4). It should be added that the nine patients who are presumed to have rebled did not have confirmatory lumbar puncture only because the clinician at the time felt that they were unequivocal cases of recurrent hemorrhage. Most of the recurrent hemorrhages in the control group occurred within the first 2 weeks after the initial ictus (Table 5). No TABLE 1 Age distribution in EAC,4-treated and control groups Age (yrs) EACA-Treated Control* (1) (2) (7) (5) (2) * Number in parentheses denotes cases with recurrent hemorrhage. TABLE 2 Site of intracranial aneurysm in 142 patients with S.4H Site of Aneurysm EACA-Treated Control anterior communicating and anterior cerebral artery middle cerebral artery posterior communicating and internal carotid artery vertebral, basilar, and multiple 7 13 sites TABLE 3 Clinical grade on admission (Botterell' s classification) EACA-Treated Control I II III 8 16 IV I -- V TABLE 4 Incidence of recurrent hemorrhage and thromboembolic complications among 142 SAH patients Complications EACA-Treated Control rebleed 0 17 (8)* thrombotic 2 0 complications * Patients subjected to a repeat lumbar puncture for confirmation of recurrent hemorrhage. 480 J. Neurosurg. / Volume 44 / April, 1976

3 EACA in management of ruptured aneurysms TABLE 5 Clinical grade at the time oj" rebleeding since initial hemorrhage TABLE 6 Clinical grade related to interval between hemorrhage and surgery Days Post-ictus I II In Days l I I l or more total total EACA-Treated Control 1 li II lli TABLE 7 Reasons~rwithhol~ngsu~e~ in39sah patients Reason EACA-Treated I li III Control I II In deterioration with proven rebleed deterioration with presumed rebleed deterioration from other causes I 1 3 technical reasons, e.g., refusal for operation, multiple aneurysms total patient in IV or V was operated on. Intracranial surgery was performed upon 88% of the patients in the EACA-treated group, and only 60% in the control group (Table 6). The reasons for withholding surgery in the remaining patients in both groups is shown in Table 7. Of 31 patients in the control group without surgery, 15 had rebleeding and eight continued to deteriorate from the initial hemorrhage. Of the 17 who rebled in the control group, only two patients improved enough to receive surgical treatment for their aneurysms (Table 8). The patients who deteriorated with recurrent bleeding were returned to their local hospital and therefore their final outcome is not included in this study. Two patients in the EACA-treated group developed thrombotic phenomena. One developed thrombosis of the middle cerebral artery on the opposite side from the aneurysm which was confirmed at autopsy. The other patient developed deep vein thrombosis in the calf after 5 days on oral EACA therapy and subsequently died of massive pulmonary emboli. Discussion Factors contributing to the spontaneous arrest of hemorrhage after an intracranial aneurysm has ruptured have not been clearly defined. It is reasonable to assume that the hemorrhage is stopped by the formation of a blood clot inside the aneurysmal sac. If this initial physiological clot is allowed to mature and subsequently to organize, fibrosis and endothelial repair may take place, sealing up the rent in the aneurysm. The fact that the risk of recurrent hemorrhage is highest during the first 3 weeks suggests that mechanisms must TABLE 8 Fate of patients with recurrent bleeding Proven Presumed Result Rebleed Rebleed improved for definitive surgery deteriorated died J. Neurosurg. / Volume 44 / April,

