Chen 2021
Chen 2021
Chen 2021
Phytomedicine
journal homepage: www.elsevier.com/locate/phymed
A R T I C L E I N F O A B S T R A C T
Keywords: Background: Current treatments for overactive bladder (OAB) have limited efficacy, low persistence and a high
overactive bladder rate of adverse events commonly leading to treatment cessation in clinical practice. Clinicians in Asia commonly
cinnamon use traditional Chinese medicine as an alternative for OAB treatment despite it having uncertain efficacy and
herbal patch
safety. To evaluate the efficacy and safety of cinnamon patch (CP) treatment for alleviating symptoms of OAB, a
acupoint
overactive bladder symptom score
double-blind randomized, placebo-controlled trial was conducted in the present study.
Materials and Methods: In this 6-week randomized clinical trial conducted in an outpatient setting, 66 subjects
diagnosed as having OAB were enrolled and treated with a placebo (n=33) or CP (n=33). The OAB symptom
score (OABSS) was selected as the primary end point, and a patient perception of bladder condition (PPBC), an
urgency severity scale (USS), and post-voiding residual urine (PVR) volume were selected as secondary end
points. Statistical analyses were performed with IBM SPSS Statistics 20. Groups were compared using an inde
pendent sample t-test, Fisher exact test, and Chi-squared test.
Results: In total, 66 participants (40 women and 26 men), 60.35 ± 12.77 years of age, were included in the
intention-to-treat analyses. Baseline characteristics were comparable between the CP (n ==33) and placebo (n
==33) groups. Treatment with a CP showed statistically significant differences in reductions in OABSS scores
(9.70 ± 2.20 to 6.33 ± 2.42), PPBC scores (3.36 ± 0.60 to 2.15 ± 0.83), and USS scores (2.67 ± 0.54 to 1.64 ±
0.60).
Conclusions: Compared to a placebo, treatment with CP might be considered an effective and safe complementary
therapy for OAB. Further studies employing a positive control, different dosage forms, larger sample sizes, and
longer treatment periods are warranted.
Introduction nocturia (D’Ancona et al., 2019; Haylen et al., 2010). OAB affects pa
tients’ physical function, social life, and sleep quality, and causes situ
Overactive bladder (OAB) is a clinical syndrome characterized by ations like loss of productivity, a lower self-image, and increased
frequent urination, with or without urge incontinence, urgency, and morbidity, such as falls and fractures, and mortality (Szabo et al., 2018).
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CP, cinnamon patch; Cr, serum creatinine; MID,
minimally important difference; OAB, overactive bladder; OABSS, overactive bladder symptom score; PPBC, patient perception of bladder condition; PVR, post-
voiding residual; SAE, severe adverse event; TCM, traditional Chinese medicine; US, ultrasound; USS, urgency severity scale.
* Corresponding author: Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei 11031, Taiwan, Tel.:
+886-2-27371661 ext. 6151; fax: +886-2-27357983
E-mail address: lmh@tmu.edu.tw (M.-H. Lee).
https://doi.org/10.1016/j.phymed.2020.153380
Received 24 April 2020; Received in revised form 20 September 2020; Accepted 11 October 2020
Available online 12 October 2020
0944-7113/© 2020 Elsevier GmbH. All rights reserved.
L.-L. Chen et al. Phytomedicine 80 (2021) 153380
One of the largest population-based surveys that studied the prevalence investigator who handed it to the patient. Neither the patient nor
of lower urinary tract symptoms and OAB conducted in five European investigator was aware of which treatment was being administered. The
countries in 2016 discovered that the prevalence of OAB was 11.8% study was approved by the Institutional Review Board of En Chu Kong
(Eapen and Radomski, 2016). In Taiwan, 19.8% of people suffer from Hospital (no. ECKIRB1051203, Supplement 1), and registered at Clin
OAB symptoms, and its prevalence increases with age, with similar icalTrials.gov (NCT03532789 https://clinicaltrials.gov/ct2/show/NC
proportions in both sexes (18.7% of women and 19.9% of men) (Chiu T03532789).
