Available via license: CC BY 4.0
Content may be subject to copyright.
Citation: Sharma, S.; Kim, Y.; Bajgai,
J.; Rahman, M.H.; Jeong, Y.J.; Goh,
S.H.; Park, H.J.; Kim, C.-S.; Kim, H.I.;
Lee, K.-J. The Effect of Electrolyzed
Hydrogen-Rich Alkaline Reduced
Water on Patients with Chronic
Constipation—A Clinical Trial.
Processes 2023,11, 2142. https://
doi.org/10.3390/pr11072142
Academic Editors: Alessandro
Trentini and Malgorzata
Polz-Dacewicz
Received: 17 June 2023
Revised: 14 July 2023
Accepted: 14 July 2023
Published: 18 July 2023
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
processes
Article
The Effect of Electrolyzed Hydrogen-Rich Alkaline Reduced
Water on Patients with Chronic Constipation—A Clinical Trial
Subham Sharma 1, 2, †, Yundeok Kim 3, † , Johny Bajgai 1, Md. Habibur Rahman 1, Yun Ju Jeong 1,
Seong Hoon Goh 1, Hong Jun Park 4, Cheol-Su Kim 1, Hyun Il Kim 4, * and Kyu-Jae Lee 1, 2, *
1Department of Convergence Medicine, Wonju College of Medicine, Yonsei University,
Wonju 26426, Republic of Korea
2Department of Global Medical Science, Wonju College of Medicine, Yonsei University,
Wonju 26426, Republic of Korea
3Department of Internal Medicine, Division of Hematology-Oncology, Wonju Severance Christian Hospital,
Wonju 26426, Republic of Korea
4Department of Gastroenterology, Yonsei University, Wonju 26426, Republic of Korea
*
Correspondence: kimhyunil@gmail.com (H.I.K.); medbio@yonsei.ac.kr (K.-J.L.); Tel.: +82-33-741-0331 (K.-J.L.)
†These authors contributed equally to this work.
Abstract:
Chronic constipation is a common symptom-based disorder that affects patient quality of
life. Electrolyzed hydrogen-rich alkaline reduced water (EHARW) helps treat gastrointestinal disorders
owing to its various bioactive properties. This single-arm, open-labelled study aimed to investigate the
improvement of EHARW (pH 9.5; H
2≈
0.5 mg/L) in chronic constipation patients. Thirty patients with
chronic constipation were enrolled after screening as intention-to-treat (ITT). During the intervention
period, two patients dropped out, and 28 patients completed the study as per protocol (PP). The selected
patients were instructed to drink EHARW (pH 9.5; H
2≈
0.5 mg/L) (20 mL/kg body weight/day)
generated from a home medical device for four weeks. Complete spontaneous bowel movement
(CSBM) frequency was measured as the primary outcome, and Bristol stool form, patient assessment
of constipation–symptoms (PAC-SYM) score, and patient assessment of constipation–quality of life
(PAC-QOL) score were measured as the secondary outcomes after the 4-week intervention compared to
baseline. As a result of EHARW treatment, no adverse events were observed during the study period.
Moreover, the frequency of CSBM/week (29.8%, p< 0.05) and Bristol stool form score (24.6%,
p< 0.01
)
significantly increased compared to baseline. Finally, the overall and subscale scores of the PAC-SYM
(58.0%) and PAC-QOL (54.2%) questionnaires significantly decreased (p < 0.001). These results suggest
that daily ingestion of EHARW (pH 9.5; H
2≈
0.5 mg/L) can improve CSBM frequency as a primary
outcome in chronic constipation patients. Likewise, EHARW (pH 9.5; H
2≈
0.5 mg/L) improved Bristol
stool form score, symptoms and the quality of life as a secondary outcome in patients with chronic
constipation through a home-based intervention.
Keywords:
chronic constipation; electrolyzed hydrogen-rich alkaline reduced water; complete
spontaneous bowel movement frequency; patient assessment of constipation–symptoms; patient
assessment of constipation–the quality of life
1. Introduction
Constipation is a common health problem that medical practitioners and general
surgeons encounter regularly. It is characterized by chronically incomplete, problematic,
and irregular defecation [
1
]. Constipation is also a major social problem with a global
prevalence rate of 10–15%, as it disturbs the quality of life [
2
,
3
]. Common risk factors for
constipation include inadequate diet, concurrent diseases, medication, and bowel structure
or function disorders [
4
]. The Rome IV criteria, clinical examination, and self-records of
defecation habits can aid in the diagnosis and assessment of constipation severity [
5
]. In
clinical trials, the frequency of bowel movements, stool consistency, and patient-rated
Processes 2023,11, 2142. https://doi.org/10.3390/pr11072142 https://www.mdpi.com/journal/processes
Processes 2023,11, 2142 2 of 11
symptoms have been used as objective outcomes to assess the effectiveness of interventions
in patients with chronic constipation [
6
]. In addition, abdominal, rectal and stool-associated
symptoms, such as feelings of incomplete evacuation, straining during defecation, abdom-
inal discomfort or pain, are associated with chronic constipation, which might result in
several significant complications such as anal hemorrhage, anal fissures, and rectal prolapse.
These serious complications of long-term constipation can increase morbidity and affect
the patient’s quality of life, which can be assessed by measuring the level of physical dis-
comfort, psychosocial discomfort, worries/concern, and level of satisfaction [
7
–
11
]. Thus, a
questionnaire-based assessment, such as the patient assessment of constipation symptoms
(PAC-SYM) and patient assessment of constipation quality of life (PAC-QOL), provides
reliable information to monitor the symptoms and QOL related to chronic constipation.
The PAC-SYM consists of 3 subscales and 12-questions, whereas PAC-QOL consists of
4 subscales and 28-questions [12,13].
Moreover, depending on the cause of constipation, various therapies are currently
available to relieve symptoms and complications: bulk-forming laxatives for fibre-deficient
constipation; polyethylene glycol, which draws water into the intestine; stimulant laxatives;
anorectal biofeedback therapies; and surgery [
14
,
15
]. These therapeutic approaches can
alleviate symptoms; however, they have potential adverse effects and complications due to
various etiological factors, especially over a long period. Therefore, an increasing demand
for effective and well-tolerated chronic constipation interventions exists.
