Effects of the Japanese traditional medicine Goreisan on adverse events affecting mucosal edema in patients with subarachnoid hemorrhage treated with clazosentan

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Effects of the Japanese traditional medicine Goreisan on adverse events affecting mucosal edema in patients with subarachnoid hemorrhage treated with clazosentan

https://doi.org/10.21203/rs.3.rs-4980693/v1

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Despite successful management of pulmonary complication with fluid restriction protocol in aneurysmal subarachnoid hemorrhage (aSAH) patients treated with clazosentan, management of symptoms related to mucosal edema, such as diarrhea, stuffy nose, and difficulty in breathing, remains challenging. Hence, we investigated the effect of Goreisan shown to be effective in the treatment of symptoms related with mucosal edema in aSAH patients treated with clazosentan. Patients with aSAH who received clazosentan for vasospasm after aneurysm obliteration were prospectively enrolled in the study. Fluid balance parameters and the incidence of vasospasm, pulmonary edema, mucosal edema-related symptom (such as diarrhea and swelling of the nasal mucosa) were compared between these patients treated with Goreisan (Group G) and without Goreisan (Group NG). As results, Groups NG and G comprised 29 and 40 consecutive patients, respectively. No significant differences in fluid intake, urine volume, frequency of furosemide injection, incidence of vasospasm, pulmonary edema, or discontinuation of clazosentan treatment between the two groups were found over the treatment course, although refractory hyponatremia occurred less frequently in Group G than in Group NG (0% and 10.3%, p = 0.039, respectively). The incidence of diarrhea and the relative mucosal thickness was also significantly lower in Group G than in Group NG (7.3% and 21.9%; p = 0.0004, 113.8% vs. 175.4%; p = 0.001). Clazosentan treatment combined with diuretics and Goreisan was effective in managing diarrhea and swelling of the nasal mucosa. Our treatment protocol may be reasonably applied to patients with aSAH who are treated with clazosentan.

clazosentan

Goreisan

mucosal edema

subarachnoid hemorrhage

A randomized phase 3 trial conducted in Japan has demonstrated the efficacy of clazosentan, an endothelin-1 (ET-1) receptor antagonist, on vasospasm-related morbidity and all-cause mortality in patients with aneurysmal subarachnoid hemorrhage (aSAH) [3]. Based on these findings, clazosentan was approved for use in the prevention of vasospasm in Japan in early 2022. Although the incidence of adverse events related to clazosentan treatment did not differ from that in placebo groups, discontinuation of clazosentan administration owing to adverse events related to fluid retention, such as pulmonary edema and pleural effusion, has been reported from independent facilities in real-world settings [6, 7, 11, 13]. Thus, in contrast to the conventional hydration management, a fluid restriction protocol using diuretics has been applied and safely used to avoid pulmonary complications in patients treated with clazosentan in Japan [1, 13, 16].

Although the pulmonary complications are well-managed with administration of diuretics, patients continue to experience symptoms related to mucosal edema, such as diarrhea, stuffy nose, and difficulty in breathing. However, these symptoms have not been reported as frequently occurring adverse events (presenting in 5.5% of the patients treated with clazosentan) in the clinical trials of clazosentan [3, 5]. Moreover, swelling of nasal mucosa is occasionally noted on computed tomography (CT) in patients under clazosentan treatment.

A Japanese traditional medicine, Goreisan, has been shown to be effective in the treatment of symptoms related with mucosal edema in multiple organs owing to its diuretic effect and inhibition of aquaporin upregulation [10, 12, 19, 20]. Therefore, in addition to diuretics, we hypothesized that Goreisan would be effective in improving diarrhea and mucosal edema symptoms, which require management during clazosentan administration, in patients with aSAH.

Herein, we investigated the effect of Goreisan on mucosal edema-related adverse events in patients with aSAH treated with clazosentan for vasospasm prophylaxis.

Study design

This was a prospective controlled trial with historical controls [1]. Eligible patients were prospectively assigned to Group G, which received Goreisan in addition to clazosentan. The protocol was reviewed and approved by the Iwate Medical University School of Medicine institutional ethics committee (No. MH2023-106), and written informed consent was obtained from all patients or their next of kin. Informed consent from the patients of the historical control (Group NG) was waived because of the retrospective selection and the processing of anonymous information.

