The effect of Daikenchuto on blood flow of the superior mesenteric artery and portal vein in ELBW: A prospective study

Abstract

BACKGROUND:

Focal intestinal perforation (FIP) is a devastating complication of premature birth, and extremely low birth weight (ELBW) infants are at highest risk. This study aimed to evaluate the relationship of the superior mesenteric artery (SMA) and portal vein (PV) blood flow velocities to investigate the association between intestinal blood flow and FIP. In addition, the herbal formula Daikenchuto (TJ-100) is expected to improve intestinal blood flow disorders; therefore, we evaluated its effect.

METHODS:

We conducted a prospective cohort study of 15 ELBW infants from January 2020 to August 2021. Measured variables included birth weight, 5-minute Apgar score, time of oral feeding initiation, ductus arteriosus (PDA) closure (percent), diastolic and systolic blood pressure, SMA and PV blood flow velocity, and FIP onset data. Fifteen infants were divided into three groups: a non-surgery group (Group I; 6), a surgery group with FIP (Group II; 4), and a TJ-100 administration group (Group III; 5). The main outcome parameters included SMA and PV blood flow velocities with TJ-100.

RESULTS:

SMA and PV blood flow differed significantly for the SMA of Group I and the SMA and PV of Group III (P < 0.01, P = 0.01, and P = 0.04, respectively). There was a correlation between SMA and PV in Group III (P = 0.03).

CONCLUSION:

TJ-100 may increase SMA and PV blood flow and improve intestinal blood flow in ELBW infants at risk of FIP. Therefore, the effects of TJ-100 should undergo further study.

Keywords

Daikenchuto intestinal perforation premature birth

1 Introduction

Complications from organ immaturity in extremely low birth weight (ELBW <1000 g) infants remain a major healthcare problem. Gastrointestinal dysfunction in ELBW infants is one of the most serious. It is an important factor that determines the prognosis for continuing life, especially as there can be intestinal perforation, e.g., focal intestinal perforation (FIP). Infants with FIP often have long-term complications and a high economic burden. FIP presents as isolated intestinal perforation. It is a hemorrhagic necrosis that occurs primarily in the terminal ileum and is thought to be secondary to intestinal wall immaturity and resulting ischemia [1, 2]. The risks for FIP include early steroid use, birth trauma, indomethacin, multiple gestations, chorioamnionitis, and syncytial knots [1]. Abdominal radiography is the standard test for FIP is abdominal radiographyperforation, but it is nonspecificnon-specific, and the presence of intra-abdominal free gas or intraportal gas can be found on abdominal radiography may be a sign of late therapeutic intervention, but the timing is late.

Since the superior mesenteric artery (SMA) and the portal vein (PV) is associated with gastrointestinal dysfunction [3, 4], we have focused on the relationship of the SMA and PV to predict FIP.

Tsumura Daikenchuto (TJ-100) is a Japanese herbal formula administered as a treatment for intestinal blood flow disorders [5]. Prickly ash and dry ginger of TL-100 help regulate the motility of the digestive tract [5]. We investigated the effect of TJ-100 in improving poor intestinal blood flow, which causes FIP in ELBW infants.

2 Methods

2.1 Study design

This was a prospective cohort study of ELBW infants conducted between January 2020 and August 2021. The observation period was seven days from birth. The study was approved by the Ethics Committee of Fujita Health University Hospital (HM19-477). The study procedures adhered to the tenets of the Declaration of Helsinki.

2.2 Participants

The inclusion criteria were admission to the neonatal intensive care unit (NICU) with a birth weight less than 1,000 g and the use of only donor milk for enteral feeding [6]. During the study period, the donor milk dose began with 0.5 ml and reached 3 ml at the upper limit. All infants were on blood pressure support medications, and steroids were administered to prevent chronic lung injury. Indomethacin was administered at a low dose to prevent cerebral hemorrhage regardless of ductus arteriosus status (i.e., open or closed).

The variables measured included birth weight, five-minute Apgar score, time at initiation of oral feeding, ductus arteriosus (PDA) closure percentage, diastolic blood pressure, systolic blood pressure, SMA and PV blood flow velocity, and FIP onset data. The diagnostic criteria for FIP were surgical or pathological findings and procedures including ileostomy or drainage.

The exclusion criteria were serious complications such as unstable hemodynamic status, complex cardiac malformations, and severe neonatal asphyxia.

Participants were all ELBW infants who gave their consent from January 2020 and August 2021. Daikenchuto administration was performed alternately in the order of hospitalization. Sixteen ELBW infants were admitted to the NICU. Of the 16 infants, 15 (male-to-female ratio [M:F] = 6:9) met the eligibility criteria, and one infant was excluded because of complex cardiac malformations. A flowchart of the patient selection process is shown in Fig. 1. Participants were divided into three groups. Group I comprised the non-surgical patients (not receiving TJ-100); Group II comprised the patients undergoing surgery (not receiving TJ-100); and Group III comprised the patients receiving TJ-100). No infections were observed during the observation period. No cases of intraventricular hemorrhage were observed during the observation period.