Increasing evidence suggests that hydrogen (H
2
) is an anti-oxidative, anti-apoptotic,
and anti-inflammatory substance with high potential for medical applications, including
intestinal disorders [
16
,
17
]. Moreover, H
2
is regarded as a novel antioxidant, as it can
easily penetrate the cell membrane, diffuse into various organelles, and reduce free radicals
(i.e., hydroxyl radicals and peroxynitrite) [
18
,
19
]. Previous studies on intestinal diseases
have demonstrated that H
2
may improve gastrointestinal symptoms, such as ulcerative
colitis and chronic constipation [
20
–
23
]. The H
2
also acts through various mechanistic
pathways to rescue from oxidative stress or toxicity, including enhancement of antioxi-
dants, anti-inflammation, signal modulation, and cytoprotection [
24
]. EHARW exhibits
a negative oxidation-reduction potential (ORP) due to its alkaline pH and the dissolved
H
2
gas, which H
2
is responsible for the antioxidant effects [
25
]. The EHARW is also con-
sidered an effective and convenient method for delivering H
2
and is suitable for medical
applications [
19
]. Moreover, an alkaline pH and high mineral content help to improve
digestive function [
26
,
27
]. The Japanese Ministry of Health and Welfare approved us-
ing ERW for gastrointestinal (GI) disorders, such as hyperacidity, diarrhea, indigestion,
and abnormal gastrointestinal fermentation [
28
–
30
]. Several GI symptoms can also be
significantly improved with ERW [
30
,
31
]. The Korean Ministry of Food and Drug Safety
guidelines categorize ARW as functional water from a pH of 8.6 to 10.0. Additionally, the
ARW generator was authorized as a grade II home medical device, and the Korean and
Japanese regulations mandate that alkaline water ionizer pH should not exceed pH 9.8
for drinking [
28
,
29
,
32
,
33
]. Furthermore, EARW (pH 9.5) has been shown to reduce the
symptoms of GI disorders, including indigestion, diarrhea, and dyspepsia [25,34].
Considering the information above on EHARW and GI diseases, we hypothesized that
four weeks of EHARW (pH 9.5; H
2≈
0.5 mg/L) consumption generated by a home medical
device could relieve chronic constipation. The frequency of complete spontaneous bowel
movements (CSBM), Bristol stool form scale, PAC-SYM, and PAC-QOL questionnaires
were used to investigate the treatment effectiveness.
2. Materials and Methods
2.1. Ethical Approval
This clinical study was approved by the Research Review Board of Yonsei University
Wonju Severance Christian Hospital (IRB number: CR222010) in Korea and registered with
Clinical Trials.gov under the identifier NCT05734859. All the patients provided written
informed consent before participating in the clinical trial. The study protocol was conducted
Processes 2023,11, 2142 3 of 11
in accordance with the Declaration of Helsinki (October 1996), Good Clinical Practice, and
the applicable laws and regulations.
2.2. Study Population
Potential participants (ages 19–70 years) were screened to determine study eligibility,
including baseline characteristics (age, height, and weight), vital signs (blood pressure and
body temperature), medical history, medication use, and history of self-reported chronic
constipation (an average of three or fewer defecations/week over the past 3-months). In
addition, the physician confirmed that the patients met two or more of the following
symptoms for at least three months: straining during defecation, lumpy or hard stools, the
sensation of incomplete evacuation, the sensation of anorectal obstruction, and manual
maneuvers to facilitate defecation at least 25% of the time, according to the Rome IV criteria
for chronic constipation. The inclusion and exclusion criteria are presented in Table 1. A
total of 30 patients were enrolled in this study.
Table 1. Inclusion and exclusion criteria of patients.
Inclusion Criteria Exclusion Criteria
1. Men and women aged 19 to 70 years old adult 1. Those taking drugs such as opioid analgesics, antipsychotics,
calcium blockers, and parasympathetic antagonists
2. Those who meet Roma IV diagnostic criteria for
chronic constipation
2. Those with kidney disease (renal failure, potassium excretion
disorder, etc.)
3. Symptoms began six months prior and have lasted for
>3 months
3. Those with colon-related diseases (colon cancer, intestinal stenosis,
rectal flow, anal fissure, rectal bleeding, irritable bowel syndrome,
inflammatory bowel disease, recent gastrointestinal surgery, etc.)
4. Those without structural abnormalities that may
cause constipation 4. Pregnancy or breastfeeding
5. A patient who has personally signed the written
informed consent
5. Those who are judged to be difficult to conduct research with by the
clinical trial director
6. If all the criteria meet 6. Those who meet at least one exclusion criteria mentioned above
2.3. Study Design
Thirty patients with chronic constipation who met the inclusion criteria were enrolled
as intention-to-treat (ITT) based on an eligibility test performed by a physician. Before start-
ing the intervention, a medical device generating EHARW (BTM-1200, Biontech, Gunpo-si,
Republic of Korea) was installed in each patient’s house. Patients were instructed by the
investigator on how to operate the device and drink the EHARW. The intervention period
was four weeks. The primary efficacy endpoint was the difference in the mean number
of CSBM between baseline and post-intervention. The secondary efficacy endpoints were
self-observation records related to constipation symptoms (Bristol stool form score, strain-
ing at defecation, stiffness of the stool, sensation of incomplete evacuation, and sensation
of obstruction) and PAC-SYM and PAC-QOL scores. Only twenty-eight patients who
completed the clinical study as per protocol (PP) were included in the analysis. All data
were collected at baseline and after four weeks of intervention (Figure 1).
2.4. Experimental Device and Water Characteristics
EHARW (pH 9.5; H
2≈
0.5 mg/L) was produced by the electrolysis of water using
an EHARW generator (BTM-1200, Biontech, Gunpo-si, Republic of Korea). This device
has been approved as a Class II medical device by the Ministry of Food and Drug Safety
of the Republic of Korea. EHARW had a pH of 9.5 (HM-31P, TOA DKK, Tokyo, Japan),
oxidation-reduction potential value of
−
100
±
5 mV (RM-30P, TOA DKK, Tokyo, Japan),
and a hydrogen molecule (H
2
) content of approximately 0.5 mg/L (MARK-509, Hydrogen
Meter, Nizhny Novgorod, Russia).
