Effects of Saireito (TJ-114), a traditional Japanese herbal medicine, on high-output syndrome after the creation of a temporary ileostomy in rectal cancer surgery

Effects of Saireito (TJ-114), a traditional Japanese herbal medicine, on high-output syndrome after the creation of a temporary ileostomy in rectal cancer surgery | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Effects of Saireito (TJ-114), a traditional Japanese herbal medicine, on high-output syndrome after the creation of a temporary ileostomy in rectal cancer surgery Chikako Kusunoki, Mamoru Uemura, Yuki Sekido, Mitsunobu Takeda, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6682371/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose: In rectal cancer surgery, a temporary ileostomy is often created to prevent clinical anastomotic leakage. However, high-output syndrome (HOS) frequently arises as a postoperative complication. We aimed to investigate the preventive effect of Saireito, a traditional Japanese herbal medicine, on HOS in patients with a temporary ileostomy. Methods: At our institution, Saireito has been routinely administered to patients undergoing rectal cancer surgery with temporary ileostomy since October 2022. Patients received 9 g / day of Saireito in three divided doses starting from the afternoon of postoperative day 1 (POD1). After excluding eight patients who discontinued Saireito or took it for less than 5 days, 63 patients were analyzed. HOS was defined as a stoma output exceeding 1,500 mL / day by POD10. Patients were divided into two groups: the Saireito group (≥ 5 days of Saireito, n = 37) and the control group (no Saireito, n = 26), and the incidence of HOS was compared. Result : There were no significant differences in patient background characteristics between the two groups (p > 0.05). HOS occurred in 13 patients (20.6%). The incidence of HOS was significantly lower in the Saireito group (4 / 37, 10.8%) compared to the control group (9 / 26, 34.6%) (p = 0.0291). Conclusion: Postoperative administration of Saireito in rectal cancer patients with temporary ileostomy was associated with a reduced incidence of high-output syndrome. Saireito may be a promising option for preventing HOS in such cases. Rectal cancer Temporary ileostomy High-output syndrome Kampo medicine Saireito Figures Figure 1 Figure 2 Introduction In rectal cancer surgery, the incidence of anastomotic leakage following low anterior resection has been reported to be 9.7–15.9%, and the mortality rate associated with leakage is as high as 6–22%( 1 , 2 , 3 , 4 ). To reduce the rates of clinical leakage, reoperation, and mortality, temporary diverting stomas are frequently constructed. However, temporary ileostomy itself can often lead to high-output syndrome (HOS), a significant clinical issue. The reported incidence of HOS ranges from 16–43.3%, and it accounts for 4–43% of readmissions after surgery( 4 , 5 , 6 , 7 , 8 ). When the daily stoma output exceeds 1,500 mL, patients are at increased risk for electrolyte imbalances and fluid loss, often requiring intravenous or oral rehydration, electrolyte correction, and administration of antisecretory or antidiarrheal agents. This condition is commonly referred to as HOS ( 8 , 9 ). The perioperative use of Kampo medicines (traditional Japanese herbal medicines) in gastrointestinal surgery has gained increasing attention, with several reports suggesting their clinical utility( 10 ). Among these, Daikenchuto has been widely studied and shown to suppress postoperative inflammatory responses—such as C-reactive protein elevation( 11 )—reduce the incidence of postoperative ileus, and shorten the time to first flatus following laparoscopic colorectal surgery( 12 ). Given their relatively mild but multifaceted pharmacologic effects, Kampo medicines may offer benefits in postoperative management following colorectal cancer surgery. Saireito, a Kampo formula composed of Shosaikoto and Goreisan, is commonly prescribed for conditions such as watery diarrhea, acute gastroenteritis, and edema( 13 , 14 ). It exerts diuretic effects through sodium channel inhibition and also exhibits anti-inflammatory activity, suggesting potential regulation of fluid balance( 15 ). These properties raise the possibility that Saireito may help prevent HOS following rectal cancer surgery with temporary ileostomy. The aim of this study was to investigate whether postoperative administration of Saireito reduces the incidence of HOS in patients who underwent rectal cancer surgery with the creation of a temporary ileostomy. Patients and Methods