Effects of rikkunshito administration after distal pancreatectomy on postoperative oral intake and weight loss

Abstract

BACKGROUND

Reduced oral intake and postoperative weight loss are common after distal pancreatectomy and may impair postoperative recovery and tolerance to adjuvant therapy. Rikkunshito (RT), a traditional Japanese Kampo medicine, has been reported to improve appetite and gastrointestinal function. However, its clinical impact after distal pancreatectomy remains unclear.

AIM

To evaluate the association between postoperative RT administration and oral intake, as well as body weight loss, after distal pancreatectomy.

METHODS

This retrospective cohort study included 241 patients who underwent distal pancreatectomy at a single hepatobiliary-pancreatic center between July 2005 and July 2024. Patients were divided into an RT (+) group (n = 117) and an RT (-) group (n = 124) according to whether or not they received postoperative RT. The primary endpoint was oral intake on postoperative day (POD) 7. The secondary endpoint was change in body weight from before surgery to 1 month after surgery.

RESULTS

Oral intake on POD 7 was significantly higher in the RT (+) group than in the RT (-) group. The median weight loss at 1 month postoperatively was -2.00 kg in the RT (+) group and -2.65 kg in the RT (-) group, indicating a smaller degree of weight loss in the RT (+) group (P = 0.044). The differences between the groups in the development of clinically relevant postoperative pancreatic fistulas, delayed gastric emptying, or major complications (Clavien-Dindo grade ≥ IIIa) were not significant. By multivariable analysis adjusted for age, preoperative body mass index, and major postoperative complications, RT administration remained independently associated with reduced postoperative body weight loss.

CONCLUSION

The postoperative administration of RT was associated with improved oral intake and reduced body weight loss after distal pancreatectomy, without increasing postoperative complications. RT may be effective for the early postoperative nutritional management of patients after distal pancreatectomy.

Key Words: Rikkunshito; Distal pancreatectomy; Oral intake; Body weight loss; Postoperative nutrition support

Core Tip: Postoperative weight loss and reduced oral intake are common problems after distal pancreatectomy and may adversely affect postoperative recovery and tolerance to adjuvant therapy. Rikkunshito (RT), a traditional Japanese herbal medicine, is reported to improve appetite and gastrointestinal motility. In this retrospective study, patients who received RT after distal pancreatectomy showed significantly improved oral intake on postoperative day 7 and less body weight loss 1 month postoperatively compared with those who did not receive RT. In the absence of established strategies for early postoperative nutritional support after distal pancreatectomy, these findings provide clinically relevant evidence for a simple and feasible intervention.

INTRODUCTION

Rikkunshito (RT) is a traditional Japanese Kampo medicine composed of eight herbal components: Atractylodis macrocephalae rhizoma, Ginseng radix, Pinelliae tuber, Hoelen, Zizyphi fructus, Aurantii nobilis pericarpium, Glycyrrhizae radix, and Zingiberis rhizoma[1]. It is prescribed to regulate gastrointestinal function and improve digestion[2]. Since the report that RT enhances ghrelin secretion[3], accumulating evidence suggests that it is effective for various digestive disorders. RT is often used to treat upper gastrointestinal disorders[4]. It has been reported to suppress weight loss after esophageal cancer surgery[5] and reduce gastrointestinal symptoms after gastrectomy[6]. Furthermore, it has been shown to improve gastrointestinal and psychological symptoms in patients with functional dyspepsia[2,7]; and in breast cancer patients, the combined administration of RT and antiemetics reduced vomiting and loss of appetite associated with chemotherapy[8]. It is also expected to be effective for treating patients with cachexia syndrome[9]. However, its clinical effects after distal pancreatectomy remain unclear.

Distal pancreatectomy is highly invasive and is often followed by reduced oral intake and postoperative weight loss[10]. These nutritional problems may impair postoperative recovery, increase susceptibility to complications, and reduce tolerance to adjuvant chemotherapy in patients with pancreatic malignancies[11,12].

Therefore, strategies to support early postoperative nutritional recovery are clinically important. At our institution, a clinical pathway that incorporated the early postoperative administration of RT was introduced in January 2018 to support oral intake after distal pancreatectomy. This study aimed to evaluate the impact of postoperative RT by comparing the postoperative oral intake and body weight loss of patients who received RT and those who did not after distal pancreatectomy.