Processes 2023,11, 2142 4 of 11
Processes 2023, 11, x FOR PEER REVIEW 4 of 12
evacuation, and sensation of obstruction)
and
PAC-SYM and PAC-QOL scores. Only
twenty-eight patients who completed the clinical study as per protocol (PP) were included
in the analysis. All data were collected at baseline and after four weeks of intervention
(Figure 1).
Figure 1. Flowchart for the clinical study.
2.4. Experimental Device and Water Characteristics
EHARW (pH 9.5; H
2
≈ 0.5 mg/L
)
was produced by the electrolysis of water using an
EHARW generator (BTM-1200, Biontech, Gunpo-si, Republic of Korea). This device has
been approved as a Class II medical device by the Ministry of Food and Drug Safety of
the Republic of Korea. EHARW had a pH of 9.5 (HM-31P, TOA DKK, Tokyo, Japan),
oxidation-reduction potential value of −100 ± 5 mV (RM-30P, TOA DKK, Tokyo, Japan),
and a hydrogen molecule (H2) content of approximately 0.5 mg/L (MARK-509, Hydrogen
Meter, Nizhny Novgorod, Russia).
2.5. Interventions
For the home-based intervention, the medical device was installed in each patient’s
house, and the patients were instructed on how to operate the device and drink the
EHARW (pH 9.5; H2 ≈ 0.5 mg/L) generated by the experimental device. The total daily
amount of EHARW was 20 mL/kg body weight, which was individually calculated based
on the patient’s body weight. The patient was instructed to drink water three times a day,
especially on an empty stomach after digestion of the meal, for four weeks during the
intervention period.
2.6. Outcome Measures
As a primary ecacy endpoint, the frequency of CSBM was approached by the mean
number of CSBMs per week, and the data were collected during the two weeks of pre-
treatment (baseline) and the last two weeks of the total intervention period using the
patient’s self-observation diary [11,35]. CSBM was dened as non-rescue medication-
induced defecation with the sensation of complete evacuation.
Figure 1. Flowchart for the clinical study.
2.5. Interventions
For the home-based intervention, the medical device was installed in each patient’s
house, and the patients were instructed on how to operate the device and drink the EHARW
(pH 9.5; H
2≈
0.5 mg/L) generated by the experimental device. The total daily amount
of EHARW was 20 mL/kg body weight, which was individually calculated based on
the patient’s body weight. The patient was instructed to drink water three times a day,
especially on an empty stomach after digestion of the meal, for four weeks during the
intervention period.
2.6. Outcome Measures
As a primary efficacy endpoint, the frequency of CSBM was approached by the mean
number of CSBMs per week, and the data were collected during the two weeks of pre-
treatment (baseline) and the last two weeks of the total intervention period using the
patient’s self-observation diary [
11
,
35
]. CSBM was defined as non-rescue medication-
induced defecation with the sensation of complete evacuation.
The Bristol stool form scale and a self-observation diary were secondary outcome
measures to evaluate constipation-related symptoms. The Bristol stool form was rated
on a 7-point Likert scale ranging from 1 (hard lumps) to 7 (watery) at baseline and af-
ter four weeks of treatment [
11
]. Likewise, straining during defecation, stool stiffness,
sensation of incomplete evacuation, and sensation of obstruction were assessed using a
5-point Likert scale ranging from 0 to 4, with a lower score indicating reduced symptom
severity. In addition, the PAC-SYM questionnaire was used to assess the patient-rated
severity of constipation symptoms using a 5-point Likert scale ranging from 0 to 4. This
questionnaire consisted of 12 questions categorized into three subscales: abdominal, rectal,
and stool symptoms (Table 2) [
9
,
10
]. Each subscore and overall score were presented as
mean ±standard
deviation (SD), which was analyzed with a paired t-test, and lower scores
indicated the degree of symptom improvement. The PAC-QOL questionnaire measured
the patient-rated impact of constipation on QOL. It consisted of 28 questions categorized
into four subscales: physical discomfort, psychosocial discomfort, worries/concerns, and
satisfaction, as shown in Table 3[
36
]. PAC-QOL scores were presented as
mean ±SD
, and
lower scores indicated better QOL. Questions 24–28 related to satisfaction were scored
using inverse transformation, which contributed positively to the overall score.
Processes 2023,11, 2142 5 of 11
Table 2. Subscales of PAC-SYM questionnaire.
Subscales Questionnaires
Abdominal
symptoms
1. Stomach discomfort
2. Stomach pain
3. Stomach bloating
4. Stomach cramps
Rectal
symptoms
5. Painful bowel movements
6. Rectal burning during or after a bowel movement
7. Rectal bleeding or tearing during or after a bowel movement
Stool
Symptoms
8. Incomplete bowel movement
9. Bowel movements were too hard
10. Bowel movements were too small
11. Straining or squeezing to try and pass bowel movements
12. Feeling like you had to pass a bowel movement, but you could not (False alarm)
Patient assessment of constipation symptoms (PAC-SYM) has 12 questions categorized with three subscales,
which are scored on a 5-point Likert scale ranging from 0 (no symptoms) to 4 (very severe symptoms).
Table 3. Subscales of PAC-QOL questionnaire.
Questionnaires
Subscales Questions
Physical discomfort
1. Felt bloated to the point of bursting
2. Felt heavy because of constipation
3. Felt any physical discomfort
4. Felt the need to have a bowel movement but was unable to do so
Psychosocial discomfort
5. Been embarrassed to be with other people
6. Been eating less and less because of not being able to have bowel movements
7. Had to be careful what you eat
8. Had a decreased appetite
9. Been worried about not being able to choose what you eat
10. Been embarrassed about staying in the bathroom for so long when away from home
11. Been embarrassed about staying in the bathroom so often when away from home
12. Been worried about having to change your daily routine
Worries
/Concerns
13. Felt irritable because of your condition
14. Been upset by your condition
15. Felt obsessed by your condition
16. Felt stressed by your condition
17. Felt less self-confident because of your condition
18. Felt in control of your situation
19. Been worried about not knowing when you can have a bowel movement
20. Been worried about not being able to have a bowel movement
21. Been increasingly bothered by not being able to have a bowel movement
22. Been worried that your condition will get worse
23. Felt that your body was not working properly
Satisfaction
24. Fewer bowel movements than desired
25. Satisfied with how often you have a bowel movement
26. Satisfied with the regularity of your bowel movements
27. Satisfied with the time it takes for food to pass through the intestines
28. Satisfied with your treatment
The Patient Assessment of Constipation-Quality of Life (PAC-QOL) has 28 questions categorized into four
subscales, which are scored on a 5-point scale ranging from 0 (not at all) to 4 (all times). Questions 25–28 were
scored using an inverse transformation.