Between January 2022 and August 2024, we enrolled consecutive patients who underwent rectal cancer surgery with simultaneous creation of a temporary ileostomy at our institution. Patients with underlying conditions considered to directly influence the development of HOS, such as inflammatory bowel diseases (Crohn’s disease or ulcerative colitis), were excluded. A total of 71 patients were included in the final analysis. Since October 2022, our department has introduced the routine administration of Saireito postoperatively as part of an observational protocol. Patients treated prior to this implementation served as the control group for comparison. Saireito was administered orally in three divided doses per day (3 g per dose, totaling 9 g / day), starting from the afternoon of postoperative day 1 (POD1). Eight patients who discontinued Saireito or took it for fewer than five days were excluded. The remaining patients were divided into two groups: the Saireito group (≥ 5 days of administration, n = 37) and the control group (n = 26) (Fig. 1 ). Definition of High-Output Syndrome (HOS) HOS was defined as a stoma output of ≥ 1,500 mL per day by postoperative day 10 (POD10). Statistical analysis Numerical data are presented as medians with interquartile ranges (IQRs). Differences between the variables were compared using Fisher's exact test or chi-square test. Differences in quantitative parameters were compared using the Wilcoxon rank-sum test. Cumulative survival curves were constructed with the Kaplan-Meier method. A p -value < 0.05 was considered to indicate statistical significance. Univariate and multivariate analyses were performed to identify factors associated with the development of HOS after surgery. All statistical analyses were carried out using JMP Pro software version 17.0.0 for Mac (SAS Institute Inc., Cary, NC, USA). This study was approved by the institutional review board of The University of Osaka (Approval no. 20163-3). All informed consent was obtained from the participants in accordance with the institutional general consent policy for clinical research. Results Patients characteristics: Of the 63 patients included in the final analysis, 37 were assigned to the Saireito group (≥ 5 days of administration), and 26 to the control group (no administration). There were no significant differences in baseline characteristics between the two groups, including age, sex, body mass index (BMI), tumor stage, surgical procedure, or laparoscopic surgery rate (all p > 0.05). However, the prevalence of smoking history was significantly lower in the Saireito group. The prevalence of diabetes mellitus also tended to be lower in the Saireito group, although the difference was not statistically significant (Table 1). Surgical outcomes and postoperative course: The operation time tended to be shorter in the Saireito group than in the control group. In addition, the rate of loperamide use was lower, and the postoperative hospital stay tended to be shorter in the Saireito group, although none of these differences reached statistical significance (Table 2). Incidence of High-Output Syndrome (HOS): HOS was observed in 13 patients (20.6%) overall. The incidence was significantly lower in the Saireito group (4 / 37, 10.8%) compared with the control group (9 / 26, 34.6%) (p = 0.0291) (Fig. 2 , Table 3). Other Postoperative Complications: No significant differences were observed between the two groups in the incidence of postoperative ileus, anastomotic leakage, outlet obstruction, or the requirement for intravenous fluid therapy for HOS (all p > 0.1) (Table 4). Multivariate Analysis: Multivariate analysis revealed that the absence of Saireito administration and intraoperative blood loss of ≥ 30 mL were independent risk factors for the development of HOS, defined as stoma output ≥ 1,500 mL / day by POD10 (Table 5). Discussion This study demonstrated that the postoperative administration of Saireito significantly reduced the incidence of HOS in patients who underwent rectal cancer surgery with temporary ileostomy. Saireito, a traditional Japanese Kampo medicine composed of Shosaikoto and Goreisan, is known for its anti-edema, diuretic, and anti-inflammatory properties. These pharmacologic effects may contribute to the regulation of fluid balance and intestinal secretion, potentially explaining the observed reduction in HOS. Goreisan exerts a diuretic effect by inhibiting sodium channels in the distal renal tubules. A previous study reported that the diuretic effect of Saireito is approximately 1.4 times greater than that of Goreisan