Fig. 1

A flowchart of the patient selection process. Participants (N = 15) were divided into Group I (N = 6); without TJ-100 and non-surgery, Group II (N = 4); without TJ-100 and surgery group, and Group III (N = 5); with TJ-100.

2.3 Treatment

TJ-100 controls blood flow through transient receptor potential (TRP) channels in the intestinal epithelium, promotes 5-HT release from enterochromaffin cells in the intestine, induces acetylcholine, and enhances gastrointestinal motility. Potential side effects include drug-induced liver damage, rashes, and anorexia, although other studies using TJ-100 have shown no clinical effects [7].

A dose of 0.2 g/kg of TJ-100 was administered per rectum twice daily using a tube. The administration of TJ-100 was initiated within 12 h of the start of oral feeding.

2.4 Doppler flowmetry

The ultrasonic pulse-Doppler method was used in this study. Ultrasonic waves were generated using a PHILIPS iE33 imaging system, and a linear S12 ultrasound probe was used. The examinations were performed by a neonatologist. The infants were placed in a supine position, and measurements were taken at approximately the same time. If an infant was receiving enteral feeding, the examination was performed before light enteral feeding. Warm gel was used to reduce movement, minimize discomfort, and maintain respiration and heart rate, thereby avoiding blood circulation changes. To measure SMA blood flow velocity, the Doppler window was positioned such that the SMA was centered, and the peak systolic velocity, which was measured at least three times, was used to determine absolute indices. To measure the PV blood flow velocity, the hilar region and portal trunk were identified.

2.5 Outcomes

Longitudinal evaluation of SMA and PV blood flow, which were measured using the ultrasound pulsed Doppler method, was performed to investigate their relationship with TJ-100.

2.6 Statistical analysis

The Steel-Dwass test and chi-squared test was used to compare multiple continuous variables between groups. All measurement values are presented as the mean±standard deviation and rate. Regression analysis was also performed to compare the variables of SMA and PV blood flow. Statistical significance was set at P≤0.05. Statistical tests were performed using JMP12.2 (SAS Institute Inc., Cary, NC, USA).

3 Results

3.1 Participants

Table 1 shows the characteristics (sex, birth weight, five-minute Apgar score, time of oral feeding initiation, PDA close number, and FIP onset data). In Group II, three patients underwent ileostomy and one underwent drainage procedures. All perforations were located near the terminal ileum. In Group III, there were no surgical cases. No significant differences were observed during the study period. No statistically significant differences in sex, systolic and diastolic blood pressure were observed between Groups I, II, and III (Fig. 2).

Table 1
Characteristics of the Group I, Group II, and Group III

Group I Group II p value^* Group III p value^**

Male: Female 1: 5 3: 1 0.06 2: 3 0.39

Birth weight (g) 710.3±16.6 678.3±13.4 0.86 807.7±18.1 0.46

Apgar score at five minutes 6.2±0.4 7.3±0.2 0.90 9.0±0.3 0.18

Time of initiation of oral feeding (day) 1.0±0.1 1.3±0.2 1.0 1.0±0.2 0.65

PDA closure number (%) 83.3 75.0 0.75 100.0 0.26

The onset data of FIP N/A 8.8±1.0 N/A N/A N/A

	Group I	Group II	p value^*	Group III	p value^**
Male: Female	1: 5	3: 1	0.06	2: 3	0.39
Birth weight (g)	710.3±16.6	678.3±13.4	0.86	807.7±18.1	0.46
Apgar score at five minutes	6.2±0.4	7.3±0.2	0.90	9.0±0.3	0.18
Time of initiation of oral feeding (day)	1.0±0.1	1.3±0.2	1.0	1.0±0.2	0.65
PDA closure number (%)	83.3	75.0	0.75	100.0	0.26
The onset data of FIP	N/A	8.8±1.0	N/A	N/A	N/A

Data are shown as standard deviation values and rate. Quantitative analysis was carried out with the help of the Steel–Dwass test and Chi-squared test. ^*comparison of the Group I and Group II, p < 0.05. ^**comparison of the Group I and Group III, p < 0.05. Group I; without Tsumura Daikenchuto (TJ-100) and non-surgery, Group II; without TJ-100 and surgery group, and Group III; with TJ-100. FIP: Focal intestinal perforation, M: Male, F: Female, PDA: Patent ductus arteriosus.

Fig. 2

Changes of systolic blood pressure and diastolic blood pressure. No statistically significant differences in systolic and diastolic blood pressures were observed between the Group I, Group II, and Group III. P values ≤0.05 were considered statistically significant. Group I; without Tsumura Daikenchuto (TJ-100) and non-surgery, Group II; without TJ-100 and surgery group, and Group III with TJ-100.