MATERIALS AND METHODS

Study design and patient selection

This was a retrospective cohort study conducted at a single hepatobiliary-pancreatic surgery center. Patients who underwent distal pancreatectomy between July 2005 and July 2024 were eligible for inclusion. Patients were divided into two groups according to whether they received or did not receive postoperative [(RT (+) group and RT (-) group, respectively]. Patients were excluded if postoperative oral intake data on postoperative day (POD) 7 or data on body weight at 1 month postoperatively were unavailable.

Postoperative management and intervention

A new clinical pathway incorporating the early postoperative administration of RT was introduced at our institution in January 2018. In the RT (+) group, RT administration was initiated on POD 3 at the time that oral intake was initiated, and was administered orally three times daily before meals until hospital discharge. No enteral tube feeding was used for either group, and all patients received oral nutrition alone. Additionally, pancreatic enzyme replacement therapy was routinely administered to all patients.

Outcome measures

The primary endpoint was oral intake on POD 7. Oral intake was assessed separately for each meal component. Oral intake was assessed from nursing flowsheet records in the medical charts. Values represent percentages of the provided meals that were consumed.

The secondary endpoint was change in body weight from before surgery to 1 month postoperatively. The frequencies of postoperative complications, including clinically relevant postoperative pancreatic fistula, delayed gastric emptying, and Clavien-Dindo grade ≥ IIIa complications, were also compared between the groups.

Ethics

This study was approved by the Institutional Review Board of Nagoya City University Graduate School of Medical Sciences (approval No. 60-24-0099). The requirement for written informed consent was waived because of the retrospective study design, and an opt-out approach was used in accordance with institutional policy.

Statistical analysis

Categorical variables were compared using the χ² test or Fisher exact test, as appropriate. Continuous variables were compared using the student t-test or Mann-Whitney U test, depending on data distribution. Prior to analysis, the normality of continuous variables was assessed by the Shapiro-Wilk test. A two-sided P value < 0.05 was considered statistically significant.

RESULTS

Patient characteristics

A total of 241 patients who underwent distal pancreatectomy were analyzed, comprising 117 in the RT (+) group and 124 in the RT (-) group. The baseline demographic, nutritional, and operative characteristics were generally comparable between the two groups, although the difference between the ages of the two groups was significant (Table 1).

Table 1 Baseline characteristics of patients, n (%).

	RT (-) (n = 124)	RT (+) (n = 117)	P value
Age, years, median (IQR)	65 (53-73)	71 (55-78)	0.006
Sex, male/female	73 (58.9)/51 (41.1)	59 (50.4)/58 (49.6)	0.198
Height, cm, mean ± SD	160.2 ± 8.7	159.7 ± 8.9	0.638
Weight, kg, mean ± SD	57.44 ± 11.33	58.48 ± 12.33	0.496
Body mass index, kg/m2, mean ± SD	22.2 ± 3.6	22.8 ± 4.2	0.258
Underlying disease			0.230
PDAC	57 (46.0)	55 (46.6)
IPMN	31 (25.0)	30 (25.4)
NET	4 (3.2)	9 (7.6)
Chronic pancreatitis	8 (6.5)	11 (9.3)
Others	24 (19.4)	13 (11.0)
Postoperative complication
Clavien-Dindo grade ≥ IIIa	22 (17.7)	20 (17.1)	1.00
Pancreatic fistula (Grade B or C)	14 (11.3)	8 (6.8)	0.232
Delayed gastric emptying	2 (1.6)	2 (1.7)	1.00

Baseline demographic and clinical characteristics were compared between the rikkunshito (RT) (-) group (n = 124) and the RT (+) group (n = 117). Variables included age, sex, height, weight, body mass index, underlying disease, major postoperative complications (Clavien-Dindo grade ≥ IIIa), postoperative pancreatic fistula (Grade B or C), and delayed gastric emptying. RT: Rikkunshito; PDAC: Pancreatic ductal adenocarcinoma; IPMN: Intraductal papillary mucinous neoplasm; NET: Neuroendocrine tumor; IQR: Interquartile range.

Postoperative oral intake

On POD 7, the postoperative oral intake was significantly higher in the RT (+) group than in the RT (-) group. Intake of the breakfast main dish, breakfast side dish, lunch main dish, lunch side dish, and dinner side dish were significantly higher in the RT (+) group. The oral intake of the dinner main dish also showed a higher trend in the RT (+) group (Table 2).

Table 2 Oral intake on postoperative day 7.