Patient selection

We prospectively included consecutive patients treated at three institutions with clazosentan for vasospasm prophylaxis within 72 h of aSAH onset. The following patients were excluded: those with no aneurysmal treatment regardless of the reason, those who received aneurysmal treatment on day 4 or later, those with cardiopulmonary dysfunction, or those with pulmonary edema requiring specific treatment on admission.

Treatment protocol during vasospasm prophylaxis and management of fluid balance

Over the course of the vasospasm prophylaxis, systolic blood pressure was maintained below 160 mmHg with intravenous nicardipine or oral amlodipine; fasting blood glucose was controlled below 200 mg/dL with subcutaneous insulin and/or oral medication, and enteral or oral fludrocortisone and/or sodium chloride were administered in patients with serum sodium values < 135 mEq/l. Refractory hyponatremia was defined as a decrease in serum sodium value < 135 mEm/L despite sodium correction for 3 days. Medical therapy for comorbidities was continued as needed.

Accumulated fluid balance was checked every 12 h and maintained between − 500 ml and + 1000 ml cumulatively. Fluid intake was calculated by adding the total amount of water consumed as infusion fluid, drinking water, and water consumed from food, as estimated by hospital nutritionists. Fluid output was calculated by adding the amount of urine and insensible fluid loss (mL) determined by the formula: 800 (mL) + 20% × 800 (mL) × (maximum temperature − 37) [15]. The amount of drained cerebral spinal fluid was also included in the fluid output if drain tubes were placed. Fluid balance was determined by subtracting the fluid output (mL) from the intake at each time point. Throughout the prophylactic treatment for vasospasm, the intravenous infusion volume was restricted between 0.4 mL/kg/h and 0.8 mL/kg/h owing to the fluid retention effect caused by administering clazosentan.

In the historical Group NG, as a previously reported control data [1], only clazosentan was administered. The same inclusion and exclusion criteria as the present study were applied to the historical group. In patients with fluid retention (Group G) (defined as a weight gain ≥ 500 g on postoperative day 1 compared with the preoperative body weight), Goreisan was administered via the oral or enteral route (7.5 g/day in three divided doses) during clazosentan administration. In both groups, fluid balance was managed by injecting 10 mg of furosemide when the accumulated fluid balance was > 1000 ml, as described previously [1].

Variables and data source

The variables included baseline patient demographics, radiographic characteristics on CT and CT angiography, and procedure-related data. Data sources included patients’ medical records and radiographic reports. Patient demographics included age, sex, preoperative SAH severity (determined using the World Federation of Neurological Surgeons [WFNS] Grading Scale) [14], and the baseline modified Rankin scale (mRS). Radiographic characteristics included a modified Fisher scale on admission and location of the aneurysm [4].

Comparison of the treatment outcomes

Presence of asymptomatic and symptomatic vasospasm, rescue treatment for symptomatic vasospasm (balloon angioplasty and/or intra-arterial fasudil injection), incidence of discontinuation of clazosentan for any reason, pulmonary edema, hyponatremia, brain edema, percentage of diuretic use per total days of clazosentan administration, and poor functional outcome (defined as mRS ≥ 3 at the 3-month follow-up) were compared between Group NG and Group G. The presence of vasospasm was defined as a < 75% diameter reduction in the intracranial internal carotid artery or M1 segment of the middle cerebral artery on days 7 and 10 after the onset of SAH, as compared to magnetic resonance angiography or CT angiogram imaging obtained 4 weeks after SAH. Vasospasm was defined by two experienced neurosurgeons (T.K. and H.K. who have been more than 15 years as a certified surgeon).

Comparison of the incidences of diarrhea and swelling of nasal mucosa

The incidence of diarrhea was defined by stools classified as 6 or 7 (muddy or watery stool) on the Bristol stool chart [8], occurring three or more times within a day [17]. The frequency of diarrhea was calculated as a percentage by dividing the total number of days with diarrhea by the total days receiving clazosentan for each patient. The incidence of diarrhea was also evaluated based on nutritional methods, such as enteral or oral intake.