alone in water-loaded mouse models( 16 ). Furthermore, Shosaikoto may influence the hypothalamic-pituitary-adrenal axis, enhancing endogenous steroid secretion and exhibiting anti-inflammatory and anti-allergic properties( 13 , 15 ). In this study, the incidence of HOS—defined as stoma output ≥ 1,500 mL / day by POD10—was significantly lower in the Saireito group. While no significant differences were observed in other postoperative complications such as ileus, anastomotic leakage, or outlet obstruction, the selective effect of Saireito on HOS prevention is clinically meaningful. Multivariate analysis identified two independent risk factors for the development of HOS: the absence of Saireito administration and intraoperative blood loss ≥ 30 mL. These findings suggest that surgical factors and perioperative fluid dynamics may interact with intestinal secretion patterns contributing to HOS onset. This study has several limitations. It was a single-center, retrospective, non-randomized observational study, and baseline differences between the groups cannot be completely excluded. Nevertheless, HOS remains a significant cause of rehospitalization and postoperative morbidity in clinical practice. The use of Kampo medicines such as Saireito may represent a promising strategy for the prevention of HOS in selected patients. Further validation through prospective, randomized controlled trials is warranted. Conclusion Postoperative administration of Saireito significantly reduced the incidence of high-output syndrome in patients undergoing rectal cancer surgery with temporary ileostomy. Saireito may serve as a safe and effective option for HOS prevention in this setting. Declarations Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Conflict of interest The authors declare no conflicts of interest. Author contribution All authors contributed to patient management, manuscript preparation, and approved the final version of the manuscript. Acknowledgments Not applicable. References Watanabe J, Takemasa I, Kotake M, Noura S, Kimura K, Suwa H et al (2023) Blood Perfusion Assessment by Indocyanine Green Fluorescence Imaging for Minimally Invasive Rectal Cancer Surgery (EssentiAL trial): A Randomized Clinical Trial. Ann Surg 278(4):e688–e94 Shiomi A, Ito M, Maeda K, Kinugasa Y, Ota M, Yamaue H et al (2015) Effects of a diverting stoma on symptomatic anastomotic leakage after low anterior resection for rectal cancer: a propensity score matching analysis of 1,014 consecutive patients. J Am Coll Surg 220(2):186–194 van der Pas MH, Haglind E, Cuesta MA, Fürst A, Lacy AM, Hop WC et al (2013) Laparoscopic versus open surgery for rectal cancer (COLOR II): short-term outcomes of a randomised, phase 3 trial. Lancet Oncol 14(3):210–218 Pak J, Uemura M, Fukuda Y, Miyake M, Ikeda M, Nishikawa K et al (2017) Predictors of High-Output Stoma After Low Anterior Resection With Diverting Ileostomy for Rectal Cancer. Int Surg 102(7–8):313–317 Baker ML, Williams RN, Nightingale JM (2011) Causes and management of a high-output stoma. Colorectal Dis 13(2):191–197 Harris DA, Egbeare D, Jones S, Benjamin H, Woodward A, Foster ME (2005) Complications and mortality following stoma formation. Ann R Coll Surg Engl 87(6):427–431 Caricato M, Ausania F, Ripetti V, Bartolozzi F, Campoli G, Coppola R (2007) Retrospective analysis of long-term defunctioning stoma complications after colorectal surgery. Colorectal Dis 9(6):559–561 Arenas Villafranca JJ, López-Rodríguez C, Abilés J, Rivera R (2015) Gándara Adán N, Utrilla Navarro P. Protocol for the detection and nutritional management of high-output stomas. Nutr J 14:45 Lederhuber H, Massey LH, Kantola VE, Siddiqui MRS, Sayers AE, McDermott FD et al (2023) Clinical management of high-output stoma: a systematic literature review and meta-analysis. Tech Coloproctol 27(12):1139–1154 Ishizuka M, Shibuya N, Nagata H, Takagi K, Iwasaki Y, Hachiya H et al (2017) Perioperative Administration of Traditional Japanese Herbal Medicine Daikenchuto Relieves Postoperative Ileus in Patients Undergoing Surgery for Gastrointestinal Cancer: A Systematic Review and Meta-analysis. Anticancer Res 37(11):5967–5974 Yoshikawa K, Shimada M, Nishioka M, Kurita N, Iwata T, Morimoto S et al (2012) The effects of the Kampo medicine (Japanese herbal medicine) Daikenchuto on the surgical inflammatory response following laparoscopic colorectal resection. Surg Today 42(7):646–651 Zhang L, Cheng Y, Li H, Zhou Y, Sun B, Xu L (2018) Meta-analysis of randomized controlled trials on the efficacy of daikenchuto on improving intestinal dysfunction after