Goreisan is a herbal Kampo medicine used for treating chronic subdural hematoma (CSDH) in Japan. Experimental studies have suggested that Goreisan exerts a hydrogogue effect, but clinical evidence for the effectiveness of Goreisan in CSDH is currently lacking. Using a national Japanese inpatient database, we examined the association between Goreisan use and reoperation rates after burr-hole surgery for CSDH. We identified 36,020 patients, including 3,889 Goreisan users and 32,131 nonusers. Propensity scores of receiving Goreisan were calculated based on hospital characteristics and patient backgrounds (age, sex, body mass index, activities of daily living, consciousness level, comorbidities, antithrombotic agent use, mannitol infusion, and corticosteroid infusion). One-to-one propensity-score matching created 3,879 pairs of Goreisan users and nonusers. Propensity-matched analysis revealed that Goreisan use was significantly associated with a lower reoperation rate (4.8%) compared with nonuse (6.2%) (risk difference, −1.4%; 95% confidence interval (CI), −2.4% to −0.38%). The number needed to prevent one reoperation was 72 (95% CI, 41–265). Instrumental-variable analysis showed similar results to the propensity-matched analysis. These results suggest that Goreisan use reduced the need for reoperation after burr-hole surgery for CSDH.
Chronic subdural hematoma (CSDH) is a common type of intracranial hemorrhage, particularly in the elderly. CSDHs are well-delineated collections of blood between the dura matter and arachnoid space. Burr-hole craniotomy is a well-established, first-choice treatment for CSDH; however, studies have shown high recurrence rates of 4%–30% after burr-hole surgery [
Several treatments have been shown to be useful for treating CSDH. Mannitol or glycerol may be infused as an adjunctive therapy to surgery or as conservative therapy in inoperable patients. Corticosteroid infusion represents another feasible option for the postoperative treatment of CSDH [
Goreisan is a Japanese herbal Kampo medicine that has been used to treat asymptomatic CSDH and prevent postoperative recurrence of CSDH in Japan. Experimental studies have suggested that Goreisan exerts a hydrogogue effect [
In the present study, we examined the association between the use of Goreisan and the need for reoperation after burr-hole surgery for CSDH, using information from a national Japanese inpatient database.
The present study utilized the Japanese Diagnosis Procedure Combination (DPC) inpatient database. The details of the database have been described elsewhere [
A Japan Coma Scale of 0 indicates alert consciousness; single-digit scores (1, 2, 3) indicate being drowsy but awake without any stimuli; two-digit scores (10, 20, 30) indicate somnolence but being aroused by some stimuli; and three-digit scores (100, 200, 300) indicate coma. The Japan Coma Scale and Glasgow Coma Scale are well correlated [
The Barthel Index is a reliable disability scale for stroke patients, which measures the patient’s performance in activities of daily life related to self-care (feeding, grooming, bathing, dressing, bowel and bladder care, and toilet use) and mobility (ambulation, transfers, and stair climbing). The maximal score is 100, indicating that the patient is fully independent in terms of physical functioning, while the lowest score is 0, representing a totally dependent, bedridden state [
The database also includes estimated total hospitalization costs based on reference prices in the Japanese national fee schedule that determines item-by-item prices for surgical, pharmaceutical, laboratory, and other inpatient services.
The requirement for informed consent was waived because of the anonymous nature of the data. Study approval was obtained from the Institutional Review Board at The University of Tokyo.
We included patients aged ≥40 years who were hospitalized with CSDH (ICD-10 code, I62.0) as a main diagnosis at admission and who underwent burr-hole surgery within 2 days after admission (i.e., on the day of admission or the following day). We excluded patients younger than 40 years old; patients diagnosed with cerebral infarction, cerebral hemorrhage, or subarachnoid hemorrhage at admission; and patients who used Kampo medicines other than Goreisan. We divided the eligible patients into the following groups: (i) those who started Goreisan within 2 days after surgery (Goreisan users) and (ii) those who did not receive Goreisan (Goreisan nonusers).
We examined the following patient characteristics: age, sex, Japan Coma Scale at admission, Barthel Index at admission, body mass index (kg/m2), comorbidities present at admission, receipt of antithrombotic therapy (including anticoagulants and antiplatelet drugs), mannitol or glycerol infusion started within 2 days after surgery, and corticosteroid infusion within 2 days after surgery.
Body mass index was classified into the following four categories according to the World Health Organization criteria: <18.5 kg/m2 (underweight), 18.5–24.9 kg/m2 (normal weight), 25.0–29.9 kg/m2 (overweight), and ≥30 kg/m2 (obesity) [
The primary outcome was reoperation after burr-hole surgery performed during the same hospitalization or at readmission during the study period. The secondary outcome was total hospitalization costs for both the initial admission and readmissions.