Oral or enteral nutrition was initiated within 3 days after the administration of clazosentan, and the dose was gradually increased depending on the patient’s condition and medical comorbidities.

To assess swelling of the nasal mucosa, non-contrast CT scans of the craniomaxillofacial region obtained for brain examination on admission and at follow-up (day 5–7 after administration of clazosentan) were evaluated on axial images displayed with a fixed window level of 300 Hounsfield units (HU) and a window width of 1300 HU. The thickness of the nasal septal mucosa was measured at the point of maximum thickness from the floor of the nasal septum. The relative thickness of the nasal septal mucosa was calculated using the following formula: (thickness of the nasal mucosa at follow-up/thickness of the nasal mucosa on admission) × 100.

To avoid reactive swelling of the nasal mucosa in patients receiving nasal enteral feeding, mucosal thickness was measured on the side contralateral to the side of the tube.

Statistical analysis

Statistical analyses were aimed at testing the superiority of Goreisan treatment in terms of adverse events related to clazosentan treatment, such as symptomatic pulmonary edema, diarrhea, and swelling of the nasal mucosa. The required sample size in Group G was determined as follows: the total incidence of adverse events was 41.5% in the NG group (n = 29 subjects) based on the present series and our previous study [1]. Based on previous studies [10, 19, 20], the incidence of these adverse events in patients under Goreisan treatment was estimated to be 20.8%. Therefore, to detect a 20.7% difference in the incidence of the adverse events in Group G with one-sided significance, 40 patients would be required for a statistical power of 80% and an error of 5%.

MedCalc version 15.0 (MedCalc Software, Ostend, Belgium) was utilized for the statistical analyses.

Fisher’s exact test was used to analyze categorical variables (patient demographics, symptomatic vasospasm incidence, rescue endovascular treatment, pulmonary edema, brain edema, discontinuation of clazosentan). Mann–Whitney U tests were employed to compare continuous variables (fluid intake and output every day within 14 d after vasospasm prophylaxis, diarrhea, and the relative thickness of nasal mucosa) between Groups NG and G. Significance was set at p < 0.05 for all statistical analyses.

Patient characteristics

This study enrolled 85 patients diagnosed with aSAH, of which 16 were excluded for the following reasons: nine patients had not undergone surgical treatment for aneurysms owing to a severe neurological condition or upon the request of the patient’s family; five patients were hospitalized for more than 4 days following aSAH onset; and two patients had hypoxia due to neurogenic pulmonary edema. As a result, 29 and 40 consecutive patients were included in Group NG and G between June 2022 and April 2024, respectively. Baseline patient characteristics, including age, sex, severity of SAH, radiological grading of SAH, aneurysm location, and treatment methods, did not differ between Groups NG and G (Table 1).

Table 1

Patient demographics and, disease characteristics and treatments
	Group NG (n = 29)	Group G (n = 40)	p value
Mean age, yrs	60.9 (16.5, 18–86)	60.9 (16.5, 18–86)	0.2631
Men/Women	10/19	15/25	0.7983
WFNS grade			0.9223
1	1	2
2	12	18
3	7	9
4	7	10
5	2	1
Modified Fisher scale			0.8582
0–2	6	9
3–4	23	31
Aneurysm location (anterior circulation)	27	35	0.45
Treatments			0.509
Clipping	11	10
Coiling	17	28
Trapping and bypass	1	2
Values are number (%) or mean (SD, range) where appropriate.

Management of fluid balance

Figure 1 shows the fluid intake (Fig. 1A) and urine volume (Fig. 1B) of the patients in each group over the course of vasospasm prophylaxis. No significant differences in fluid intake or urine volume were noted between the two groups over the treatment course.