Processes 2023,11, 2142 6 of 11
2.7. Statistical Analysis
Statistical analyses were performed using the Prism software (version 8.0; GraphPad
Software, San Diego, CA, USA). Data were presented as mean
±
SD. The differences
between baseline and post-treatment related to constipation (QOL, symptoms, Bristol stool
form, and CSBM frequency) were analyzed using a parametric two-sample paired t-test,
which was normally distributed and had equal variances. At p< 0.05, the findings were
considered statistically significant.
3. Results
3.1. Demographic Data of Pre- and Post-Intervention in Patients
Of the 30 participants with chronic constipation, two patients withdrew from the
clinical trial due to COVID-19 infection, and 28 completed the trial. Patient demographics
(age, height, and body weight) and vital signs (blood pressure and body temperature) were
recorded at baseline and after four weeks of treatment. By gender, females accounted for
66.7% of the participants. These parameters showed no remarkable differences between
the baseline and post-treatment time points (Table 4).
Table 4. Demographics and vital signs of the participants.
Parameters Baseline Post-Treatment Mean Difference
(Paired t-Test) p-Value
Female 20 (66.7%) 19 (67.9%) 1
Male 10 (33.3%) 9 (32.1%) 1
Age (years) 48.79 ±9.63 48.79 ±9.63 0 -
Height (cm) 161.48 ±7.93 161.50 ±7.91 −0.02 p = 0.692
Weight (kg) 62.93 ±7.93 62.64 ±10.84 0.27 p = 0.93
Systolic blood pressure (mmHg) 121.07 ±10.58 123.64 ±10.75 −2.57 p = 0.160
Diastolic blood pressure (mmHg) 79.32 ±7.33 81.54 ±7.45 −2.21 p = 0.141
Body temperature (◦C) 36.21 ±0.19 36.26 ±0.19 −0.05 p = 0.215
Data are presented as mean ±standard deviation.
3.2. Efficacy End Point
The primary efficacy endpoint of EHARW in patients with chronic constipation was
assessed based on CSBM frequency. At two weeks of the baseline, all patients showed
≤
3
or less CSBM per week (1.81
±
0.59); however, after the EHARW treatment, the frequency
of CSBMs significantly increased (2.58
±
1.72, F = 5.47, p< 0.05) compared to baseline
(Table 5). The proportion of patients who reported higher CSBMs after treatment increased
by 29.8%.
Table 5. Assessment of constipation-related symptoms from patient’s self-observation diary.
Outcomes Baseline
Normal
Distribution
(Area)
Post-
Treatment
Normal
Distribution
(Area)
F-Test Mean Difference
(Paired t-Test) p-Value
CSBM frequency/week
1.81 ±0.59 0.3997 2.58 ±1.72 * 0.6408 5.47 −0.771 p< 0.05
Bristol stool form score 2.48 ±1.00 0.6985 3.29 ±0.98 ** 0.9126 9.18 −0.804 p< 0.01
Straining at defecation 3.32 ±1.31 0.8504 2.36 ±0.99 ** 0.6569 9.91 0.964 p< 0.01
Stiffness of the stool 3.14 ±1.27 0.8236 2.61 ±1.13 0.7174 2.44 0.536 p= 0.130
The sensation of
incomplete evacuation 3.11 ±0.92 0.8944 2.11 ±1.13 *** 0.5528 17.2 1.000 p< 0.001
Sensation of
obstruction 2.96 ±1.29 0.7809 2.00 ±0.98 ** 0.5163 12.3 0.964 p< 0.01
Data are presented as mean
±
standard deviation. * p < 0.05, ** p < 0.01, and *** p < 0.001 vs. baseline indicate
significant differences after analysis with paired t-test. The data were analyzed using a parametric two-sample
paired t-test, normal distribution, and F-test. CSBM; Complete spontaneous bowel movement.
Processes 2023,11, 2142 7 of 11
As a secondary endpoint, we evaluated the Bristol stool form related to stool consis-
tency using the patient’s self-observation diary. The score showed a significant increase
after intervention (3.29
±
0.98, F = 9.18, p< 0.01) over the baseline (2.48
±
1.00). In addition,
regarding constipation-related symptoms, straining during defecation (F = 9.91,
p< 0.01
),
sensation of incomplete evacuation (F = 17.2,
p< 0.001
), and sensation of anorectal obstruc-
tion (F = 12.3,
p< 0.01
) showed a significant decrease compared with the baseline; however,
stool stiffness did not differ significantly after EHARW treatment (Table 5).
3.3. Changes in PAC-SYM and PAC-QOL Scores between Baseline and Post-Treatment
The overall PAC-SYM scores after the 4-week intervention significantly decreased
compared to the baseline (58%, p < 0.001), indicating that constipation-related symptoms
improved after drinking the EHARW. The subscales of the PAC-SYM, categorized by
abdominal, rectal, and stool symptoms, also showed a significant decrease (p < 0.001
vs. baseline). Likewise, the PAC-QOL score also showed a significant decrease in the
overall score (54.2%) as well as subscale scores after the intervention, such as physical
discomfort, psychosocial discomfort, and worries (p < 0.001 vs. baseline in all cases).
Patients reported high satisfaction (60.1%) after intervention (1.34
±
0.66, p< 0.001) over
the baseline (
3.36 ±0.58
) with the EHARW (pH 9.5; H
2≈
0.5 mg/L) intervention in terms
of constipation-related QOL (Table 6).