3.2 SMA and PV blood flow

Regression analysis was used for the longitudinal evaluation of SMA and PV blood flow (Fig. 3a). In Group I, SMA blood flow was increased compared in the Group II, but SMA blood flow was not statistically significant (p = 0.40). Whereas PV blood flow was statistically significant in Group I (P < 0.01). In Group II, SMA and PV blood flows were not statistically significant (P = 0.90 and P = 0.23, respectively). In Group III, SMA and PV blood flows were statistically significant (P = 0.01 and P = 0.04,respectively).

Fig. 3a

The relationship between longitudinal evaluation of SMA and PV blood flows on regression analysis. In Group I, PV blood flow was statistically significant (p < 0.01). In Group III, SMA and PV blood flows were statistically significant (p = 0.01 and p = 0.04, respectively).

Regression analysis was also performed to determine the relationship between SMA and PV blood flow (Fig. 3b). No statistically significant differences were observed between Groups I and II (P = 0.46 and P = 0.74, respectively). In Group III, a statistically significant difference was observed(P = 0.03).

Fig. 3b

The relationship between SMA and PV blood flows on regression analysis. A scatter plot and the corresponding regression line and regression equation for the relationship between the dependent variable PV (cm/s) and the independent variable SMA (cm/s). R2 = coefficient of determination. Group I; without Tsumura Daikenchuto (TJ-100) and non-surgery, Group II; without TJ-100 and surgery group, and Group III; with TJ-100. PV: portal venous, SMA: superior mesenteric artery, R2: coefficient of determination.

4 Discussion

In addition to immature gastrointestinal motility and poorly functioning gastrointestinal enzymes, ELBW infants have inadequate nutritional reserves at birth and are deficient in various nutrients [8 –10].

In utero, the fetus digests amniotic fluid, which promotes gastrointestinal growth [11]. Postnatal fasting decreases villus numbers, gastrointestinal enzyme activity, and barrier function [12]. Early enteral nutrition has been studied because prolonged fasting after birth has negative effects, including FIP [1]. The mortality rate of patients with FIP is 20.6% in Japan [13]; none of the patients with FIP died in this study. Recent advances in neonatal care may have improved survival rates of infants with ELBW. Nevertheless, it is believed that FIP develops in ELBW infants because of intestinal wall fragility and perfusion problems. In general, there is no gender difference in the causes of FIP, nor was this study. PDA patency may be the cause of FIP, but no statistically significant difference was observed in this study [14]. Therefore, it was considered that further continuous research is necessary in the future.

Ischemia associated with gastrointestinal dysfunction causes gastrointestinal perforation by decreasing PV blood flow [3]. PV circulation comprises gastrointestinal blood flow including the ileocecal region. The absorption of nutrients around the ileocecal region increases blood flow, and the PV blood flow may increase over time. In Group II, PV blood flow might have been involved in the case of FIP. Since the perforations were near the terminal ileum, it is possible that an ischemic region developed in the ileocecal region, and secondary peristaltic disorders caused FIP at the time of increased intestinal pressure. Increased intestinal pressure may be more likely to occur after the 5th day of life. The cause of the increased intestinal pressure may be related to immature intestinal function and nutrient absorption in the ileocecal region; however, this was not revealed in this study. PV blood flow velocity may be useful for predicting FIP in infants with ELBW.

TJ-100 is a Japanese traditional herbal compound consisting of four crude substances: ginseng, sansho, kankyo, and koui [15]. TJ-100 may increase microvascular dilation and blood flow in the intestine through gastrointestinal TRP channels [5]. It has been reported to increase SMA blood flow in adults [16]. SMA blood flow is involved in intestinal motility and is thought to be related to the immaturity of intestinal peristalsis in Group I [4]. Comparison of Groups I and III suggests that TJ-100 regulates SMA blood flow.

TJ-100 has also been reported to increase PV blood flow [17, 18]. We found that the correlation between SMA and PV blood flow could be because of TJ-100 in Group III. We believe that TJ-100 may modulate SMA and PV blood flow by acting on intestinal microvessels, and that modulation of SMA and PV blood flow may prevent FIP in ELBW infants by improving intestinal blood flow disorders. Therefore, we continue to investigate the incidence of FIP and its long-term clinical outcomes with TJ-100.

5 Conclusions

In this study, we found that PV blood flow velocity may be used to screen for FIP in ELBW infants. We believe that TJ-100 increases SMA and PV blood flow and improves intestinal blood flow disorders in ELBW infants at risk for FIP. Therefore, we will continue to study the effects of TJ-100.

Conflicts of interest

The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Data, material and/or code availability

All data generated or analysed during this study are included in this published article.

Ethics approval/informed consent

Approval was obtained from the Ethics Committee of the Fujita Health University Hospital. The procedures used in this study adhered to the tenets of the Declaration of Helsinki.

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