The Effect of Japanese Herbal Medicines (Kampo) Goreisan and Saireito on the Prevention of Recurrent Chronic Subdural Hematoma

1. MACQUARIE NEUROSURGERY
JOURNAL CLUB
Matsumoto, H., Matsumoto, A., Miyata, S., Tomogane, Y., Minami, H., Masuda, A.,
Yamaura, I., Yoshida, Y., & Hirata, Y. (2024). The Effect of Japanese Herbal
Medicines (Kampo) Goreisan and Saireito on the Prevention of Recurrent Chronic
Subdural Hematoma: A Prospective Randomized Study. Neurosurgery, 94(1), 80–
89.
Ayfer Aslan
07/03/2024

2. Is the study question relevant?
Why was the study done?
• The recurrence of chronic subdural hematoma (CSDH) => reoperation => prolonged
hospital stays and higher morbidity and mortality.
• Japanese herbal medicines (Kampo), such as Goreisan and Saireito => to prevent the
recurrence of CSDH
• No prospective randomized study has proven the efficacy of Kampo medicine
Originality of the work?
• The first prospective randomized study => to investigate the effect of Saireito on the
recurrence of CSDH.
• The first study => Kampo medicine reduced the recurrence of CSDH in an overall
population.
Did the study add anything new?
• Yes => statistical proof of the efficacy of Kampo medicine.
Where was the study published?
• Journal => Neurosurgery, IF 4.8, 5-year IF 5.0, Q1, H-index 228
• Author / Institution metrics => Matsumoto, H (H-index 11); Matsumoto, A (H-index 1);
Miyata, S (H-index 14); Tomogane, Y (H-index 9); Minami, H (H-index 8); Masuda , H (H-
index 6); Yamaura, I (H-index 16); Yoshida, Y (H-index 9); Hirata, Y (H-index 3)

3. Traditional Japanese Herbal Medicines
(Kampo)
Goreisan => 5 herbal components: Alisma tuber, Poria sclerotium, Polyporus sclerotium,
Atractylodes rhizome (byakujutsu), and cinnamon bark.

4. Saireito => A combination of 2 herbal medications: Shosaikoto and Goreisan. Shosaikoto is
composed of 7 herbal components: Bupleurum root, Pinellia tuber, Scutellaria root, Ginseng,
Jujube, Glycyrrhiza, and ginger.
Traditional Japanese Herbal Medicines
(Kampo)

5. Byakujutsu = > containing Atractylodes rhizome
Traditional Japanese Herbal Medicines
(Kampo)

6. Byakujutsu Goreisan
• Mainly inhibits aquaporin (AQP) 1 and 4 channels
• Adjust the body’s water balance
Byakujutsu Saireito
• Shosaikoto => anti-inflammatory effect by inhibiting proinflammatory cytokines and
promoting endogenous enhancement of steroid secretion.
• Saireito has both anti-inflammatory and water utilization benefits.
• Saireito has a stronger anti-inflammatory benefit than Goreisan
Traditional Japanese Herbal Medicines
(Kampo)
Angiogenesis of the
outer membrane => <= fluid to flow into
the subdural space

7. Research hypothesis
What was the research hypothesis? Was it explicitly stated?
• Byakujutsu Goreisan and Saireito may reduce the recurrence rate of
CSDH in overall patients.
• Saireito treatment may be associated with a greater reduction in the
recurrence of CSDH in comparison with Goreisan.
Did the study follow a protocol? Was the protocol followed throughout?
• Yes => Investigator-indicated, single-center prospective, randomized
controlled trial

8. Study design
What type of research question was being asked? (Intervention,
Diagnostic accuracy, Prognosis, Etiology, Screening)
• Intervention
What was the study design? (RCT, Cohort, Case-control, Cross-sectional,
Case report / case series)
• Randomized controlled trial (RCT)
• Is there an appropriate Critical Appraisal checklist that can be used?
E.g. CASP, BestBets, CEBM. See Guide:
https://libguides.mq.edu.au/c.php?g=674377&p=4748716
- No
• Duration of Follow-up
- Follow-up CT scans each month for 3 months after the operation.
- Follow-up was ceased when patient was considered cured (disappearance
of hematoma on follow-up CT).