	RT (-) (n = 124)	RT (+) (n = 117)	P value
Time to start liquid intake	1 (1-1)	1 (1-1)	-
Time to start oral intake	3 (3-3)	3 (3-3)	-
Breakfast main dish, %	55 (7.5-100)	80 (50-100)	0.007
Side dish, %	50 (10-100)	80 (50-100)	< 0.001
Lunch main dish, %	50 (20-100)	80 (40-100)	0.043
Side dish, %	60 (20-100)	90 (50-100)	0.006
Dinner main dish, %	50 (7.5-100)	80 (20-100)	0.063
Side dish, %	50 (17.5-100)	90 (50-100)	0.001

Oral intake on postoperative day 7 was compared between the rikkunshito (RT) (-) group (n = 124) and the RT (+) group (n = 117). The times to initiation of liquid intake and oral intake were identical in the two groups. Liquid intake was initiated on postoperative day 1 and oral intake on postoperative day 3 in all patients according to the institutional clinical pathway. Intake was evaluated for each component of the meal, which included the breakfast main dish, breakfast side dish, lunch main dish, lunch side dish, dinner main dish, and dinner side dish. Oral intake was expressed as the percentage of the provided meal consumed. Values are presented as medians (interquartile range). Continuous variables were compared using the Mann-Whitney U test. RT: Rikkunshito.

Changes in body weight

The median changes in body weight at 1 month postoperatively were -2.00 kg in the RT (+) group and -2.65 kg in the RT (-) group, indicating a lower postoperative weight loss in the RT (+) group (P = 0.044) (Table 3).

Table 3 Changes in body weight.

	RT (-) (n = 124)	RT (+) (n = 117)	P value
Preoperative, kg	57.44 ± 11.33	58.48 ± 12.33	0.496
1 month postoperatively, kg	54.76 ± 10.87	56.45 ± 11.45	0.240
Weight loss, kg	-2.65 (-4.32 to -0.87)	-2.00 (-3.70 to -0.20)	0.044

Preoperative body weight, body weight at 1 month postoperatively, and postoperative weight loss were compared between the rikkunshito (RT) (-) group (n = 124) and the RT (+) group (n = 117). Preoperative body weight and body weight at 1 month postoperatively are presented as mean ± SD, whereas body weight loss values are presented as median (interquartile range). Weight loss is expressed as a negative value. Comparisons between groups were performed using the student t-test or the Mann-Whitney U test depending on distributions of data. RT: Rikkunshito.

Multivariable linear regression analysis was performed to evaluate the factors associated with postoperative body weight loss, with adjustments for age, preoperative body mass index (BMI), and major postoperative complications (Clavien-Dindo grade ≥ IIIa). RT administration was independently associated with reduced postoperative body weight loss [coefficient -0.77, 95% confidence interval (CI): -1.39 to -0.15, P = 0.015]. In contrast, higher preoperative BMI was independently associated with increased postoperative body weight loss (coefficient 0.20, 95%CI: 0.12-0.28, P < 0.001), whereas age was not significantly associated with postoperative body weight loss. Major postoperative complications showed a trend toward greater postoperative weight loss but did not reach statistical significance (Table 4).

Table 4 Multivariable linear regression analysis for postoperative body weight loss.

Variable	Coefficient (β)	95%CI	P value
RT (+)	-0.77	-1.39 to -0.15	0.015
Age	-0.01	-0.02 to 0.01	0.388
Body mass index	0.20	0.12 to 0.28	< 0.001
Clavien-Dindo grade ≥ IIIa	0.78	-0.03 to 1.59	0.059

Multivariable linear regression analysis was performed to identify factors associated with postoperative body weight loss at 1 month after distal pancreatectomy. Variables included in the model were rikkunshito administration, age, preoperative body mass index, and major postoperative complications (Clavien-Dindo grade ≥ IIIa). RT: Rikkunshito; CI: Confidence interval.

Postoperative complications

There were no significant differences between the groups for rates of clinically relevant postoperative pancreatic fistula, delayed gastric emptying, or Clavien-Dindo grade ≥ IIIa complications. In addition, no adverse events related to RT administration were observed in this cohort.