abdominal surgery. Ann Surg Treat Res 95(1):7–15 Kawaji T, Shizuta S, Yaku H, Kaneda K, Yoneda F, Nishiwaki S et al (2024) Efficacy and safety of Saireito (TJ-114) in patients with atrial fibrillation undergoing catheter ablation procedures: A randomized pilot study. PLoS ONE 19(8):e0307854 Bailly C (2024) Efficacy and safety of the traditional herbal medication Chai-Ling-Tang (in China), Siryung-tang (in Republic of Korea) or Sairei-To (in Japan). J Ethnopharmacol 319(Pt 1):117127 Matsumoto H, Matsumoto A, Miyata S, Tomogane Y, Minami H, Masuda A et al (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 Ohnishi N, Nagasawa K, Yokohama T (2000) The verification of regulatory effects of Kampo formulations on body fluid using model mice. J Trad Med 17(3):131–136 Tables Tables 1 to 5 are available in the Supplementary Files section. Supplementary Files 20250516Table.pptx Table 1. Baseline characteristics of the patients Table 2. Perioperative and postoperative outcomes Table 3. Incidence of high-output syndrome (HOS) in the Saireito and control groups Table 4. Association between Saireito use and postoperative complications Table 5. Univariate and multivariate analyses of factors associated with HOS Multivariate logistic regression identified independent risk factors associated with the development of high-output syndrome (HOS). Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6682371","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":459376984,"identity":"87632edd-36a0-4644-ba55-c373305bc4f7","order_by":0,"name":"Chikako 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Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Hidetoshi","middleName":"","lastName":"Eguchi","suffix":""},{"id":459376995,"identity":"0c4b740e-df38-4aa8-932f-84f50e26a452","order_by":11,"name":"Yuichiro Doki","email":"","orcid":"","institution":"Osaka University: Osaka Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Yuichiro","middleName":"","lastName":"Doki","suffix":""}],"badges":[],"createdAt":"2025-05-16 16:24:47","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6682371/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6682371/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":83328036,"identity":"fa9d4cf8-cc55-4d38-a04c-52cf2b83c1cc","added_by":"auto","created_at":"2025-05-23 07:06:33","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":31284,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePatient selection flowchart\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients who underwent rectal cancer surgery with temporary ileostomy between January 2022 and August 2024 were screened. After excluding those with inflammatory bowel disease, 71 patients were included and divided into the Saireito group (n=45) and the control group (n=26). Eight patients who discontinued Saireito or received it for fewer than five days were excluded. The final analysis included 63 patients: 37 in the Saireito group and 26 in the control group.\u003c/p\u003e","description":"","filename":"Slide1.png","url":"https://assets-eu.researchsquare.com/files/rs-6682371/v1/9ef6c1986660c3540644abbc.png"},{"id":83328035,"identity":"b9648711-cd09-45c7-ab23-36dce431b2f5","added_by":"auto","created_at":"2025-05-23 07:06:33","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":29645,"visible":true,"origin":"","legend":"\u003cp\u003eIncidence of high-output syndrome (HOS) in the Saireitoand control groups\u003c/p\u003e","description":"","filename":"Slide2.png","url":"https://assets-eu.researchsquare.com/files/rs-6682371/v1/7f9e27366a554e52218d19b3.png"},{"id":84048501,"identity":"f7cde39c-b39b-4cf0-a151-976555edfcb0","added_by":"auto","created_at":"2025-06-06 07:56:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":558642,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6682371/v1/976fb4c9-c181-4393-a74b-46b015076337.pdf"},{"id":83328037,"identity":"54eb92ab-25f0-46ed-baa4-4ab6ddeeacf1","added_by":"auto","created_at":"2025-05-23 07:06:33","extension":"pptx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":62612,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTable 1. Baseline characteristics of the patients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Perioperative and postoperative outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3. Incidence of high-output syndrome (HOS) in the Saireito and control groups\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4. Association between Saireito use and postoperative complications\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 5. Univariate and multivariate analyses of factors associated with HOS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMultivariate logistic regression identified independent risk factors associated with the development of high-output syndrome (HOS).