9. Study design
• Outcome Assesment
- Primary outcome => The recurrence of CSDH within 3 months
postoperatively
 The recurrence of CSDH:
 ipsilateral hematoma
 increased on follow-up CT
 objective deteriorated neurological deficits
 required reoperation within 3 months after the last operation.
- Secondary outcome
 Complications of Kampo medicine
 Functional outcome => assessed using the modified Rankin Scale [mRS] at
the final medical examination

10. Internal Validity (Sources of Bias)
Trial design
• Single-center, between April 2017 and July 2019
• Surgical procedure => Burr hole irrigation with closed-system drainage
under local anesthesia
• Early ambulation => ?how soon
• The drain was removed within 2 days after placement.
• In the absence of complications, patients were generally discharged within
10 days.
• In all cases, antiplatelet or anticoagulant therapy was discontinued
before surgery => usually restarted 1 week after the last operation.
• Three groups:
1) Group G => Goreisan for 3 months
2) Group S => Saireito for 3 months
3) Group N => No medication

11. Internal Validity (Sources of Bias)
Trial design
• Based on the CT, 4 hematoma subtypes => (1) homogeneous type, (2) mixed
type, (3) niveau formation type, (4) acute on chronic type
• The hematoma volumes were calculated by the XYZ/2 method.

12. Internal Validity (Sources of Bias)
Sources of selection bias
• Only unilateral CSDH
• Only mRS <3
• Only age of >20 years
Differences in baseline characteristics
• Underlying diseases that have been reported as risk
factors for recurrence => hypertension, diabetes mellitus,
malignant neoplasm, cerebral vascular disease, liver
disease, renal disease, coagulopathy, and heart disease
etc.
• Use of anticoagulants or antiplatelet medicines before
and after surgery => Some patients recommenced
antiplatelet / anticoagulant therapy 1 week after the last
operation.
• Aetiology => traumatic or nontraumatic
• Different mRS before admission
• NO SIGNIFICANT DIFFERENCES were observed among
demographics of 3 groups.

13. Internal Validity (Sources of Bias)
Sample size / power calculations
• Previously reported recurrence rate of CSDH at authors’ institution =>
13.3%
• The previously reported recurrence rate in the literature => 5%–33%
• The estimated recurrence rate => 30% in the control group and 2% in the
group of Kampo medicines
• The estimated sample size with the 2-tailed t test => 33 patients in each
group
Randomization
• After burr hole surgery, patients were randomized into 1 of the 3 groups with
reference to a random number table => (1) Group G, (2) Group S, and (3)
Group N
Blinding
• No blinding

14. Internal Validity (Sources of Bias)
Statistical analysis – were appropriate statistical tests used?
Yes
• To compare the clinical characteristics and postoperative recurrence
rate => Bartlett test, χ2 test of independence, Fisher exact test, and
Welch test
• To compare the postoperative recurrence rate among the 3 groups =>
the Holm test as a post hoc test
• All values are expressed as the mean and standard deviation.
• P values of <.05 were considered to indicate statistical significance.
• To identify factors independently related to the recurrence of CSDH => a
multivariate logistic regression analysis
• Variables with P values of <.1 in a univariate analysis were selected for the
multivariate analysis.
• All of these statistical analyses were performed using Statcel version 4
(OMS Publishing).

15. External validity (generalisability)
Inclusion / exclusion criteria
• Inclusion criteria:
1) >20 years of age
2) Underwent initial surgery for symptomatic unilateral CSDH and
3) Objective neurological deficits
• The exclusion criteria:
1) Bilateral CSDH
2) Severe dementia
3) mRS >3
4) Treatment with drugs that are reported to have a preventative effect against the
recurrence of CSDH (eg, corticosteroids, carbazochrome sodium sulfonate
hydrate, etizolam, statin, and tranexamic acid)
5) Treatment with Kampo medicine.
Study population - Can the results be applied to my patient?
- Can not be generalized to all patients with CSDH

16. Results
Patient Population

17. Results
Participant flow chart

18. Results
Primary outcomes => recurrence
Secondary outcomes => complications and functional outcome

19. Results
Primary outcomes

20. Results
Comparison of the Clinical Characteristics of Patients With Recurrent CSDH
=> no significant difference in age or recurrence period among the 3 groups

21. Results
Comparison of the recurrence rate in each hematoma subtype between Group N and
patients taking Kampo medicine (Groups G + S) => Kampo medicine may have reduced
the recurrence rate in all types of hematoma, especially the acute on chronic type.