Table 6. Assessment of PAC-SYM and PAC-QOL questionnaires.
Subscales Baseline Post-Treatment p-Value
PAC-SYM:
1. Abdominal 2.36 ±0.55 0.83 ±0.54 *** p< 0.001
2. Rectal 2.48 ±0.72 0.81 ±0.16 *** p< 0.001
3. Stools 3.57 ±0.58 1.86 ±0.20 *** p< 0.001
Overall 9.92 ±1.38 4.17 ±2.09 *** p< 0.001
PAC-QOL:
1. Physical 2.68 ±0.74 1.30 ±0.56 *** p< 0.001
2. Psychosocial 2.08 ±0.64 0.96 ±0.51 *** p< 0.001
3. Worries 2.31 ±0.61 0.89 ±0.65 *** p< 0.001
4. Satisfaction 3.36 ±0.58 1.34 ±0.66 *** p< 0.001
Overall 17.7 ±3.90 8.10 ±5.39 *** p< 0.001
Scores are presented as mean
±
standard deviation. *** p < 0.001 vs. baseline indicates significant differences
after analysis with paired t-test. PAC-SYM; Patient Assessment of Constipation–Symptom, PAC-QOL; Patient
Assessment of Constipation–Quality of Life.
4. Discussion
This clinical study investigated the effect of drinking EHARW (pH 9.5; H
2≈
0.5 mg/L)
in patients with chronic constipation by measuring bowel function, constipation-related
symptoms, and quality of life. As outcome measures, patients’ self-recorded diaries on
CSBMs frequency and stool consistency and patient-rating questionnaires, such as PAC-
SYM and PAC-QOL, have been used to evaluate the efficacy of treatments for chronic
constipation [
37
,
38
]. Regarding the effect of EHARW, several studies on IBS, gastritis, and
constipation have been conducted on gastrointestinal disease
in vivo
and
in vitro
[
25
,
39
].
However, few clinical studies have investigated the effects of EHARW (pH 9.5) on patients
with chronic constipation. Hence, we performed a home-based interventional clinical trial
to evaluate the effect of drinking EHARW (pH 9.5, 20 mL/kg body weight/day) over
four weeks on chronic constipation [40].
First, we evaluated patients’ baseline characteristics and vital signs with chronic
constipation before and during pre-post treatment, including age, height, weight, blood
pressure, and temperature. Baseline characteristics and vital signs are essential in clinical
studies to identify potential confounding factors, select patients, interpret study results, and
monitor safety [
41
,
42
]. In this study, there were no significant differences in demographics,
Processes 2023,11, 2142 8 of 11
and vital signs between pre-and post-treatment, and no adverse effects were reported
during the 4-week intervention period (Table 4).
In this study, we used the frequency of CSBM as the primary endpoint to investigate
the effects of EHARW on chronic constipation, as CSBM frequency is associated with
a complete sense of evacuation [
43
]. After four weeks of EHARW intervention, CSBM
frequency significantly improved (29.8%, p < 0.05). In addition, the proportion of patients
with
≥
3 CSBMs/week and patients experiencing an increase of
≥
1 CSBMs/week increased.
The frequency of CSBM is related to bowel function in maintaining normal defecation
habits. Complete bowel movements should result in a stool corresponding to a type 3 or
4 bristol stool form chart [
7
]. Categories 3 (sausage shape with cracks) and 4 (smooth and
soft sausage shape) on the Bristol stool scale were considered normal bowel movements. In
our result of Bristol stool form score, a 4-week treatment of EHARW scored 3.29
±
0.98,
which was indicated in normal stool formation, while baseline scored 2.48
±
1.00. The
improved Bristol stool score (24.6%, p < 0.01) is related to stool consistency. It supports the
understanding of improving self-reported constipation symptoms, such as straining during
defecation, sensation of incomplete evacuation, and sensation of anorectal obstruction
(Table 5).
The PAC-SYM and PAC-QOL scores are reliable measurements for symptom monitor-
ing and QOL of patients with chronic constipation [
12
,
13
,
36
]. Specifically, the PAC-SYM
score questionnaire is frequently used to monitor improvements in constipation symp-
toms categorized into three subscales (abdominal, rectal, and stool symptoms) in clinical
trials [
44
]. According to our results, four weeks of treatment with EHARW (pH 9.5;
H2≈0.5 mg/L
) showed significant improvement in the patient-rated chronic symptoms
based on the overall score (58%) and each subscale score. Similarly, in the PAC-QOL, drink-
ing the EHARW (pH 9.5; H
2≈
0.5 mg/L) significantly improved the constipation-related
QOL of patients by 54.2%, and patients showed markedly high satisfaction (60.1%) with
the EHARW (Table 6).
Our results suggest that drinking EHARW (pH 9.5; H
2≈
0.5 mg/L) has beneficial
effects on chronic constipation, as indicated by the patient-reported data. On average,
ERW has an H
2
concentration of less than 0.01 mg/L to nearly 2 mg/L over the pH
range of 8 to 12. This concentration of H
2
depends on the machine, electrode material,
water source, TDS, flow rate, surface area, applied voltage, and minerals in the water
source [
33
]. Our study measured H
2
concentration as approximately 0.5 mg/L. Here, our
results explained the therapeutic properties of the EHARW, including high pH (9.5) and
rich in H
2
(
≈0.5 mg/L
), which results in negative ORP (
−100 ±5 mV
). H
2
is also produced
by many human microbiota and has a beneficial role in the human GI tract that impacts
human nutrition, health, and well-being. Carbohydrates are normally broken down in the
GI tract via glycolysis, which leads to the generation of H
2
molecules. These produced
H
2
molecules are essential for bacterial metabolism and play a role in maintaining the GI
environment [
45
]. Thus, the addition of H
2
through EHARW is effective in maintaining the
GI environment during chronic constipation.
Moreover, changes in the pH and ORP of the gut can significantly affect the growth
and composition of the microbiota, resulting in changes in the intestinal environment [
46
].