\u003c/p\u003e","description":"","filename":"20250516Table.pptx","url":"https://assets-eu.researchsquare.com/files/rs-6682371/v1/95cbe742779658e6b9c978ba.pptx"}],"financialInterests":"","formattedTitle":"\u003cp\u003eEffects of Saireito (TJ-114), a traditional Japanese herbal medicine, on high-output syndrome after the creation of a temporary ileostomy in rectal cancer surgery\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eIn rectal cancer surgery, the incidence of anastomotic leakage following low anterior resection has been reported to be 9.7\u0026ndash;15.9%, and the mortality rate associated with leakage is as high as 6\u0026ndash;22%(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). To reduce the rates of clinical leakage, reoperation, and mortality, temporary diverting stomas are frequently constructed.\u003c/p\u003e \u003cp\u003eHowever, temporary ileostomy itself can often lead to high-output syndrome (HOS), a significant clinical issue. The reported incidence of HOS ranges from 16\u0026ndash;43.3%, and it accounts for 4\u0026ndash;43% of readmissions after surgery(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). When the daily stoma output exceeds 1,500 mL, patients are at increased risk for electrolyte imbalances and fluid loss, often requiring intravenous or oral rehydration, electrolyte correction, and administration of antisecretory or antidiarrheal agents. This condition is commonly referred to as HOS (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe perioperative use of Kampo medicines (traditional Japanese herbal medicines) in gastrointestinal surgery has gained increasing attention, with several reports suggesting their clinical utility(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Among these, Daikenchuto has been widely studied and shown to suppress postoperative inflammatory responses\u0026mdash;such as C-reactive protein elevation(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e)\u0026mdash;reduce the incidence of postoperative ileus, and shorten the time to first flatus following laparoscopic colorectal surgery(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Given their relatively mild but multifaceted pharmacologic effects, Kampo medicines may offer benefits in postoperative management following colorectal cancer surgery.\u003c/p\u003e \u003cp\u003eSaireito, a Kampo formula composed of Shosaikoto and Goreisan, is commonly prescribed for conditions such as watery diarrhea, acute gastroenteritis, and edema(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). It exerts diuretic effects through sodium channel inhibition and also exhibits anti-inflammatory activity, suggesting potential regulation of fluid balance(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). These properties raise the possibility that Saireito may help prevent HOS following rectal cancer surgery with temporary ileostomy.\u003c/p\u003e \u003cp\u003eThe aim of this study was to investigate whether postoperative administration of Saireito reduces the incidence of HOS in patients who underwent rectal cancer surgery with the creation of a temporary ileostomy.\u003c/p\u003e"},{"header":"Patients and Methods","content":"\u003cp\u003eBetween January 2022 and August 2024, we enrolled consecutive patients who underwent rectal cancer surgery with simultaneous creation of a temporary ileostomy at our institution. Patients with underlying conditions considered to directly influence the development of HOS, such as inflammatory bowel diseases (Crohn\u0026rsquo;s disease or ulcerative colitis), were excluded. A total of 71 patients were included in the final analysis.\u003c/p\u003e \u003cp\u003eSince October 2022, our department has introduced the routine administration of Saireito postoperatively as part of an observational protocol. Patients treated prior to this implementation served as the control group for comparison. Saireito was administered orally in three divided doses per day (3 g per dose, totaling 9 g / day), starting from the afternoon of postoperative day 1 (POD1). Eight patients who discontinued Saireito or took it for fewer than five days were excluded. The remaining patients were divided into two groups: the Saireito group (\u0026ge;\u0026thinsp;5 days of administration, n\u0026thinsp;=\u0026thinsp;37) and the control group (n\u0026thinsp;=\u0026thinsp;26) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eDefinition of High-Output Syndrome (HOS)\u003c/h2\u003e \u003cp\u003eHOS was defined as a stoma output of \u0026ge;\u0026thinsp;1,500 mL per day by postoperative day 10 (POD10).