et al., 2012). Several conditions may contribute to signs and symptoms
of OAB, including neurological disorders, such as stroke and multiple Interventions
sclerosis, diabetes, acute urinary tract infections (UTIs), abnormalities of
the bladder, such as tumors or bladder stones, and declining cognitive Patients visited our clinic four times over a time span of 7 weeks:
function due to aging (Patra and Patra, 2014). Current treatments of screening (visit 1), 1 week later for randomization and start of patch
OAB, including behavioral therapy, medication with antimuscarinic treatment (visit 2, baseline), 2 weeks after beginning treatment (visit 3,
drugs, and sacral neuromodulation or intradetrusor onabotulinumtoxin end of treatment), and 4 weeks after the end of treatment (follow-up)
A injections are not completely effective (Michel, 2020). In addition, (Fig. 2). At visit 2, the experimental group was treated with a CP 4 h
these treatments can cause various side effects, like dry mouth, con every 2 days. Each CP contained 1.5 g of crude cinnamon powder (batch
stipation, migraines, infections, and gross hematuria (Corcos et al., no.: BA101012A, containing 2.58% cinnamaldehyde; Ministry of Health
2017). and Welfare Manufacturing no. 053990) manufactured by Shen Chang
The main manifestations of OAB such as “frequent urination”, GMP-certified Pharmaceutical (Taoyuan, Taiwan), 1 g of corn starch,
“nocturia”, and “urinary incontinence” are clearly recorded in a Chinese and 4 ml of reverse-osmosis water in a 11.6 × 7.8-cm-sized patch. The
medical classic Zhu bing yuan hou lun (諸病源候論) from the Sui Dynasty placebo patch for the control group contained 2.5 g of corn starch and 4
(581~618 CE) (Chao, 1966). Several traditional Chinese medicine ml of reverse-osmosis water in the same-sized patch. Crude cinnamon
(TCM) prescriptions, such as cinnamon twig decoction plus cinnamon powder was qualitatively tested by ultra-performance liquid
(桂枝加桂湯), which contains an incremental dose of cinnamon, are chromatography-diode array detector-tandem mass spectrometry
used to promote the elimination of coldness and water in the urinary (UPLC-DAD-MS/MS) (Supplement 2) in accordance with specifications
bladder (Pan et al., 2006). TCM physicians usually prescribe a decoction using appropriate reference standards. All analytical methods were
of cinnamon bark with other herbs to reduce abdominal pain and in validated for selectivity, accuracy, and precision. All study products
crease the blood circulation, especially in the urogenital system and were kept in a secure, locked place and were only accessible to autho
lower extremities (Zhang et al., 2019). Several studies confirmed the rized personnel. The application sites for all patches was between the
role of cinnamaldehyde and cinnamic acid in reducing cardiovascular umbilicus and pubic symphysis and in front of the urinary bladder, and
diseases (Rao and Gan, 2014). Cell culture studies provided evidence for acupoints CV3, CV4, CV5, and CV6 were covered (Fig. 1). In total, seven
the efficacy of cinnamaldehyde in inhibiting angiogenesis and patches were distributed to each patient for 2 weeks, then the patient
enhancing tumor cell apoptosis (Abbasi et al., 2020). Other pharmaco returned 4 weeks after finishing treatment for the final follow-up.
logical activities of cinnamon were reported, including Duration of patch treatment was according to the result of our pre
anti-inflammatory, antioxidant, neuroprotective, antidiabetic, and liminary study (Supplement 3). After dispensing, all patches were stored
antimicrobial activities (Rao and Gan, 2014). OAB is closely related to at a temperature of 4~8 ◦ C in each patient’s refrigerator before use.