4 R. P. Sengupta, et al. be at work counteracting the natural process of clot maturation. It is well established that in human blood a fibrinolytic system of plasminogen and plasmin exists that constantly lyses intravascular microthrombi. Dissolution of the aneurysmal clot would certainly favor recurrent hemorrhage. EACA is a mono-amino-carboxylic acid that lacks the alpha amino group. Its therapeutic value in the management of bleeding disorders, particularly in the presence of systemic hyperfibrinolytic states, has been extensively investigated and has proved to be valuable. 1'1~ It acts by competitive inhibition of the activator that converts plasminogen into the proteolytic enzyme plasmin. By means of this clot stabilizing effect it promotes clot maturation, and thereby decreases the likelihood of further hemorrhage. Nibbelink and Jacobsen 1~ found that the drug also inhibited the effect of plasmin and reduced plasminogen in the blood. However Gibbs and O'Gorman e did not find any change in blood plasminogen level. Although Tovi, et al., 29 did not find any evidence of accelerated fibrinolysis in the peripheral blood, they observed local fibrinolysis in the CSF and felt that antifibrinolytic agents reach the target area by crossing the blood-brain barrier and inhibit local fibrinolysis? ~ Its use in case of ruptured intracranial aneurysms is therefore justified from the theoretical point of view. In spite of the physiological basis, experience with the use of EACA in patients with ruptured intracranial aneurysms is not uniform. We had a striking result of no rebleeding in 66 patients who were treated with EACA in contrast to 17 cases of rebleeding in the control group. On the other hand, Gibbs and O'Gorman, 8 who conducted an excellent and original trial on the value of EACA for patients with SAH, did not find any convincing effectiveness of this drug. However, the clinical evidence of its value in reducing recurrent bleeding, which is considered to be between 20% and 25%, '2 is mounting. Mullan and Dawley, 15 in a series of 35 patients, had two cases of rebleeding. Norl~n and Thulin 2~ had no recurrent bleeding during 16 preoperative days of its use. Ransohoff, et al.fl 4 also had excellent results. Tovi 2' found a reduction in the rate of recurrent bleeding in the early period after the initial hemorrhage. The most convincing evidence of the value of EACA comes from the report of Nibbelink is for the cooperative aneurysm study on "Antihypertensive and antifibrinolytic therapy following SAH from ruptured intracranial aneurysms." This study summarizes the results of randomized use of antihypertensive drugs alone, antifibrinolytic therapy alone, and their combination in 242 patients. During a 2-week interval 28.9% died among those who received drug-induced hypotension, 5.8% died among the antifibrinolytic group, and 23.8% died in the combined therapy group. Our present study has two added advantages. The patients on EACA have been compared to a control group which received no specific agents to influence the result and they were admitted to one neurosurgical center under uniform facilities. Yet, the striking results in our series may have been influenced by factors such as only referring patients to neurosurgery who were in clinical s I to III. It was not a strictly controlled clinical trial with a fixed period of preoperative treatment with EACA, and patients were operated on within the first 2 weeks in most cases, or as soon as their clinical condition permitted. Nevertheless, our experiences strongly support the beneficial role of EACA in the preoperative management of ruptured intracranial aneurysms. Failure to obtain anticipated results by Gibbs and O'Gorman, e and Girvin 7 may be due to several reasons. Most of the rebleeding in the EACA-treated group in the series of Gibbs and O'Gorman occurred at least 2 weeks after the initial hemorrhage. Tovi 2~ found similar bleeding after 3 weeks, and showed that the antifibrinolytic agent is most effective in the early stages. These observations suggest that EACA may not be useful as a permanent cure for ruptured intracranial aneurysms as Plum had hoped? 8 It is probable that "factors" which provoke an unruptured aneurysm to bleed remain uninfluenced by EACA therapy although EACA can prevent early rebleeding in some cases by reinforcing the rent with a firm clot. However, once those "factors" come into play, even a securely sealed aneurysm again becomes vulnerable, so obliteration of the aneurysm by a clip or ligature as soon as the patient's condition permits, remains the only safeguard against rebleeding. Most of the recurrent bleeding in the control group in our series also occurred within the first 2 weeks. 482 J. Neurosurg. / Volume 44 / April, 1976

EACA in management of ruptured aneurysms It is now established that EACA must be given at frequent intervals of 2 hours or less to provide sustained antifibrinolytic effect, t7 It is notable that