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eNumerical data are presented as medians with interquartile ranges (IQRs). Differences between the variables were compared using Fisher's exact test or chi-square test. Differences in quantitative parameters were compared using the Wilcoxon rank-sum test. Cumulative survival curves were constructed with the Kaplan-Meier method. A \u003cem\u003ep\u003c/em\u003e-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered to indicate statistical significance. Univariate and multivariate analyses were performed to identify factors associated with the development of HOS after surgery. All statistical analyses were carried out using JMP Pro software version 17.0.0 for Mac (SAS Institute Inc., Cary, NC, USA).\u003c/p\u003e \u003cp\u003e This study was approved by the institutional review board of The University of Osaka (Approval no. 20163-3). All informed consent was obtained from the participants in accordance with the institutional general consent policy for clinical research.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003ePatients characteristics:\u003c/h2\u003e \u003cp\u003eOf the 63 patients included in the final analysis, 37 were assigned to the Saireito group (\u0026ge;\u0026thinsp;5 days of administration), and 26 to the control group (no administration). There were no significant differences in baseline characteristics between the two groups, including age, sex, body mass index (BMI), tumor stage, surgical procedure, or laparoscopic surgery rate (all p\u0026thinsp;\u0026gt;\u0026thinsp;0.05). However, the prevalence of smoking history was significantly lower in the Saireito group. The prevalence of diabetes mellitus also tended to be lower in the Saireito group, although the difference was not statistically significant (Table\u0026nbsp;1).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSurgical outcomes and postoperative course:\u003c/h3\u003e\n\u003cp\u003eThe operation time tended to be shorter in the Saireito group than in the control group. In addition, the rate of loperamide use was lower, and the postoperative hospital stay tended to be shorter in the Saireito group, although none of these differences reached statistical significance (Table\u0026nbsp;2).\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eIncidence of High-Output Syndrome (HOS):\u003c/h2\u003e \u003cp\u003eHOS was observed in 13 patients (20.6%) overall. The incidence was significantly lower in the Saireito group (4 / 37, 10.8%) compared with the control group (9 / 26, 34.6%) (p\u0026thinsp;=\u0026thinsp;0.0291) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, Table\u0026nbsp;3).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eOther Postoperative Complications:\u003c/h3\u003e\n\u003cp\u003eNo significant differences were observed between the two groups in the incidence of postoperative ileus, anastomotic leakage, outlet obstruction, or the requirement for intravenous fluid therapy for HOS (all p\u0026thinsp;\u0026gt;\u0026thinsp;0.1) (Table\u0026nbsp;4).\u003c/p\u003e\n\u003ch3\u003eMultivariate Analysis:\u003c/h3\u003e\n\u003cp\u003eMultivariate analysis revealed that the absence of Saireito administration and intraoperative blood loss of \u0026ge;\u0026thinsp;30 mL were independent risk factors for the development of HOS, defined as stoma output\u0026thinsp;\u0026ge;\u0026thinsp;1,500 mL / day by POD10 (Table\u0026nbsp;5).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study demonstrated that the postoperative administration of Saireito significantly reduced the incidence of HOS in patients who underwent rectal cancer surgery with temporary ileostomy. Saireito, a traditional Japanese Kampo medicine composed of Shosaikoto and Goreisan, is known for its anti-edema, diuretic, and anti-inflammatory properties. These pharmacologic effects may contribute to the regulation of fluid balance and intestinal secretion, potentially explaining the observed reduction in HOS.