Introduction

Early surgery or endovascular coil embolization for an aneurysmal subarachnoid hemorrhage (aSAH) is now generally accepted for preventing rebleeding and as an active treatment for ensuing vasospasms. During the time when delayed aneurysmal clipping was standard, continuing antifibrinolytic therapy with epsilon aminocaproic acid (EACA) or tranexamic acid (TXA) was

done to prevent rebleeding before the operation. However, it was soon realized that prolonged antifibrinolytic therapy results in a higher incidence of vasospasm and/or hydrocephalus, which offsets any benefit from the prevention of rebleeding.9,10,13) Subsequently, prolonged use of antifibrinolytics was replaced by their preoperative short-term use to prevent ultra-early rebleeding before the operation. It has been reported that preoperative short-term use of TXA did not increase postoperative vasospasm or hydrocephalus but did decrease the rebleeding rate.2-6) While

we were giving TXA to patients with aSAH, however, more of them seemed to develop post-operative complications such as postoperative cerebral ischemia or hydrocephalus,

which required shunt operations. Here we investigated the effect of the preoperative short-term use of TXA on the clinical course of aSAH, including various complications and outcomes.

Materials and Methods

From January 2004 to December 2006, 80 consecutive patients who had been treated for aSAH by clipping of aneurysms were enrolled in this prospective study. Of these patients, 38 (48%) were treated with tranexamic acid (Transamin-SⓇ, Daiichi Sankyo company, Japan) (TXA

group) and 42 (52%) were treated without it (n-TXA group). In the TXA group, 1 gram of TXA was given intravenously every 4 hours before surgery. The majority of our patients

were given TXA only one or two times due to our policy of doing ultra-early surgery (mostly within 6 hours after arrival). We analyzed data for age, sex, time from ictus to arrival at our hospital, time from arrival to operation, aneurysmal location, Hunt and Hess grade, Fisher group,

postoperative transcranial Doppler (TCD) findings, modified Rankin scale (mRS) score, and the number of cases with hydrocephalus. Patients who showed over 120 cm/sec of mean middle cerebral arterial blood flow were defined as having a vasospasm; those who showed neurological deterioration with TCD criteria for vasospasm were defined as having symptomatic vasospasm. Hydrocephalus was defined as ventricular dilatation requiring a shunt operation. The baseline characteristics of the two groups are detailed in Table 1.

Patient outcomes and statistical analysis

We analyzed the clinical outcomes of all 80 patients 6 months after surgery, and classified these according to mRS scores. Modified Rankin scale scores from 1 to 3 were considered to be good outcomes and scores from 4 to death as bad ones. For statistical analysis, SPSS software (version 12.0, 2003; SPSS, Inc.; Chicago, IL) was used. Categorical variables were compared using the Fisher exact two-tailed test and the Pearson chi-square test. The Mann-Whitney U

test was used for statistical analysis on the differences in non-categorical variables between preoperative factors and postoperative outcomes. Possible univariate association between the groups was tested using Spearman rank correlation coefficients. A p-value of less than 0.05 was

considered statistically significant.

Results

Age distribution and preoperative clinical factors are shown in Table 1. Mean age was 51.5 ± 12.9, 52.1 ± 11.4 and the male to female ratio was 1:1.9, 1:1.7 in the TXA and n-TXA groups, respectively (p>0.05). Eighty percent of the patients were between 40 and 69 years old. Locations of the aneurysms were 27 (33.7%) on the anterior communicating artery, 26 (32.5%) on the middle cerebral artery (MCA), 9 (11.2%) on the posterior communicating artery, 5 (6.2%) on the basilar tip, 2 (2.5%) on the distal anterior cerebral artery, and 6 (7.5%) on the posterior cerebral artery. Differences in the locations of aneurysms between the two groups were not

significant.

Hunt and Hess grades were as follows: 3 (3.7%) patients in grade I, 37 (46.2%) in grade II, 23 (28.7%) in grade III, 11 (13.7%) in grade IV, and 6 (7.5%) in grade V. Patients with

Hunt and Hess grades II and III were most common constituting 81.6% (31/38) and 69.0% (29/42) in the TXA and n-TXA groups, respectively (p>0.05). Distributions of the Fisher groups were as follows: 3 (3.7%) in group I, 24 (30.0%) in group II, 29 (36.2%) in group III, and 24 (30.0%) in group IV. There was no significant difference in the distribution of the Fisher groups between the two study groups (p>0.05).

The mean time from ictus to arrival at our hospital was 4.2 ± 4.8 hours in the TXA group and 4.5 ± 5.5 hours in the n- TXA group (p>0.05). The mean time from arrival to surgery was 3.9 ± 3.1 hours in the TXA group and 3.5 ± 3.3 hours in the n-TXA group, excluding late-diagnosed aneurysms (p>0.05). The mean number of days in the intensive care unit

were 8.0 ± 7.1 in the TXA group and 6.6 ± 6.4 days in the n-TXA group (p>0.05). The mean number of hospital days were 30.8 ± 20.7 in the TXA group and 30.0 ± 24.0 days in the n-TXA group (p>0.05).