We compared the baseline characteristics between Goreisan users and nonusers using the standardized difference. An absolute standardized difference >10 indicated a significant imbalance in a covariate [
One-to-one propensity-score matching was performed between Goreisan users and nonusers. Propensity-score matching addresses the confounding bias inherent in retrospective observational studies, where outcomes may reflect a lack of comparability between treatment groups rather than the effects of the study treatment [
The above results were confirmed using instrumental-variable analysis. Propensity-score analysis and conventional multivariate regression analysis are unable to remove hidden biases caused by unmeasured confounders. Instrumental-variable analysis is another pseudorandomization process that can technically address unmeasured confounders. The key assumptions of the instrumental variable are that (i) it is highly correlated to the treatment assignment, (ii) it is not correlated to any measured or unmeasured patient backgrounds, and (iii) it does not affect patient outcomes except through treatment [
All statistical analyses were performed using Stata version 13 (StataCorp, College Station, TX), including the “teffects psmatch” procedure for propensity-score matching and the “ivreg2” procedure for instrumental-variable analysis. A two-tailed significance level of 0.05 was used in all statistical analyses.
We identified 36,020 eligible patients from 797 hospitals, including 3,889 (10.8%) Goreisan users and 32,131 (89.2%) nonusers. One-to-one propensity-score matching created 3,879 pairs (
Table
Baseline characteristic of patients with and without Goreisan in unmatched and propensity-matched groups.
Unmatched groups ( |
Propensity-matched groups ( | |||||
---|---|---|---|---|---|---|
Goreisan users |
Goreisan nonusers |
Standardized difference | Goreisan users |
Goreisan nonusers |
Standardized difference | |
Type of hospital, |
||||||
Nonacademic | 2,997 (77.1) | 27,644 (86.0) | 19.6 | 2,997 (77.3) | 3,016 (77.8) | 1.0 |
Academic | 892 (22.9) | 4,487 (14.0) | −19.6 | 882 (22.7) | 863 (22.2) | −1.0 |
Hospital volume (per year), |
||||||
≤22 | 1,133 (29.1) | 9,836 (30.6) | 2.6 | 1,131 (29.2) | 1,098 (28.3) | −1.5 |
23–36 | 1,283 (33.0) | 10,848 (33.8) | 1.3 | 1,275 (32.9) | 1,340 (34.5) | 2.9 |
≥37 | 1,473 (37.9) | 11,447 (35.6) | −3.8 | 1,473 (38.0) | 1,441 (37.1) | −1.4 |
Fiscal year, |
||||||
2010 | 568 (14.6) | 7,748 (24.1) | 19.2 | 568 (14.6) | 564 (14.5) | −0.2 |
2011 | 1,278 (32.9) | 12,066 (37.6) | 8.0 | 1,278 (32.9) | 1,305 (33.6) | 1.2 |
2012 | 2,043 (52.5) | 12,317 (38.3) | −23.6 | 2,033 (52.4) | 2,010 (51.8) | −1.0 |
Age (years), mean (SD) | 76.5 (10.7) | 76.4 (11.1) | −1.4 | 76.2 (10.7) | 76.2 (10.7) | 0.0 |
Sex, |
||||||
Male | 2,644 (68.0) | 21,577 (67.2) | −1.5 | 2,636 (68.0) | 2,618 (67.5) | −0.8 |
Female | 1,245 (32.0) | 10,554 (32.8) | 1.5 | 1,243 (32.0) | 1,261 (32.5) | 0.8 |
Body mass index (kg/m2), |
||||||
<18.5 | 487 (12.5) | 4,164 (13.0) | 1.1 | 486 (12.5) | 452 (11.7) | −2.2 |
18.5–22.9 | 1,712 (44.0) | 14,065 (43.8) | −0.4 | 1,709 (44.1) | 1,746 (45.0) | 1.6 |
23.0–24.9 | 681 (17.5) | 5,356 (16.7) | −1.8 | 681 (17.6) | 723 (18.6) | 2.3 |
25.0–29.9 | 556 (14.3) | 4,079 (12.7) | −3.9 | 550 (14.2) | 536 (13.8) | −0.9 |
≥30.0 | 57 (1.5) | 459 (1.4) | −0.3 | 57 (1.5) | 46 (1.2) | −2.1 |
Missing | 396 (10.2) | 4,090 (12.7) | 6.4 | 396 (10.2) | 376 (9.7) | −1.4 |
Barthel Index at admission, |
||||||
0 | 794 (20.4) | 7,676 (23.9) | 6.8 | 794 (20.5) | 809 (20.9) | 0.8 |
5–45 | 671 (17.3) | 5,679 (17.7) | 0.9 | 670 (17.3) | 609 (15.7) | −3.5 |
50–95 | 808 (20.8) | 6,016 (18.7) | −4.2 | 804 (20.7) | 746 (19.2) | −3.1 |