22. Results
Risk Factors for Recurrence =>The acute on chronic type was an independent risk
factor for an increased recurrence rate; Kampo medicine was independently
associated with a decreased recurrence rate

23. Results
Risk Factors for Deteriorated Functional Outcomes => The age of patients with
deteriorated mRS was significantly older in comparison with patients without deteriorated
mRS; Recurrence was an independent risk factor for deteriorated functional outcomes.

24. Results
Adverse events
• Possible side effects with Kampo medicine => general fatigue, allergic
reaction, hepatic dysfunction, and interstitial pneumonia
• No complications
Statistical analysis (estimate of effect size and precision)
• Statistically significant results are not necessarily clinically significant
- The size of subgroups of hematoma subtypes is small
• Have allowances been made for multiple comparisons?
- Yes => Multiple comparisons between 3 groups in terms of recurrences,
mRS, complications etc

25. Discussion / conclusions
Were all clinically important outcomes considered?
• Kampo medicine significantly reduced the postoperative recurrence rate
in the overall population of patients with CSDH.
• The Saireito group had the lowest recurrence rate.
• Recurrence was an independent risk factor for deteriorated functional
outcomes.
• Outcomes only within 3 months postoperatively
Did the data justify the conclusions?
No
• A conclusion based on other studies => ”This study demonstrated that
byakujutsu Goreisan and Saireito may have favorable effects, unlike other
studies, because byakujutsu has stronger anti-inflammatory activity than
sojutsu.”
• No molecular or histological investigations for assessment of anti-inflammatory
activity

26. Discussion / conclusions
What were the study limitations?
• The study population was smaller in comparison with other prospective
randomized studies.
• Excluded cases of bilateral hematoma, <20-year-old patients, >3 mRS
• Outcomes only within 3 months postoperatively
• Neither a placebo arm nor a comparator arm to analyze the effects of
conventional anti-inflammatory medications such as steroids and atorvastatin.
• Not blinded - The mRS and CT findings were assessed by the attending
neurosurgeon
Are the likely treatment benefits worth the potential harms and costs?
No side effects were detected
Were there any conflicts of interest (declared or otherwise)?
No

27. Presentation and style
Clarity of writing, economy of words, organization of paper
• Well organized, clear sentences
Number & quality of figures, tables & illustrations
• Moderate number of figures and tables with high quality
Relevance, accuracy and completeness of bibliography
• Sufficient

28. Conclusion
Summary of key strengths and weaknesses (take away message)
• No investigations on pathogenesis of Kampo medicine prevention against recurrent CSDH
=> no molecular or histopathological evidence of anti-inflammatory activities
• This study may be considered a pilot study.
• Further investigation including a larger sample, a placebo arm, and a comparator arm of
conventional anti-inflammatory medications may be needed to validate these results.
Is the study believable (internally valid)?
• Yes => statistically significant and consistent outcomes
• No => 3 prospective and randomized studies to investigate whether Goreisan reduces the
recurrence rate of CSDH => no beneficial effect in overall patients.
- Byakujutsu Goreisan has a stronger anti-inflammatory effect than sojutsu Goreisan.
- Retrospective studies => Goreisan and Saireito reduced the rate of postoperative
recurrence
Is the study relevant (externally valid)?
• If Kampo medicine is found effective for these sample patients, will it also be effective for other
patients, such as with bilateral CSDH or other CSDH subtypes???
• No => independent variables (such as hematoma subtype) and selection criteria (only
unilateral CSDH, older than 20 years of age) limiting generalizability
Will the study change my practice?
• The size of the groups, selection criteria are limiting the generalizability of the results to our
practice.

29. Thank you