DISCUSSION

This study provides clinical evidence from a relatively large cohort that the postoperative administration of RT after distal pancreatectomy was associated with improved oral intake on POD 7 and attenuated postoperative weight loss (i.e., less postoperative weight reduction) at 1 month. Importantly, these benefits were achieved without increasing postoperative morbidity. These findings suggest that RT may be a useful supportive treatment for early postoperative nutritional management after distal pancreatectomy. In the multivariable analysis, RT administration remained independently associated with reduced postoperative body weight loss even after adjustment for clinical background factors. This finding suggests that the beneficial effect of RT on postoperative nutritional status cannot be explained solely by differences between patient characteristics or postoperative morbidity.

Interestingly, a higher preoperative BMI was independently associated with greater postoperative body weight loss. This finding is clinically reasonable because patients with higher body mass tend to experience larger absolute reductions in body weight after major abdominal surgery. Importantly, RT administration remained a significant protective factor after adjustment for BMI, supporting its independent contribution to early postoperative nutritional recovery after distal pancreatectomy.

Several mechanisms may explain our findings. RT has been reported to enhance ghrelin signaling, promote gastric emptying[13-15], and improve gastric adaptive relaxation[16-18]. Through these effects, RT may improve appetite and feeding tolerance in the early postoperative period when reduced intake is common after major pancreatic surgery.

The clinical relevance of these findings is considerable. Reduced oral intake and increased postoperative weight loss may impair recovery, reduce physical resilience, and limit eligibility for or tolerance to adjuvant chemotherapy[19,20]. Therefore, interventions that support early postoperative nutritional recovery may translate into improved postoperative recovery and better tolerance to adjuvant therapy. Postoperative oral intake on POD 7 was selected as the primary endpoint because recovery of oral intake within the first postoperative week represents a clinically meaningful indicator of early postoperative functional recovery in the context of enhanced recovery after surgery (ERAS) pathways. The ERAS guidelines for pancreatic surgery strongly recommend early resumption of oral intake beginning shortly after surgery and emphasize the importance of achieving adequate oral nutritional recovery during the early postoperative period. Furthermore, perioperative nutrition guidelines suggest that patients who fail to achieve sufficient oral intake within the first postoperative week may require an additional nutritional intervention.

In this study, RT was initiated early after surgery and was administered in a relatively standardized postoperative setting. Because no enteral tube feeding was used and all patients received oral nutrition alone, the observed differences in intake are likely to reflect true differences between appetites and feeding tolerances rather than differences between modes of nutritional delivery. In addition, pancreatic enzyme replacement therapy was routinely used in all patients, which may have reduced confounding related to postoperative exocrine insufficiency.

To reduce clinical heterogeneity and potential temporal bias, we limited the study population to patients undergoing distal pancreatectomy. In particular, pancreaticoduodenectomy is a more complex procedure in which surgical reconstruction methods, perioperative management strategies, and postoperative care have evolved substantially over time. These changes may significantly influence postoperative nutritional outcomes, thereby introducing confounding effects in a long-term retrospective analysis. In contrast, distal pancreatectomy is a relatively standardized procedure with fewer variations in reconstruction and more consistent perioperative management approaches throughout the study period. Therefore, the focus on distal pancreatectomy allowed a more homogeneous patient cohort and reduced the effects of temporal and procedural variables on the evaluations of postoperative oral intake and changes in body weight.

This study has several limitations. First, it was a retrospective single-center study and is therefore subject to selection bias and unmeasured confounding. The indication for RT administration changed during the study period. Before 2018, the decision to administer RT was made at the discretion of the attending surgeons, generally based on postoperative appetite, oral intake status, and clinical recovery. Therefore, some degree of selection bias based on postoperative conditions may have been present during this period. In contrast, after 2018, RT was routinely administered as part of a standardized clinical pathway for patients undergoing distal pancreatectomy, which resulted in a more uniform treatment strategy. Accordingly, this study includes both a physician-dependent treatment period and a protocol-based treatment period. This may have introduced selection bias, and therefore the observed differences should be interpreted with caution.

Second, the introduction of RT was linked to a change in the institutional clinical pathway, and perioperative management may have evolved over time, possibly introducing temporal bias related to changes in perioperative care. Third, long-term nutritional outcomes, quality of life, and completion of adjuvant chemotherapy were not assessed. Prospective studies are needed to confirm the findings of this study and to determine the optimal timing, duration, and target population for the administration of postoperative RT. The study findings suggest that RT may contribute not only to early nutritional recovery but also to improved postoperative recovery.

CONCLUSION

The postoperative administration of RT was associated with improved oral intake and attenuated body weight loss after distal pancreatectomy. RT may represent a simple and feasible adjunct for early postoperative nutritional support after distal pancreatectomy.