In an animal study using guinea pig ileum, H
2
shortened the colonic transit time by 47%
in the proximal colon and 10% in the distal colon compared to the baseline [
47
]. One
of the potential adverse effects of hydrogen water has been the tendency of loose stools
and increased frequency of bowel movements [
48
]. The favorable effects of H
2
on the
microbiome and the shortened colonic transit time indicate that the dissolved H
2
is most
likely responsible for the observed therapeutic effects. However, more research is needed
to determine if the effects are exclusively due to H
2
as indicated by a recent review of
ERW [45].
Based on several studies, it is speculated that the improvements in constipation
symptoms seen in our study may be because of the antioxidant efficacy of EHARW due
to H
2
molecules that are dissolved in the water. This dissolved H
2
may positively affect
Processes 2023,11, 2142 9 of 11
the gut environment by lowering ORP, decreasing oxidative stress, increasing beneficial
bacteria, and improving patients’ constipation-related symptoms and QOL. However,
beyond the numerous benefits of this study, there are some limitations. In this study,
patients were instructed to drink specifically 20 mL/kg body weight/day of EHARW
(pH 9.5;
H2≈0.5 mg/L
) for four weeks. Hence, it would be preferable to investigate
the therapeutic mechanism of EHARW in more detail, using a higher volume, time, and
biochemical examinations. In addition, further clinical research is also needed to determine
if the biological benefits observed in this study are exclusively due to the molecular H
2
also
from the alkaline pH or a combination of them.
5. Conclusions
In this clinical study, drinking EHARW (pH 9.5; H
2≈
0.5 mg/L) over four weeks
alleviated symptoms related to chronic constipation, as evident by the frequency of CSBM,
stool consistency, and self-rated PAC-SYM scores, and the patients showed high satisfaction
in their disease-related QOL. In addition, there were no adverse effects during the study
period. These results suggest that daily ingestion of EHARW can be an effective and safe
adjuvant treatment for managing chronic constipation, especially through home-based
administration. However, further in-depth clinical studies are required to confirm the
efficacy of EHARW in treating chronic constipation, considering the long-time treatment
and elaborating on various mechanisms.
Author Contributions:
Conceptualization, K.-J.L.; Methodology, S.S., J.B., H.I.K., M.H.R. and
C.-S.K.
;
Software, S.S. and J.B.; Validation, Y.K., C.-S.K. and H.I.K.; Formal Analysis, Y.K. and H.I.K.; In-
vestigation, Y.K., C.-S.K. and S.H.G.; Resources, C.-S.K., Y.K. and S.H.G.; Data Curation, S.S., J.B.
and M.H.R.; Writing—Original Draft Preparation, S.S.; Writing—Review and Editing, S.S., Y.K.,
J.B., M.H.R., Y.J.J., S.H.G., H.J.P., C.-S.K. and H.I.K.; Visualization, Y.K., J.B. and H.I.K.; Supervision,
C.-S.K.; Project Administration, K.-J.L.; Funding Acquisition, K.-J.L. All authors have read and agreed
to the published version of the manuscript.
Funding: This research was supported by a grant (2021-51-0662) from Biontech Co., Ltd.
Institutional Review Board Statement:
Ethical approval was granted by the Institutional Research
Ethics Review Board, Yonsei University, Wonju Severance Christian Hospital (IRBN: CR222010).
Informed Consent Statement: Not applicable.
Data Availability Statement:
The data presented in this study are available in the article (tables
and figures).
Acknowledgments:
The authors thank Biontech Co., Ltd. for providing the EHARW-producing
medical device for the clinical trial (BTM-1200, Biontech, Gunpo-si, Republic of Korea). We also thank
all the participants for their support in performing this study.
Conflicts of Interest: The authors declare no conflict of interest.
Abbreviation
PAC-SYM Patient assessment of constipation-symptoms
PAC-QOL Patient assessment of constipation-quality of life
IBS Intestinal bowel movement
H2Hydrogen
EHARW Electrolyzed hydrogen-rich alkaline reduced water
ORP Oxidation-reduction potential
GI Gastrointestinal
CSBM Complete spontaneous bowel movement
ITT Intention-to-treat
PP Per-protocol
SD Standard deviation
ANOVA Analysis of variance
Processes 2023,11, 2142 10 of 11
References
1.
Fabrizio, A.C.; Alimi, Y.; Kumar, A.S. Methods of evaluation of anorectal causes of obstructed defecation. Clin. Colon Rectal Surg.
2017,30, 046–056. [CrossRef] [PubMed]
2.
Chen, C.; Liu, J.; Liu, B.; Cao, X.; Liu, Z.; Zhao, T.; Lv, X.; Guo, S.; Li, Y.; He, L. Efficacy of acupuncture in subpopulations with
functional constipation: A protocol for a systematic review and individual patient data meta-analysis. PLoS ONE
2022
,17, e0266075.
[CrossRef] [PubMed]
3.
Rajindrajith, S.; Devanarayana, N.M.; Weerasooriya, L.; Hathagoda, W.; Benninga, M.A. Quality of life and somatic symptoms in
children with constipation: A school-based study. J. Pediatr. 2013,163, 1069–1072.e1061. [CrossRef]
4.
Talley, N.J.; Jones, M.; Nuyts, G.; Dubois, D. Risk factors for chronic constipation based on a general practice sample.
Am. J. Gastroenterol. 2003,98, 1107–1111. [CrossRef]
5.
Sharma, A.; Rao, S.S.; Kearns, K.; Orleck, K.D.; Waldman, S.A. Diagnosis, management and patient perspectives of the spectrum
of constipation disorders. Aliment. Pharmacol. Ther. 2021,53, 1250–1267. [CrossRef]
6.
Lin, S.-R.; Ke, M.-Y.; Luo, J.-Y.; Yuan, Y.-Z.; Wang, J.-Y.; Walter, V.; Huang, J. A randomized, double-blind, placebo-controlled trial
assessing the efficacy and safety of tegaserod in patients from china with chronic constipation. World J. Gastroenterol.
2007
,13, 732.
[CrossRef]
7.
Talley, N.J.; Lasch, K.L.; Baum, C.L. A gap in our understanding: Chronic constipation and its comorbid conditions.
Clin. Gastroenterol. Hepatol. 2009,7, 9–19. [CrossRef] [PubMed]
8.