Angiographic and clinical outcomes

Table 2 shows a comparison of angiographic and clinical outcomes between the groups. The incidences of asymptomatic (10.3% and 5% in Groups NG and G, respectively) and symptomatic vasospasm (0% and 2.5% in Groups NG and G, respectively) and rescue treatment for symptomatic vasospasm (0% and 2.5% in Groups NG and G, respectively) did not differ between the two groups. The mean frequency of furosemide injections during clazosentan treatment did not differ between the two groups (3.4 ± 2.4 times and 4.25 ± 2.7 in Groups NG and G, p > 0.05, respectively). Refractory hyponatremia was less common in Group G (0%) than in Group NG (10.3%) (p = 0.039). No brain edema was observed in the present study. Overall, clazosentan was discontinued in four patients (5.8%), all of whom discontinued the medication owing to pulmonary edema. There was no significant difference in the incidence of discontinuation related to pulmonary edema. 3-month mRS scores did not differ significantly between the two groups.

Table 2

Comparison of the clinical and angiographic outcomes
	Group NG (n = 29)	Group G (n = 40)	p value
Asymptomatic vasospasm	3 (10.3)	2 (5)	0.4014
Symptomatic vasospasm leading to infarction	0 (0)	1 (2.5)	0.3945
Rescue treatment for symptomatic vasospasm	0 (0)	1 (2.5)	0.3945
Administration of loop diuretics (times), median [IQR]	3.4 (2.4, 0–10)	4.25 (2.7, 0–11)	0.2167
Adverse event
Symptomatic pulmonary edema	3 (10.3)	1 (2.5)	0.1718
Refractory hyponatremia	3 (10.3)	0 (0)	0.0389
Brain edema	0 (0)	0 (0)	0.1854
Discontinuation of clazosentan	3 (10.3)	1 (2.5)	0.1718
Poor mRS (≥ 3) at 3-month follow-up	8 (27.6)	14 (35)	0.5173
mRS = modified Rankin Scale. Values are number of patients (%) or mean (SD, range) where appropriate.

Comparison of the incidence of diarrhea and nasal mucosa swelling

The patients in Group G had a significantly lower incidence of muddy and watery diarrhea (Bristol stool chart 6 or 7) than did those in Group NG (7.3% and 21.9%, p = 0.0004, respectively; Fig. 2A). In terms of enteral nutrition (20.8% and 38.8%, p = 0.015, respectively; Fig. 2B) and oral nutrition (2.6% and 16.5%, p = 0.0001, respectively; Fig. 2C), significantly lower incidences of diarrhea was observed in Group G patients than in Group NG patients.

The relative mucosal thickness was significantly lower in patients in Group G than in those in Group NG (113.8% and 175.4%, p = 0.001, respectively; Fig. 2D). Representative changes in mucosal thickness on admission and at follow-up in a patient in Group NG (5 days after administration of clazosentan) are shown in Fig. 3. In most patients, the diarrhea and swelling of the nasal mucosa resolved within a few days of clazosentan administration.

The present study demonstrated that the incidence of diarrhea and nasal mucosal edema was significantly reduced with Goreisan treatment, without increasing vasospasm-related complications in patients with aSAH treated with clazosentan.

ET-1 receptor is distributed in microvessels with the ET-1A receptor, which is the most potent vasoconstrictor. The ET-1A receptor is more abundant than the ET-1B receptor in normal human intestine and colon [2, 18]. Therefore, systemic administration of clazosentan, a selective ET-1A receptor antagonist, can induce vasodilation and cause diarrhea owing to mucosal edema in the gastrointestinal tract. In contrast to the relatively low incidence (5.5%) of diarrhea observed in a phase III trial in Japan [3], a high incidence (21.9%) of diarrhea was observed during clazosentan treatment in the NG group in the present study. An underlying cause of the discrepancy may be that the present study focused on quantitatively assessing the incidence of diarrhea using the Bristol stool chart [8], which revealed the underlying incidence of diarrhea in the previous phase III trial [3]. As previously described, Goreisan has been shown to have an antidiarrheal and gastrointestinal tissue-protective effect by inhibiting intestinal aquaporin 3 expression [10]. Consistently, the patients treated with both clazosentan and Goreisan had a significantly lower incidence of muddy and watery diarrhea than did patients under clazosentan only, regardless of the nutrition format used in the present study.