\u003c/p\u003e \u003cp\u003eGoreisan exerts a diuretic effect by inhibiting sodium channels in the distal renal tubules. A previous study reported that the diuretic effect of Saireito is approximately 1.4 times greater than that of Goreisan alone in water-loaded mouse models(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Furthermore, Shosaikoto may influence the hypothalamic-pituitary-adrenal axis, enhancing endogenous steroid secretion and exhibiting anti-inflammatory and anti-allergic properties(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn this study, the incidence of HOS\u0026mdash;defined as stoma output\u0026thinsp;\u0026ge;\u0026thinsp;1,500 mL / day by POD10\u0026mdash;was significantly lower in the Saireito group. While no significant differences were observed in other postoperative complications such as ileus, anastomotic leakage, or outlet obstruction, the selective effect of Saireito on HOS prevention is clinically meaningful.\u003c/p\u003e \u003cp\u003eMultivariate analysis identified two independent risk factors for the development of HOS: the absence of Saireito administration and intraoperative blood loss\u0026thinsp;\u0026ge;\u0026thinsp;30 mL. These findings suggest that surgical factors and perioperative fluid dynamics may interact with intestinal secretion patterns contributing to HOS onset.\u003c/p\u003e \u003cp\u003eThis study has several limitations. It was a single-center, retrospective, non-randomized observational study, and baseline differences between the groups cannot be completely excluded. Nevertheless, HOS remains a significant cause of rehospitalization and postoperative morbidity in clinical practice. The use of Kampo medicines such as Saireito may represent a promising strategy for the prevention of HOS in selected patients.\u003c/p\u003e \u003cp\u003eFurther validation through prospective, randomized controlled trials is warranted.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003ePostoperative administration of Saireito significantly reduced the incidence of high-output syndrome in patients undergoing rectal cancer surgery with temporary ileostomy. Saireito may serve as a safe and effective option for HOS prevention in this setting.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to patient management, manuscript preparation, and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWatanabe J, Takemasa I, Kotake M, Noura S, Kimura K, Suwa H et al (2023) Blood Perfusion Assessment by Indocyanine Green Fluorescence Imaging for Minimally Invasive Rectal Cancer Surgery (EssentiAL trial): A Randomized Clinical Trial. Ann Surg 278(4):e688\u0026ndash;e94\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShiomi A, Ito M, Maeda K, Kinugasa Y, Ota M, Yamaue H et al (2015) Effects of a diverting stoma on symptomatic anastomotic leakage after low anterior resection for rectal cancer: a propensity score matching analysis of 1,014 consecutive patients. J Am Coll Surg 220(2):186\u0026ndash;194\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003evan der Pas MH, Haglind E, Cuesta MA, F\u0026uuml;rst A, Lacy AM, Hop WC et al (2013) Laparoscopic versus open surgery for rectal cancer (COLOR II): short-term outcomes of a randomised, phase 3 trial. Lancet Oncol 14(3):210\u0026ndash;218\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePak J, Uemura M, Fukuda Y, Miyake M, Ikeda M, Nishikawa K et al (2017) Predictors of High-Output Stoma After Low Anterior Resection With Diverting Ileostomy for Rectal Cancer. Int Surg 102(7\u0026ndash;8):313\u0026ndash;317\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBaker ML, Williams RN, Nightingale JM (2011) Causes and management of a high-output stoma. Colorectal Dis 13(2):191\u0026ndash;197\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHarris DA, Egbeare D, Jones S, Benjamin H, Woodward A, Foster ME (2005) Complications and mortality following stoma formation. Ann R Coll Surg Engl 87(6):427\u0026ndash;431\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCaricato M, Ausania F, Ripetti V, Bartolozzi F, Campoli G, Coppola R (2007) Retrospective analysis of long-term defunctioning stoma complications after colorectal surgery. Colorectal Dis 9(6):559\u0026ndash;561\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArenas Villafranca JJ, L\u0026oacute;pez-Rodr\u0026iacute;guez C, Abil\u0026eacute;s J, Rivera R (2015) G\u0026aacute;ndara Ad\u0026aacute;n N, Utrilla Navarro P. Protocol for the detection and nutritional management of high-output stomas. Nutr J 14:45\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLederhuber H, Massey LH, Kantola VE, Siddiqui MRS, Sayers AE, McDermott FD et al (2023) Clinical management of high-output stoma: a systematic literature review and meta-analysis. Tech Coloproctol 27(12):1139\u0026ndash;1154\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIshizuka M, Shibuya N, Nagata H, Takagi K, Iwasaki Y, Hachiya H et al (2017) Perioperative Administration of