Dennison, C.; Prasad, M.; Lloyd, A.; Bhattacharyya, S.K.; Dhawan, R.; Coyne, K. The health-related quality of life and economic
burden of constipation. Pharmacoeconomics 2005,23, 461–476. [CrossRef]
9.
Leppert, W. Emerging therapies for patients with symptoms of opioid-induced bowel dysfunction. Drug Des. Dev. Ther.
2015
,9, 2215.
[CrossRef]
10.
Walters, J.B.; Montagnini, M. Current concepts in the management of opioid-induced constipation. J. Opioid Manag.
2010
,6,
435–444. [CrossRef]
11.
Blake, M.; Raker, J.; Whelan, K. Validity and reliability of the bristol stool form scale in healthy adults and patients with
diarrhoea-predominant irritable bowel syndrome. Aliment. Pharmacol. Ther. 2016,44, 693–703. [CrossRef]
12.
Nour-Eldein, H.; Salama, H.M.; Abdulmajeed, A.A.; Heissam, K.S. The effect of lifestyle modification on severity of constipation
and quality of life of elders in nursing homes at ismailia city, egypt. J. Fam. Community Med. 2014,21, 100. [CrossRef]
13.
Slappendel, R.; Simpson, K.; Dubois, D.; Keininger, D.L. Validation of the pac-sym questionnaire for opioid-induced constipation
in patients with chronic low back pain. Eur. J. Pain. 2006,10, 209–217. [CrossRef] [PubMed]
14.
Aziz, I.; Whitehead, W.E.; Palsson, O.S.; Törnblom, H.; Simrén, M. An approach to the diagnosis and management of rome iv
functional disorders of chronic constipation. Expert. Rev. Gastroenterol. Hepatol. 2020,14, 39–46. [CrossRef]
15.
Shin, J.E.; Jung, H.-K.; Lee, T.H.; Jo, Y.; Lee, H.; Song, K.H.; Hong, S.N.; Lim, H.C.; Lee, S.J.; Chung, S.S. Guidelines for the
diagnosis and treatment of chronic functional constipation in korea. J. Neurogastroenterol. Motil.
2016
,22, 383. [CrossRef]
[PubMed]
16.
Ohta, S. Molecular hydrogen is a novel antioxidant to efficiently reduce oxidative stress with potential for the improvement of
mitochondrial diseases. Biochim. Biophys. Acta Gen. Subj. 2012,1820, 586–594. [CrossRef] [PubMed]
17.
Xia, C.; Liu, W.; Zeng, D.; Zhu, L.; Sun, X.; Sun, X. Effect of hydrogen-rich water on oxidative stress, liver function, and viral load
in patients with chronic hepatitis b. Clin. Transl. Sci. 2013,6, 372–375. [CrossRef]
18.
Ostojic, S.M. Targeting molecular hydrogen to mitochondria: Barriers and gateways. Pharmacol. Res.
2015
,94, 51–53. [CrossRef]
19.
Shen, N.-Y.; Bi, J.-B.; Zhang, J.-Y.; Zhang, S.-M.; Gu, J.-X.; Qu, K.; Liu, C. Hydrogen-rich water protects against inflammatory bowel
disease in mice by inhibiting endoplasmic reticulum stress and promoting heme oxygenase-1 expression. World J. Gastroenterol.
2017,23, 1375. [CrossRef]
20. Medani, M.; Collins, D.; Docherty, N.G.; Baird, A.W.; O’Connell, P.R.; Winter, D.C. Emerging role of hydrogen sulfide in colonic
physiology and pathophysiology. Inflamm. Bowel Dis. 2011,17, 1620–1625. [CrossRef]
21.
He, J.; Xiong, S.; Zhang, J.; Wang, J.; Sun, A.; Mei, X.; Sun, X.; Zhang, C.; Wang, Q. Protective effects of hydrogen-rich saline on
ulcerative colitis rat model. J. Surg. Res. 2013,185, 174–181. [CrossRef]
22.
Abe, T.; Li, X.-K.; Yazawa, K.; Hatayama, N.; Xie, L.; Sato, B.; Kakuta, Y.; Tsutahara, K.; Okumi, M.; Tsuda, H. Hydrogen-rich
university of wisconsin solution attenuates renal cold ischemia–reperfusion injury. Transplantation
2012
,94, 14–21. [CrossRef]
[PubMed]
23.
Tanaka, Y.; Kiuchi, M.; Higashimura, Y.; Naito, Y.; Koyama, K. The effects of ingestion of hydrogen-dissolved alkaline electrolyzed
water on stool consistency and gut microbiota: A double-blind randomized trial. Med. Gas Res. 2021,11, 138. [CrossRef]
24.
LeBaron, T.W.; Kura, B.; Kalocayova, B.; Tribulova, N.; Slezak, J. A new approach for the prevention and treatment of cardiovascu-
lar disorders. Molecular hydrogen significantly reduces the effects of oxidative stress. Molecules 2019,24, 2076. [CrossRef]
25.
Bajgai, J.; Kim, C.-S.; Rahman, M.; Jeong, E.-S.; Jang, H.-Y.; Kim, K.-E.; Choi, J.; Cho, I.-Y.; Lee, K.-J.; Lee, M. Effects of alkaline-
reduced water on gastrointestinal diseases. Processes 2022,10, 87. [CrossRef]
26.
Rokhmalia, F.; Hermiyanti, P. A concentrations of ph, chromium, and mpn coliform parameters in alkaline water. Int. J. Adv.
Health Sci. Technol. 2022,2, 5. [CrossRef]
27.
Rane, M.D.; Shaikh, N.; Maniyar, F. Daily ingestion of structured alkaline water (organized/regularized) and it’s effect on health
conditioning. Asian J. Adv. Res. 2022,5, 606–618.
Processes 2023,11, 2142 11 of 11
28.
Sharma, S.; Lee, K.-J.; Bajgai, J.; Trinh, T.T.; Antonio, J.M.; Rahman, M.H.; Vira, K.; Sofian, A.-N.; Cho, S.H.; Kim, C.-S. Anti-
oxidative and anti-diabetic effects of electrolyzed weakly alkaline reduced water on renal proximal tubular epithelial cells.