The pharmacological effect of clazosentan, as an antagonist of the selective ET-1A receptor, on the upper and lower respiratory mucosa (including the nasal mucosa) should also be considered, as ET-1A and B receptors are expressed in these tissues [9]. As previously described, pulmonary edema, which is related to edema of the lower respiratory mucosa, is a significant adverse event that has been well-described in a previous randomized study [3, 5]. Furthermore, in our real-world experience, some of the patients without impaired consciousness have complained of a stuffy nose and difficulty in breathing during clazosentan treatment, particularly when sleeping. In the present study, relative mucosal thickness, an objective finding of mucosal edema, in the upper respiratory tract was significantly lower in patients treated with both clazosentan and Goreisan than in those treated with clazosentan alone. Although the effect of Goreisan on the upper respiratory tract may be minimal for patients with mild to moderate clinical conditions (such as WFNS grades I–III), it could be critical for patients with severe clinical condition (such as WFNS grade IV-V) or those with upper airway comorbidities such as obesity or sleep apnea syndrome during clazosentan treatment; these patients should be closely monitored.

Goreisan has been demonstrated to increase urine output owing to its diuretic effect, without affecting electrolyte balance [10, 20]. However, because the administration of loop diuretics was equally required to control appropriate fluid balance regardless of the combination of Goreisan in the present study, the diuretic effect of Goreisan might not be strong. Regarding the electrolyte balance, the incidence of refractory hyponatremia was significantly lower in patients treated with both clazosentan and Goreisan than in those treated with clazosentan alone. This may be related to the effect of Goreisan in reducing the incidence of diarrhea, which can cause hyponatremia, although the underlying mechanism remains unclear.

This study had certain limitations that require further discussion. First, this study compared historical controls with a prospective cohort rather than using randomization. Although vasospasm management was identical between the two cohorts, the administration of Goreisan was the only difference. Second, although the pharmacological mechanism of Goreisan for improving adverse events related to mucosal edema seems to involve inhibiting aquaporin upregulation, preclinical research is required to validate this result. Third, because the sample size of the present study was small, a multicenter trial with a larger sample size would have been beneficial.

Under controlled fluid balance with loop diuretics, clazosentan treatment combined with Goreisan was effective in managing minor but potentially critical complications, such as diarrhea and swelling of the nasal mucosa. Therefore, we believe that our treatment protocol can be reasonably applied to patients with aSAH who are being treated with clazosentan.

Ethics approval

The ethics committee of Iwate Medical University School of Medicine reviewed and approved the study protocol (No. MH2023-106).

Consent to participate

Each patient provided written informed consent prior to participation.

Consent for publication

Each patient provided written informed consent prior to publication.

Funding:

This work was partly supported by Grants-in-Aid for Scientific Research, KAKENHI, from the Japan Society for the Promotion of Science (22K09215 to Dr. Kubo).

Disclosures:

The authors have no personal, financial, or institutional interests in any of the drugs, materials, or devices described in this article.

Author Contribution

Author contributions: YA: Writing- Original draft preparation, Conceptualization, Methodology, Visualization. KC, KM, DK, KY: Data curation. SF: Investigation, Validation, Statistical analysis. TM, TK, YK, HK: Validation, Supervision. KO: Reviewing and Editing, Supervision.

Acknowledgments:

The authors would like to thank Editage (https://www.forte-science.co.jp) for assistance with English language editing.

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No competing interests reported.

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You are reading this latest preprint version

Effects of the Japanese traditional medicine Goreisan on adverse events affecting mucosal edema in patients with subarachnoid hemorrhage treated with clazosentan

Status:

Version 1

Abstract

Figures

Introduction

Methods

Study design

Patient selection

Treatment protocol during vasospasm prophylaxis and management of fluid balance

Variables and data source

Comparison of the treatment outcomes

Comparison of the incidences of diarrhea and swelling of nasal mucosa

Statistical analysis

Results

Patient characteristics

Management of fluid balance

Angiographic and clinical outcomes

Comparison of the incidence of diarrhea and nasal mucosa swelling

Discussion

Conclusions

Declarations

Ethics approval

Consent to participate

Consent for publication

Funding:

Disclosures:

Author Contribution

Acknowledgments:

References

Additional Declarations

Status:

Version 1