5 EACA in management of ruptured aneurysms It is now established that EACA must be given at frequent intervals of 2 hours or less to provide sustained antifibrinolytic effect, t7 It is notable that Gibbs and O'Gorma# used 12 gm EACA three times a day. The insufficient effect of EACA may also be due to the use of too small a dose and/or too small a proportion of the dose crossing the blood-brain barrier. 2s However, the amount required for effective prevention of fibrinolysis in a particular patient, and a simple method of monitoring its effect need to be worked out. 2s Since EACA is an antifibrinolytic agent, its possible thromboembolic complications have been feared. Some reports of such complications are already available?,s,xe Certainly two of our patients who received EACA developed vascular thrombosis confirmed at autopsy despite the fact that no evidence of increased coagulability or change in such features as prothrombin time and fibrinogen level has been found by any group during its use. It is significant that Nilsson, et al./o concluded, after 5 years' experience with EACA in over 700 cases of various hemorrhagic disorders, that EACA cannot be regarded as a thrombotic agent. Recently Sonntag and Stein 26 reported three patients out of seven who developed "arteriopathic" complications. We agree with Hoo& that the angiographic appearances in these patients cannot be differentiated from those of vasospasm. Kfigstr~m and Palma u also expressed similar fears about the use of EACA. The results in the cooperative study reported by Nibbelink ts and those of our series do not confirm such views. In our experience, both delayed spasm and distant spasm of intracranial vessels after SAH have occurred. Because of the specific action of this drug on the blood clots it may be suggested that dissection during intracranial aneurysm surgery will be difficult due to increased arachnoidal adhesions. Ewald, et al./did not find any such deleterious effect in laboratory animals. One of us (RPS) treated 58 patients by direct surgery after EACA therapy and did not encounter this problem. In conclusion, the introduction of a drug to provide effective prevention of rebleeding in the postictal period when aneurysm surgery is most hazardous would be a major achievement. The role of EACA seems promising. Pharmacological aspects of this agent when administered to a patient with SAH must be more clearly defined. It should be appreciated that the optimum effect of EACA is within the first 2 weeks of hemorrhage and it is not to be regarded in itself as a cure for ruptured intracranial aneurysms. Acknowledgments The authors wish to thank Professor J. Hankinson and Mr L. P. Lassman for their advice in the preparation of this paper. References 1. Belier FK: Treatment of coagulation disorders in pregnancy. Clin Obstet Gynecol 7: , Botterell EH, Lougheed WM, Scott JW, et al: Hypothermia, and interruption of carotid, or carotid and vertebral circulation in the management of intracranial aneurysms. J Neurosurg 13:1-41, Charyton C, Purtilo D: Glomerular capillary thrombosis and acute renal failure after epsilon aminocaproic acid therapy. N Engl J Med 280: , Drake CG: Discussion of Hunt WE, Hess RM: Risk related to time of surgery in intracranial aneurysms. J Neurosurg 28:19-20, Ewald T, Mahaley MS Jr, Goodrich J, et al: Experimental epsilon aminocaproic acid (EACA) administration in the presence of subarachnoid blood. J Neurosurg 35: , Gibbs JR, O'Gorman P: Fibrinolysis in subarachnoid hemorrhage. Postgrad Med J 43: , Girvin JP: The use of antifibrinolytic agents in the preoperative treatment of ruptured intracranial aneurysms. Trans Am Neurol Assoe 98: , Gralnick HR, Greipp P: Thrombosis with epsilon aminocaproic acid therapy. Am J Clin Pathol 56: , Hood RS: Arteritis due to EACA therapy. Letter to the editor. J Neurosurg 42:117, Immergut MA, Stevenson T: The use of epsilon amino caproic acid in the control of hematuria associated with hemoglobinopathies. J Urol 93:l10-111, 1965 l l. K~gstr~m E, Palma L: Influence of antifibrinolytic treatment on the morbidity in patients with subarachnoid hemorrhage. Acta Neurol Seand 48: , 1972 (Abstract) 12. Locksley HB: Report of the Cooperative Study of Intracranial Aneurysms and Subarachnoid Hemorrhage. Section 5, Part 2. Natural history of subarachnoid hemorrhage, J. Neurosurg. / Volume 44 / April,

