We assessed 489 patients who were diagnosed with spontaneous ICH from October 2008 to October 2018. We excluded 62 patients with symptoms that developed after 24 hours. We also excluded 25 patients who refused treatment because of old age, chronic diseases, or personal issues, and 62 patients who underwent surgery after the first computed tomography (CT) scan. Eleven patients who did not undergo follow-up CT within 48 hours were excluded. Therefore, 329 who were treated appropriately with conservative management, including strict BP control and pain control, were included in the study. This study was approved by Institutional Review Board of Pusan National University Yangsan Hospital (IRB No. 05-2019-111).

All patients with neurological symptoms were routinely evaluated by neurosurgeons and admitted to our neurointensive care unit or neurosurgical unit. This series of patients did not include those with hemorrhage due to intracranial aneurysms, arteriovenous malformation, arteriovenous fistula, cavernous malformation, moyamoya disease, or tumor bleeding. Most of these diseases could be excluded by taking CT angiography or enhanced CT at the same time during their first CT. When tumor bleeding was suspected, the patient's cancer history was confirmed and magnetic resonance images (MRI) were taken after 2 to 4 weeks. Cavernous malformation was excluded via MRI after the hematoma was absorbed.

The first CT was taken within 30 minutes of arrival to the emergency room, the second CT was taken within 48 hours, and the CT was taken early if there were any changes in neurological symptoms or the Glasgow coma scale score. Hematoma size was measured in the initial and second CT images. The maximal diameter was the longest measured intraparenchymal high density among the CT axial sections. The final lesion volume was calculated by multiplying the area obtained in each section by the slice thickness. Ventricular hemorrhage was excluded in the hematoma volume calculation because of calculation difficulties. Various definition for hematoma expansion has reported to be an increase in the hematoma volume of 20% to 50% from the baseline image to the second CT scan.51316) We defined hematoma expansion as an increase of more than 20% of the maximum diameter or increase of more than 20% in volume.

Since February 2017, we have used antifibrinolytic agents in combination with BP and pain control medications in patients with ICH. When ICH was diagnosed via CT scan, patients immediately received 2 g of tranexamic acid (Transamin-S Injection, an intravenous bolus of 2 g, over a period of 10 minutes). The use of this dose was based on Sorimachi's report,27) which is the well-known study of tranexamic acid-based ICH hemostasis. Therefore, patients who did not receive tranexamic acid from October 2008 to January 2017 were compared with patients who were administered tranexamic acid.

The target systolic BP was lower than 140 mmHg. This value was determined according to several ICH guidelines.3141530) BP was monitored continuously through the arterial line. Initial high BP was controlled by a diltiazem or nicardipine bolus intravenous injection, and to maintain systolic BP under 140 mmHg, continuous intravenous administration of nicardipine was used in the neurosurgical intensive care unit during the first 48 hours after admission. For better BP control, we made great efforts to reduce pain by using non-steroidal anti-inflammatory drugs and various analgesics (e.g., narcotic or patch type analgesics). The visual analog scale was utilized to quantify pain. Analgesics were used when the patient complained of pain, including headache. In unconscious patients, analgesics were used when BP was controlled but not controlled.

We collected well-known risk factors for hematoma expansion from patients' data by using electric medical records and the PACS system: patient's age and sex, location of hematoma, level of consciousness, systolic BP at admission, medical history (e.g., hypertension, diabetes, dyslipidemia, cardiovascular disease and chronic kidney disease [CKD]), alcohol consumption, smoking status, use of an antiplatelet agent, use of anticoagulants, and hematoma volumes.

All statistical analyses were performed using SPSS statistics (version 22.0; IBM Corporation, Armonk, NY, USA). Continuous variables are presents as means±standard deviations. Categorical variables are presented as numbers and percentages. Student's t-test, χ² analysis, and the Fisher's exact test were used to assess between-group differences. Receiver operating characteristic (ROC) curves were created to determine the optimal hematoma volume and maximal diameter cut points, sensitivity, and specificity in hematoma expansion according to the second CT. Univariate and multivariate logistic regression analyses were used to assess risk factors for hematoma expansion. Multivariate logistic regressions were performed with independent variables selected from all factors with a value of p<0.1 in univariate analyses. The results are presented as odds ratios with a 95% confidence interval (CI). Statistical significance was set at p<0.05.