neurological dysfunction. Therefore, the neuroprotectivity of the
essential oil of cinnamon could be beneficial to OAB. Participants
In TCM, qi energy flows throughout the body along pathways known
as meridians. Located along these meridians are acupuncture points Adults over the age of 20 years with symptoms of OAB which were
(acupoints) where the qi rises to the surface of the body. Manipulation of simultaneously diagnosed by the urologist, Dr. Ke, and the traditional
acupoints is used to effectively reduce postoperative analgesic re Chinese physician, Dr. Chen, were recruited via a variety of advertising
quirements in patients undergoing lower abdominal surgery (Lin et al., media. The inclusion criteria for participants at the baseline visit were: aged
2002) and improve urine leakage in women with stress urinary incon ≥ 20 years, an OABSS total score of ≥ 3 points, and a question 3 (urgency)
tinence (Liu et al., 2017). Accordingly, in this study, with approaches of the OABSS of ≥ 2 points (Yamaguchi et al., 2009). Since OAB is defined by
Western medicine and TCM tools, we carried out a randomized subjective rather than objective symptoms, the patient’s perspective is
double-blind, placebo-controlled clinical trial (RCT) of a cinnamon important in managing this disease. Thus, the OABSS was used as an in
patch (CP) treatment on acupoints in OAB patients using OABSS, pa clusion criterion and diagnostic tool in our study (Chuang et al., 2018).
tient’s perception of their bladder condition (PPBC), and urgency Exclusion criteria were patients with an acute urinary tract infection ; a
severity scale (USS) to investigate the efficacy of CP treatment, as well as recurrent urinary tract infection of more than five times in the past year;
using abdominal ultrasound (US) scanning to measure changes in the hematuria; bladder stones; ongoing estrogen treatment for > 2 months
post-voiding residual (PVR) volume. before the trial; permanent or intermittent catheterization; pregnancy or
breastfeeding; a spinal cord injury; mental illness or substance abuse; and
Materials and Methods any intake of bladder-affecting drugs such as anticholinergics,
alpha-adrenergic blockers, diuretics, and phytotherapeutics in the previous
Trial design month.
2
L.-L. Chen et al. Phytomedicine 80 (2021) 153380
Figure 1. Application site including acupoints (CV3, CV4, CV5, and CV6) for the placebo and cinnamon patch.
Bladder symptoms rating scale blood urea nitrogen (BUN)), adverse events, adverse drug reactions, and
severe adverse events (SAEs) as evaluated or reported by patients.
The OABSS, PPBC, and USS are three questionnaires validated in the
Chinese language for people with bladder symptoms (Chou et al., 2014). Statistical analysis
The OABSS consists of four items that correspond to daytime frequency,
urinary urgency, incontinence, and nocturia. The relative weighting of The sample size of this study (n ==66) was calculated from the effect
the maximal score was respectively designated 2:3:5:5 for daytime fre size (n ==52, G*power 3.1) (Faul et al., 2007) according to results of our
quency, nocturia, urgency, and urge incontinence. The overall score is preliminary study (Supplement 3) and loss to follow-up rate (20%) was
the sum of the four scores, and the diagnostic criteria for OAB are a total also considered. All data analyses were performed with IBM SPSS Sta
OABSS of ≥ 3 and an urgency score for question 3 of ≥ 2. In the event tistics 20 (SPSS, Chicago, IL). The groups were compared at visit 2 using
that the OABSS is used as the standard for assessing the severity of OAB an independent-sample t-test, Fisher exact test and Chi-squared test.
(Homma et al., 2006), it is recommended that a total score of ≤ 5 be Baseline characteristics were evaluated for the 66 patients that finished
defined as mild, a score of 6~11 as moderate, and a score of ≥ 12 as the study (33 in the placebo patch group and 33 in the CP group).
severe symptoms. The PPBC (score range of 0~5) is a single item that Comparisons of primary outcomes between the two groups are
assesses a patient’s subjective impression of their current urinary expressed as the mean ± standard deviation (SD).
problems (Coyne et al., 2006). The USS (score range of 0~4) is a vali
dated patient-reported measure of urgency (Nixon et al., 2005). The Results
higher the score, the greater the severity associated with increased
symptom bother and a worse health-related quality of life. All three of General characteristics
these scales were completed at visits 2, and 3, and at the final follow-up.
