Pediatric intestinal failure is a complex clinical problem associated with high patient morbidity and mortality. Intestinal failure due to short bowel syndrome (SBS) and/or intestinal dysmotility caused by chronic intestinal pseudoobstruction (CIPO) or a postoperative state of intestinal atresia result in inadequate nutritional absorption to support normal growth and development. Short bowel syndrome (SBS) reflects a state of malabsorption resulting from the loss of a significant portion of the small bowel [
Ninjinto (NJT), a traditional Japanese Kampo medicine, is prepared from four different Chinese crude drugs. This medicine is a major prescription in Japan and most frequently used for the treatment of gastroenteritis, esogastritis, gastric atony, gastrectasis, vomiting, and anorexia [
We herein describe our experiences with seven patients with intestinal failure who received therapy with the oral administration of NJT. The aim of this report was to evaluate the effects of NJT in improving intestinal failure and increasing the quality of life (QoL) in these patients by comparing the clinical findings obtained before and after the administration of NJT.
Seven pediatric patients with intestinal failure due to CIPO, SBS, or intestinal atresia who visited our hospital between April 1, 2012, and April 30, 2014, were selected for this study. All subjects were under 18 years of age or transitioning from pediatric to adult care and continuously used NJT for at least three months. In all cases, no formula changes including modern medical treatment were attempted after the start of the oral administration of NJT.
We assessed the treatment outcomes and safety based on periodic feedback from the patients and their parents in terms of symptoms, such as abdominal distension, pain, and diarrhea, as well as consecutive abdominal X-ray findings. The primary variables for evaluating the effectiveness of NJT administration included change in the intensity of abdominal complaints from baseline to approximately 3 months following NJT administration and patient satisfaction regarding the improvement of abdominal symptoms, such as abdominal distention and pain and diarrhea. Briefly, the patients were asked to classify the intensity of all abdominal complaints by marking a 100 mm visual analogue scale (VAS) with a straight line before and three months after NJT administration. The VAS assessment was statistically analyzed using a paired
In addition, in order to examine natural killer (NK) cytotoxicity in peripheral blood mononuclear cells (PBMCs) in two patients, measurements of the cytotoxic activity of NK cells were obtained. Briefly, the NK-sensitive cell line K-562, as target cells, was cocultured with PBMCs collected from the peripheral blood of the patients before and three months after the administration of NJT. The percentage of target cells killed by effector NK cells was determined using a 51Cr release assay [
All seven patients were administered the NJT extract fine granules manufactured by Kracie (Kracie Holdings, Ltd., Tokyo, Japan) (Table
Composition of the NJT extract granules manufactured by Kracie (Kracie Holdings, Ltd., Tokyo, Japan).
Ingredient | Volume (g)* |
---|---|
JP processed ginger | 3.0 |
JP |
3.0 |
JP |
3.0 |
JP ginseng | 3.0 |
3D HPLC chart of the Kracie NJT extract fine granules manufactured by Kracie (Kracie Holdings, Ltd., Tokyo, Japan). The chemical marker, such as glycyrrhizic acid in the HPLC profile, was identified by comparison with the retention times and UV spectra (210–400 nm) of the reference standards.
A review of the patients is shown in Table
Review of pediatric patients with intestinal failure treated with NJT.
Case number | Gender | Age | Diagnosis | Targeted symptoms |
---|---|---|---|---|
1 | F | 12 | CIPO | Abdominal distention & pain |
2 | M | 13 | SBS | Diarrhea & compromised state |
3 | F | 27 | CIPO | Abdominal distention & pain |
4 | M | 10 | CIPO | Abdominal distention & pain |
5 | M | 28 | CIPO | Abdominal distention & pain |
6 | M | 1 | Ileal atresia post-OP | Diarrhea & compromised state |
7 | M | 6 | SBS | Diarrhea |
CIPO, chronic intestinal pseudoobstruction; SBS, short bowel syndrome; OP, operation.