Processes 2022,10, 2025. [CrossRef]
29.
Trinh, T.T.; Fadriquela, A.; Bajgai, J.; Sharma, S.; Rahman, M.H.; Goh, S.-H.; Khang, S.-S.; Khang, W.-R.; Kim, C.-S.; Lee, K.-J.
Anti-oxidative effect of weak alkaline reduced water in raw 264.7 murine macrophage cells. Processes 2021,9, 2062. [CrossRef]
30.
Shirahata, S.; Hamasaki, T.; Teruya, K. Advanced research on the health benefit of reduced water. Trends Food Sci. Technol.
2012
,
23, 124–131. [CrossRef]
31.
Tashiro, H.; Kitahora, T.; Fujiyama, Y.; Bammba, T. Clinical evaluation of alkali-ionized water for chronic diarrhea e placebocon-
trolled double-blind study. Dig. Absorpt. 2000,23, 52–56.
32.
Islam, R.; Faysal, S.M.; Amin, R.; Juliana, F.M.; Islam, M.J.; Alam, J.; Hossain, M.N.; Asaduzzaman, M. Assessment of ph and total
dissolved substances (tds) in the commercially available bottled drinking water. J. Nurs. Health Sci. 2017,6, 35–40.
33.
LeBaron, T.W.; Sharpe, R.; Ohno, K. Electrolyzed–reduced water: Review ii: Safety concerns and effectiveness as a source of
hydrogen water. Int. J. Mol. Sci. 2022,23, 14508. [CrossRef]
34.
Tashiro, H.; Hokudo, T.; Ono, H.; Fujiyama, Y.; Baba, T. Clinical Evaluation of Alkaline Ionized Water for Abdominal Com-
plaints: Placebo Controlled Double Blind Tests. Available online: https://wipalis.com/wp-content/uploads/2021/05/Clinical-
evaluation-of-alkaline-ionized-water-for-abdominal- complaints.pdf (accessed on 1 July 2023).
35.
Johanson, J.; Kamm, M.; Shetzline, M.; Dunger-Baldauf, C.; Cohard-Radice, M. Association of complete spontaneous bowel
movements (csbm) and symptom improvement in chronic constipation (cc) patients (pts): 931. Am. J. Gastroenterol.
2005
,100, S341.
[CrossRef]
36.
Marquis, P.; De La Loge, C.; Dubois, D.; McDermott, A.; Chassany, O. Development and validation of the patient assessment of
constipation quality of life questionnaire. Scand. J. Gastroenterol. 2005,40, 540–551. [CrossRef] [PubMed]
37.
Camilleri, M.; Hale, M.; Morlion, B.; Tack, J.; Webster, L.; Wild, J. Naldemedine improves patient-reported outcomes of opioid-
induced constipation in patients with chronic non-cancer pain in the compose phase 3 studies. J. Pain. Res.
2021
,14, 2179–2189.
[CrossRef]
38.
Turan, N.; Atabek A¸stı, T. The effect of abdominal massage on constipation and quality of life. Gastroenterol. Nurs.
2016
,39, 48–59.
[CrossRef]
39.
Ignacio, R.M.C.; Joo, K.-B.; Lee, K.-J. Clinical effect and mechanism of alkaline reduced water. J. Food Drug Anal.
2012
,20, 33.
[CrossRef]
40.
Henry, M.; Chambron, J. Physico-chemical, biological and therapeutic characteristics of electrolyzed reduced alkaline water
(eraw). Water 2013,5, 2094–2115. [CrossRef]
41.
Sharma, S.; Bajgai, J.; Fadriquela, A.; Rahman, M.H.; Thuy, T.T.; Goh, S.-H.; Kim, C.-S.; Yu, K.; Lee, K.-J. The Effect of a Granule-
type Anti-Hangover Compound, Quechung, on Acute Alcohol-Induced Hangover in Healthy Subjects: A Randomized Crossover
Study. Available online: https://www.earticle.net/Article/A385723 (accessed on 1 July 2023).
42.
Evans, D.; Hodgkinson, B.; Berry, J. Vital signs in hospital patients: A systematic review. Int. J. Nurs. Stud.
2001
,38, 643–650.
[CrossRef]
43.
Mueller-Lissner, S.; Kamm, M.A.; Wald, A.; Hinkel, U.; Koehler, U.; Richter, E.; Bubeck, J. Multicenter, 4-week, double-blind,
randomized, placebo-controlled trial of sodium picosulfate in patients with chronic constipation. Am. J. Gastroenterol.
2010
,105,
897–903. [CrossRef]
44.
Yiannakou, Y.; Tack, J.; Piessevaux, H.; Dubois, D.; Quigley, E.; Ke, M.; Da Silva, S.; Joseph, A.; Kerstens, R. The pac-sym
questionnaire for chronic constipation: Defining the minimal important difference. Aliment. Pharmacol. Ther.
2017
,46, 1103–1111.
[CrossRef] [PubMed]
45.
Smith, N.W.; Shorten, P.R.; Altermann, E.H.; Roy, N.C.; McNabb, W.C. Hydrogen cross-feeders of the human gastrointestinal tract.
Gut Microbes 2019,10, 270–288. [CrossRef] [PubMed]
46. Jay, J.M.; Loessner, M.J.; Golden, D.A. Modern Food Microbiology; Springer: Berlin/Heidelberg, Germany, 2008.
47.
Jahng, J.; Jung, I.; Choi, E.; Conklin, J.; Park, H. The effects of methane and hydrogen gases produced by enteric bacteria on ileal
motility and colonic transit time. J. Neurogastroenterol. Motil. 2012,24, 185-e92. [CrossRef] [PubMed]
48.
Nakao, A.; Toyoda, Y.; Sharma, P.; Evans, M.; Guthrie, N. Effectiveness of hydrogen rich water on antioxidant status of subjects
with potential metabolic syndrome—An open label pilot study. J. Clin. Biochem. Nutr. 2010,46, 140–149. [CrossRef]
Disclaimer/Publisher’s Note:
The statements, opinions and data contained in all publications are solely those of the individual
author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to
people or property resulting from any ideas, methods, instructions or products referred to in the content.