6 R. P. Sengupta, et al. intracranial aneurysms and arteriovenous malformations. Based on 6368 cases in the cooperative study. J Neurosurg 25: , Madsen PO, Strauch AE: The effect of aminocaproic acid on bleeding following transurethral prostatectomy. J Urol 96: , McNicol GP, Fletcher AP, Alkjaersig N, et al: The absorption, distribution and excretion of ~-aminocaproic acid following oral or intravenous administration to man. J Lab Clin Med 59:15-24, Mullan S, Dawley J: Anti-fibrinolytic therapy for intracranial aneurysms. J Neurosurg 28:21-23, Naeye RL: Thrombotic state after a hemorrhagic diathesis, a possible complication of therapy with epsilon-aminocaproic acid. Blood 19: , Nibbelink DW: Antifibrinolytic activity during administration of epsilon-aminocaproic acid. Stroke 2: , Nibbelink DW, cited by Millikan CH: Summary of the Ninth Princeton Conference on Cerebral Vascular Disease, January 9-11, Stroke 5: , Nibbelink DW, Jacobsen CD: Plasminogen depletion during administration of epsilonaminocaproic acid. Thromb Diath Haemorrh 29: , Nilsson IM, Andersson L, BjSrkman SE: Epsilon-aminocaproic acid (E-ACA) as a therapeutic agent based on 5 years clinical experience. Aeta Med Stand [Suppl] 448:5-46, Norl6n, G, Thulin C-A: The use of antifibrinolytic substances in ruptured intracranial aneurysms. Neuroehirurgia (Stuttg) 12: , Pechet L: Fibrinolysis. N Engl J Med 273: , Plum PF, cited by Millikan CH: Summary of the Ninth Princeton Conference on Cerebral Vascular Disease, January 9-11, Stroke 5: , Ransohoff J, Goodgold A, Benjamin MV: Preoperative management of patients with ruptured intracranial aneurysms. J Neurosurg 36: , Smith RR, Upchurch J J: Monitoring antifibrinolytic therapy in subarachnoid hemorrhage. J Neurosurg 38: , Sonntag VKH, Stein BM: Arteriopathic complications during treatment of subarachnoid hemorrhage with epsilon-aminocaproic acid. J Neurosurg 40: , Tovi D: The use of antifibrinolytic drugs to prevent early recurrent aneurysmal subarachnoid hemorrhage. Aeta Neurol Stand 49: , Tovi D, Nilsson IM, Thulin C-A: Fibrinolysis and subarachnoid hemorrhage. Inhibitory effect of tranexamic acid. A clinical study. Acta Neurol Seand 48: , Tovi D, Nilsson IM, Thulin C-A: Fibrinolytic activity of the cerebrospinal fluid after subarachnoid hemorrhage. Acta Neurol Scand 49: , Tovi D, Thulin C-A: Ability of tranexamic acid to cross the blood-brain barrier and its use in patients with ruptured intracranial aneurysms. Aeta Neurol Scand 48:257, 1972 (Abstract) Address reprint requests to: Ram P. Sengupta, F.R.C.S., Department of Neurosurgery, Newcastle General Hospital, Newcastle upon Tyne, NE4 6BE, England. 484 J. Neurosurg. / Volume 44 / April, 1976

I T IS generally agreed that the surgical risk

I T IS generally agreed that the surgical risk Surgical Risk as Related to Time of Intervention in the Repair of Intracranial Aneurysms WILLIAM E. HUNT, M.D., AND ROBERT M. HESS, M.D. Department of Surgery, Division of Neurological Surgery, Ohio State