Preoperative rebleeding occurred in one (2.6%) in the TXA group and one (2.3%) in the n-TXA group (p>0.05). Vasospasm developed in 18 (47.4%) in the TXA group and in 20 (47.6%) in the n-TXA group (p>0.05). The mean and peak flow velocity of the MCA were 133.5 ± 49.4 and 193.6 ± 53.5 cm/sec in the n-TXA group and 132.3 ± 53.6 and 202.3 ± 86.3 cm/sec in the TXA group, respectively (p>0.05). Among patients with vasospasm, the rates of symptomatic vasospasm were 88.9% (16/18) and 55.0% (11/20) in the TXA and n-TXA group, respectively (p<0.05) (Table 2). The incidence of hydrocephalus was 21.1% (8/38) and 14.2% (6/42) in the TXA and n-TXA groups, respectively (p>0.05).

Clinical outcomes by mRS scores were 1 in 45 (56.2%), 2 in 8 (10.0%), 3 in 5 (6.2%), 4 in 9 (11.2%), 5 in 4 (5.0%) patients; 9 (11.2%) died. There was no significant difference in outcomes between the TXA group (Good: 73.7%, Poor: 26.3%) and n-TXA group (Good: 71.4%, Poor: 28.6%) (p>0.05). However, patients in the TXA group who had symptomatic vasospasms (Good: 62.5%, Poor: 37.5%) showed worse outcomes than those in the n-TXA group with symptomatic vasospasm (Good: 81.8%, Poor 18.2%) (Table 3).

Discussion

In Korea, the 1970’s was the era of the beginning of direct aneurysmal neck clipping with or without a surgical microscope. The first computed tomography (CT) scanner was introduced in Korea in 1977 and it was only after the CT scan became a major diagnostic method for diagnosing intracranial diseases that aSAH became easily diagnosed and actively treated. However, during that period, early aneurysm surgery was avoided for two reasons. The first

reason was technical difficulties in doing the operation on a swollen brain; the second one was that there was no effective treatment for the ensuing symptomatic vasospasm. As a result, patients had to wait for about 1 to 2 weeks before the operation. However, about 15 to 30% of the patients were known to rebleed during the first 2 weeks and rebleeding was a major cause of poor outcomes.2,11) To prevent rebleeding, they were given high doses of antifibrinolytics such as EACA or tranexamic acid during the waiting period, but it was soon realized that prolonged use of antifibrinolytics led to a higher incidence of delayed ischemic complications and/or hydrocephalus. As a result, the beneficial effect of antifibrinolytics was offset by the increased risk of ischemic complications and the overall outcome of these patients was not different from those who were not given antifibrinolytics.9,13)

In the 1980’s, improved surgical techniques, newly developed aneurysm clips and triple ‘ H’ therapy (hypertension, hemodilution, and hypervolemia) for vasospasm made it possible to operate during the early period after a patient presented at the hospital. In parallel with the development of surgical techniques, Guglielmi detachable coil embolization was introduced in 1991.1) Early surgery was defined as surgery within 3 days after SAH and most of the patients are now operated on during this period. However, a certain portion of patients had to wait for surgery for longer periods for various reasons.

It has been reported that the highest rate of rebleeding occurs from the first 6 hours up to two days from the SAH.12)

To reduce the risk of rebleeding as much as possible, we operate on most patients with aSAH, except for some with very poor grades, within 6 hours after arrival at our hospital, which we call ultra-early surgery. Even for the ultra-early operation, it can take time from arrival to the clipping or coil embolization of the aneurysms. During this short period, the patient is exposed to an elevated risk for rebleeding.

Regarding the short-term use of antifibrinolytics to prevent very early rebleeding, i.e., within 6 hours of the initial SAH, there are some reports from the 1990’s.13) There has been general agreement that short-term antifibrinolytic therapy for aSAH during the early period effectively

prevents rebleeding without consequent ischemic or hydrocephalic complications.2-7) On reviewing our patients, vasospasm developed similarly in both groups but symptomatic vasospasm developed more often in the TXA group. The result of our study regarding symptomatic vasospasm is different from results of other reports. The higher incidence of symptomatic vasospasm in the TXA group may be due to antifibrinolytics. Pleym et al.8) reported that even a single bolus dose (30 mg/kg) of TXA before cardiac surgery reduced postoperative bleeding in coronary artery bypass graft patients, which supports our results that a single dose or two doses of TXA can increase the development of symptomatic vasospasm. It seems quite possible that long-term use of TXA could cause more ischemic complications and result in worse outcomes.

Therefore, it seems reasonable to be careful when TXA is used to prevent preoperative rebleeding in aneurysmal SAH patients. Further study with more patients will be needed to prove

the relationship between TXA and symptomatic vasospasm. Contrary to other studies, we found a very low rebleeding rate in the n-TXA group. This might be explained by the ultra-early surgery which minimizes the preoperative period during which the patient is exposed to an elevated risk of rebleeding.4,5,7) The incidence of hydrocephalic complications requiring shunts was similar in both groups, as reported in other studies.5,10)

One of the weaknesses of this report is that the number of patients treated by TXA is small. In addition, we excluded coiled aneurysms from this study, which may cause selection bias. Thus, a larger number of patients with a double-blinded ramdomization study design are necessary for more detailed determination of the effect of short-term use of TXA on aSAH patients.

Conclusion

Preoperative short-term use of TXA did not significantly affect the incidence of preoperative rebleeding, vasospasm and hydrocephalus, but did result in a higher incidence of symptomatic vasospasm. A preventive effect of short-term TXA on rebleeding was not substantiated. According to our results, we recommend being very cautious of vasospasm and ischemic events when TXA is used preoperatively in patients with aSAH.

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