Tranexamic acid is a synthetic derivation of the amino acid lysine. It serves as an antifibrinolytic by reversibly binding to 4 or 5 lysine receptor sites on plasminogen molecules. This binding completely blocks the interaction of plasminogen and plasmin with lysine residues on the surface of fibrin, thereby preventing proteolytic action of plasmin on fibrin and inhibiting fibrinolysis at the bleeding site.10) With this mechanism, tranexamic acid has been used for decades in multiple surgical disciplines for its ability to reduce intraoperative blood loss and the need for blood transfusions.17) Evidence suggests that tranexamic acid may also reduce postoperative edema and ecchymosis.21)

Tranexamic acid also passes through the blood-brain barrier and may be effective in hemorrhage diseases, including intracranial hemorrhages.29) In light of these concepts, some researchers have reported that tranexamic acid reduces rebleeding in aneurysmal subarachnoid hemorrhages (SAH); although it has been reported that thromboembolic events or delayed cerebral ischemia also increases.821) In addition, recent systemic reviews have reported that the use of tranexamic acid in patients with nontraumatic SAH reduces mortality; however, this finding was not statistically significant.2) In another intracranial hemorrhage study, Sorimachi et al.26) reported that the combination of rapid administration of tranexamic acid and strict BP control may prevent hematoma growth in patients with ICH.22) To the best of our knowledge, there is no evidence to show the effect of tranexamic acid in ICH aside from this study. Recently, several well-designed clinical trials, including those evaluating TICH-2, have been planned and conducted, but they have not shown statistically satisfactory results including reduce hematoma expansion and clinical outcomes.2233) Therefore, our study investigated the effect of tranexamic acid on ICH in a way similar to Sorimachi's study.27) Our results showed that there was no statistical significance in ICH patients with rapid administration of tranexamic acid and strict conservative management, but the rate of patients who experienced hematoma expansion was reduced (14.5% vs. 10.7%).

The use of tranexamic acid in cardiac, orthopedic, and spinal deformity surgeries has shown reduced hemorrhage and intraoperative transfusion. However, in the above-mentioned surgeries, hemorrhage occurs mainly in muscle and connective tissues, but most ICHs occur in small blood vessels. Therefore, a direct comparison is not appropriate.

The safety of tranexamic acid is also controversial. The primary issue with the use of tranexamic acid is the potential for an increased risk of thromboembolic events, such as myocardial infarction, ischemic stroke, deep vein thrombosis, and pulmonary embolism.631) However recent literatures, including a meta-analysis, demonstrated that tranexamic acid was not associated with an increased incidence of thromboembolic events.31) In addition to these complication, tranexamic acid has complications such as nausea, vomiting and abdominal pain, but it had been difficult to evaluate in our patients. The present study showed a limited observation duration and number of cases, but we did not observe such complications.

Our study showed that the maximal diameter of hematomas and the presence of spot sign are risk factors for hematoma expansion. These variables are risk factors for well-known hematoma expansion. Our study suggests that if the maximal diameter of the hematoma is greater than 40 mm, it should be closely monitored because of the possibility of hematoma expansion. Other previous studies identified hematoma volume as a predictor of hematoma expansion,49) however our study failed to concur, possibly because researchers did not directly calculate volume according to the CT slice thickness. In contrast, maximal diameter of hematoma could be predicted by hematoma expansion because this was easily measured and accurate.

Spot sign has been studied extensively in the last decade and might be the strongest individual predictor for subsequent hematoma expansion. One believable explanation is that spot sign might represent active bleeding or rebleeding in ruptured vessels, which reflects contrast extravasation on CT or MRI scans.7) Recently, modified spot sign and black hole sign on non-enhance CT scans have been proposed as radiologic markers similar to spot sign, and these markers are also strongly associated with hematoma expansion and prognosis.28)

Other parameters including anticoagulant and antiplatelet medication did not indicate statistical significance. These results suggest that we had a small number of cases and those adjustable parameters, including BP and pain, were strictly managed according to the guidelines.

Our study has several limitations including the retrospective nature of data collection and small population. The results of well-designed and randomized, controlled ongoing clinical trials will prove the value of our findings.