100 | 894 (23.0) | 6,740 (21.0) | −4.0 | 889 (22.9) | 991 (25.5) | 5.0 |
Missing | 722 (18.6) | 6,020 (18.7) | 0.4 | 722 (18.6) | 724 (18.7) | 0.1 |
Japan Coma Scale at admission, |
||||||
0 (alert) | 1,809 (46.5) | 14,112 (43.9) | −4.3 | 1,799 (46.4) | 1,898 (48.9) | 4.2 |
1 digit (drowsy) | 1,844 (47.4) | 15,124 (47.1) | −0.6 | 1,844 (47.5) | 1,747 (45.0) | −4.1 |
2 digits (somnolence) | 190 (4.9) | 1,965 (6.1) | 4.3 | 190 (4.9) | 185 (4.8) | −0.5 |
3 digits (coma) | 46 (1.2) | 930 (2.9) | 9.3 | 46 (1.2) | 49 (1.3) | 0.6 |
Comorbidities, |
||||||
Malignancy | 137 (3.5) | 1,359 (4.2) | 2.9 | 137 (3.5) | 125 (3.2) | −1.4 |
Ischemic heart disease | 184 (4.7) | 1,562 (4.9) | 0.5 | 184 (4.7) | 163 (4.2) | −2.2 |
Chronic heart failure | 113 (2.9) | 1,057 (3.3) | 1.8 | 113 (2.9) | 96 (2.5) | −2.2 |
Chronic renal failure | 53 (1.4) | 836 (2.6) | 6.9 | 53 (1.4) | 47 (1.2) | −1.1 |
Liver cirrhosis | 22 (0.6) | 163 (0.5) | −0.7 | 22 (0.6) | 24 (0.6) | 0.5 |
Pneumonia | 27 (0.7) | 289 (0.9) | 1.8 | 27 (0.7) | 20 (0.5) | −1.9 |
Urinary tract infection | 9 (0.2) | 104 (0.3) | 1.4 | 9 (0.2) | 12 (0.3) | 1.2 |
Sepsis | 2 (0.1) | 35 (0.1) | 1.6 | 2 (0.1) | 3 (0.1) | 0.8 |
Antithrombotic agent use, |
317 (8.2) | 2,639 (8.2) | 0.2 | 314 (8.1) | 278 (7.2) | −2.9 |
Mannitol infusion, |
104 (2.7) | 1,033 (3.2) | 2.6 | 104 (2.7) | 84 (2.2) | −2.8 |
Steroid infusion, |
15 (0.4) | 243 (0.8) | 3.8 | 15 (0.4) | 15 (0.4) | 0.0 |
Table
Reoperation rates and total hospitalization costs in Goreisan users versus nonusers in propensity-matched groups.
Goreisan users | Goreisan nonusers |
| |
---|---|---|---|
( |
( | ||
Reoperation, |
187 (4.8) | 241 (6.2) | 0.001 |
Total hospitalization costs ($), mean (SD) | 6,428 (4,646) | 6,707 (6,567) | 0.030 |
SD, standard deviation.
Table
Relative risks, risk differences, and number needed to treat in reoperation rates comparing Goreisan users with nonusers.
Relative risk | Risk difference | Number needed to treat | |
---|---|---|---|
(95% CI) | (95% CI) | (95% CI) | |
Propensity-score matching ( |
0.78 (0.64; 0.93) | −1.4% (−2.4%; −0.38%) | 72 (41; 265) |
Instrumental-variable analysis ( |
— | −2.2% (−3.8%; −0.67%) | 45 (26; 148) |
CI, confidence interval.
The present retrospective observational study using a national inpatient database showed a significant reduction in the need for reoperation after burr-hole surgery for CSDH in patients who used Goreisan, compared with those who did not. Total hospitalization costs were also significantly lower in Goreisan users.
Burr-hole surgery is a well-established treatment for CSDH, but blood collection sometimes reoccurs, requiring reoperation [
Goreisan, a Japanese herbal Kampo medicine, is a mixture of five herbs including Alismatis Rhizoma, Poria, Polyplus, Atractylodis Lanceae Rhizoma, and Cinnamomi Cortex. Experimental studies have suggested a potential mechanism of hydrostatic modulation caused by Goreisan [
Japanese clinicians have reported case series of Goreisan use for CSDH, mostly in Japanese journals [
Several limitations should be acknowledged. First, the database did not include detailed clinical information on laboratory data or computed tomography findings (e.g., size of hematoma). Second, this study was not based on a randomized controlled trial, and its retrospective nature might have been associated with residual confounders, despite the use of robust statistical methods.
Goreisan use effectively reduced reoperation rates after burr-hole surgery for CSDH, based on a large national database.
The author declares that there is no conflict of interests.
This study was funded by Grants-in-Aid from the Ministry of Health, Labour and Welfare, Japan.