Traditional Japanese Herbal Medicine Daikenchuto Relieves Postoperative Ileus in Patients Undergoing Surgery for Gastrointestinal Cancer: A Systematic Review and Meta-analysis. Anticancer Res 37(11):5967\u0026ndash;5974\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYoshikawa K, Shimada M, Nishioka M, Kurita N, Iwata T, Morimoto S et al (2012) The effects of the Kampo medicine (Japanese herbal medicine) Daikenchuto on the surgical inflammatory response following laparoscopic colorectal resection. Surg Today 42(7):646\u0026ndash;651\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang L, Cheng Y, Li H, Zhou Y, Sun B, Xu L (2018) Meta-analysis of randomized controlled trials on the efficacy of daikenchuto on improving intestinal dysfunction after abdominal surgery. Ann Surg Treat Res 95(1):7\u0026ndash;15\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKawaji T, Shizuta S, Yaku H, Kaneda K, Yoneda F, Nishiwaki S et al (2024) Efficacy and safety of Saireito (TJ-114) in patients with atrial fibrillation undergoing catheter ablation procedures: A randomized pilot study. PLoS ONE 19(8):e0307854\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBailly C (2024) Efficacy and safety of the traditional herbal medication Chai-Ling-Tang (in China), Siryung-tang (in Republic of Korea) or Sairei-To (in Japan). J Ethnopharmacol 319(Pt 1):117127\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMatsumoto H, Matsumoto A, Miyata S, Tomogane Y, Minami H, Masuda A et al (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\u0026ndash;89\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOhnishi N, Nagasawa K, Yokohama T (2000) The verification of regulatory effects of Kampo formulations on body fluid using model mice. J Trad Med 17(3):131\u0026ndash;136\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 5 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Rectal cancer, Temporary ileostomy, High-output syndrome, Kampo medicine, Saireito","lastPublishedDoi":"10.21203/rs.3.rs-6682371/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6682371/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn rectal cancer surgery, a temporary ileostomy is often created to prevent clinical anastomotic leakage. However, high-output syndrome (HOS) frequently arises as a postoperative complication. We aimed to investigate the preventive effect of Saireito, a traditional Japanese herbal medicine, on HOS in patients with a temporary ileostomy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt our institution, Saireito has been routinely administered to patients undergoing rectal cancer surgery with temporary ileostomy since October 2022. Patients received 9 g / day of Saireito in three divided doses starting from the afternoon of postoperative day 1 (POD1). After excluding eight patients who discontinued Saireito or took it for less than 5 days, 63 patients were analyzed. HOS was defined as a stoma output exceeding 1,500 mL / day by POD10. Patients were divided into two groups: the Saireito group (≥ 5 days of Saireito, n = 37) and the control group (no Saireito, n = 26), and the incidence of HOS was compared.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResult :\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere were no significant differences in patient background characteristics between the two groups (p \u0026gt; 0.05). HOS occurred in 13 patients (20.6%). The incidence of HOS was significantly lower in the Saireito group (4 / 37, 10.8%) compared to the control group (9 / 26, 34.6%) (p = 0.0291).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePostoperative administration of Saireito in rectal cancer patients with temporary ileostomy was associated with a reduced incidence of high-output syndrome. Saireito may be a promising option for preventing HOS in such cases.\u003c/p\u003e","manuscriptTitle":"Effects of Saireito (TJ-114), a traditional Japanese herbal medicine, on high-output syndrome after the creation of a temporary ileostomy in rectal cancer surgery","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-23 07:06:28","doi":"10.21203/rs.3.rs-6682371/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"faeebedc-1493-4941-9202-719a09bf81ef","owner":[],"postedDate":"May 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-06-06T07:48:18+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-23 07:06:28","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6682371","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6682371","identity":"rs-6682371","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}