The abdominal distension and pain improved in all four patients, and the intensity of abdominal distension and pain significantly improved on the VAS after 3 months of the oral administration of NJT (Figure
Analyses of the effectiveness of the oral administration of NJT for abdominal symptoms using the visual analogue scale. (a) Abdominal distention and pain (
Comparison of abdominal roentgenograms in Cases
An improvement in the symptoms was observed in six of the seven patients. The patient who did not notice an improvement in his symptoms after the oral administration of NJT did not have remarkable inner cold or qi deficiency, while the other six patients had both of these problems.
The details of two representative cases are described below.
A 12-year-old female suffered from repeated abdominal pain, distension, and diarrhea as a result of megacystis-microcolon-intestinal hypoperistalsis syndrome, a condition of CIPO and a representative cause of intestinal failure. Since birth, the patient had been hospitalized on 12 occasions due to periodic abdominal distension three to four times per month and easily developed infections, such as catheter-related bloodstream infections and enteritis. As shown in Figure
Natural killer activity in the peripheral blood in Cases
A 13-year-old male suffered from SBS due to intestinal necrosis associated with gastroschisis at birth. He experienced constant watery diarrhea as well as frequent hospitalization (5-6 times a year) due to bronchitis and pneumonia, probably due to the weakness of his immune system. Based on our experience in Case
Intestinal failure is a complex clinical problem that is associated with high patient morbidity and mortality. Although surgical treatment is often successful, dietary manipulation and pharmacological management of abdominal distension, diarrhea, and a compromised state both have the potential to substantially improve the overall health and quality of life (QoL) of SBS patients [
Surprisingly, in the present study, the administration of NJT increased the NK activity in PBMCs in two patients, who consequently became relatively insusceptible to treatment. There are several hypotheses explaining this phenomenon. First, in an animal study, Kaga et al. confirmed that NJT augments the NK activity in vivo, and the authors suggested that certain components of NJT, which contains four different components, directly stimulate immune system in vivo [
Panax ginseng is one of the most important crude drugs in NJT. Ginseng contains ginsenoside Rb1 as its main constituent and is traditionally used in Kampo formulas for cancer, inflammation, stress, and ageing. Ginsenoside Rb1 present in orally administered ginseng is metabolized to bioactive compounds, including compound K, by gut microbiota prior to absorptions in the blood. Colonic bacteria cleave the oligosaccharide connected to the aglycone compound stepwise from the terminal sugar to yield the major metabolites [
In this study, NJT was administrated to pediatric patients with intestinal failure without the Kampo diagnosis because most of the pediatric patients with intestinal failure could be considered to have the disease pattern of NJT. As a result, one of the patients with SBS without the disease pattern of NJT, such as inner cold or qi deficiency, did not have a symptomatic improvement following NJT treatment. It is important to determine the cause, nature, and location of the pathological change at specific stages of the disease by the Kampo diagnosis for case selection in order to obtain sufficient effects. In future investigation, the selection criteria according to the Kampo diagnosis should be included in the selection of the patients. It may be possible to find inner cold in the diagnostic process with an interview, for example, and whether the patient’s symptoms exacerbate with cold stress.
Similar to that observed in our cases, various Kampo formulas have been prescribed for pre- and postoperative pediatric patients with gastrointestinal anomalies and diseases. Representative Kampo formulas used for daily treatment in the pediatric surgical field include rikkunshito after upper gastrointestinal surgery [
Kampo medicine is in general very safe. There are few adverse effects reported in connection with some Kampo formulas, such as pneumonitis, pseudoaldosteronism, and liver dysfunction. Nevertheless the patient’s condition should be continuously monitored during treatment using careful history-taking, laboratory assessments, and physical examination. Since in Japan Kampo medicines are prescribed by medical doctors and are monitored by the national pharmacovigilance system, safe use can be insured.
NJT may be effective in controlling the symptoms of intestinal failure, CIPO, and SBS, and further randomized controlled trials are warranted to evaluate the clinical efficacy of NJT for patients with these disorders. The use of Kampo medicine in the field of pediatric surgery may contribute to improving the quality of life in children suffering from such conditions.
None of the authors disclose any potential conflict of interests.
The authors thank Dr. Brian Quinn, Japan Medical Communication, for revising the paper.