The primary outcome was the change in the OABSS total score from visit Among 91 patients screened, 66 patients who were enrolled at the
2 to visit 3, while secondary outcomes included changes in voiding baseline in this study, were equally and randomly assigned to a placebo
symptoms if any. group (including four patients who withdrew) and CP group. Reporting
of this randomized trial followed the Consort 2010 checklist (Fig. 2).
PVR volume by US There were no statistically significant differences between the placebo
group and the CP group in terms of age, sex, parturition, number of
Evaluating the PVR volume is typically performed using US with a comorbidities, or consumption of alcohol, tea, tobacco, and betel nuts at
bladder scanner. The PVR volume is the amount of urine retained in the the start of the study (p > 0.05). At visit 2 (baseline), there were no
bladder after voluntary voiding and functions as a diagnostic tool. For statistically significant differences between the CP group and placebo
the transabdominal bladder volume evaluation, the probe was placed group in the OABSS (9.70 ± 2.20 vs. 10.52 ± 2.12), including frequency
over the suprapubic area with the patient in a prone position. Bladder (1.06 ± 0.35 vs. 1.18 ± 0.46), nocturia (2.46 ± 0.79 vs. 2.36 ± 0.65),
images were recorded in both the sagittal and transverse planes. The urgency (4.42 ± 0.50 vs. 4.48 ± 0.57), or incontinence (1.76 ± 1.73 vs.
greatest transverse (width), anteroposterior (depth), and superior- 2.48 ± 1.79) (all p > 0.05) (Table 2), or subjective feelings of the bladder
inferior (height) distances were recorded: volume = length × width × condition, PPBC, and USS (p > 0.05). Basic demographics and study data
height × 0.52. The PVR volume was determined at visits 2 and 3. were collected at the baseline (Table 1).
A safety analysis was conducted at every visit and consisted of blood CP treatment had statistical significance in decreasing the OABSS by
routine, liver function (aspartate aminotransferase (AST) and alanine 34.7% (9.70 to 6.33), the score of nocturia by 36.7% (2.45 to 1.55), the
aminotransferase (ALT)), renal function (serum creatinine (Cr) and score of urgency by 36.2% (4.42 to 2.82), and the score of incontinence
3
L.-L. Chen et al. Phytomedicine 80 (2021) 153380
Figure 2. Consolidated Standards of Reporting Trials (CONSORT) flow chart of enrollment and follow-up showing progression of patients throughout the trial.
by 43.2% (1.76 to 1.00) (Table 2). For the primary endpoint, the severity Effects of the CP on the PPBC and USS
of the OABSS was categorized as moderate at visit 2 (baseline) (placebo
group 10.52 ± 2.12, CP group 9.70 ± 2.20, p > 0.05). At visit 3 (after Subjective feelings of the bladder condition were evaluated by the
treatment), the OABSS exhibited a statistically significant reduction in PPBC and USS (Figs. 3, S3 and Table 3). After CP treatment, PPBC and
the CP group versus the placebo group (6.33 ± 2.42 vs. 9.73 ± 2.52, p < USS scores were statistically significantly lower at visit 3 (PPBC 2.15 ±
0.001). Especially in terms of nocturia, urgency, and incontinence, CP 0.83, p < 0.001 and USS 1.64 ± 0.60, p < 0.001). After 4 weeks of
treatment was better than the placebo at visit 3 (1.55 ± 0.90 vs. 2.18 ± follow-up, the PPBC and USS were still statistically significantly lower in
0.77, p < 0.001, 2.82 ± 1.24 vs. 4.18 ± 0.73, p < 0.001, and 1.00 ± 1.37 the CP group (PPBC 2.24 ± 0.83, p < 0.001 and USS 1.64 ± 0.65, p <
vs. 2.12 ± 1.88, p < 0.01, respectively). At 4 weeks following visit 3, the 0.001). There were no statistically significant differences between the
decrease in the OABSS in the CP group had still further statistical sig placebo and CP groups in either the PPBC (placebo group 3.36 ± 0.86,
nificance (6.33 ± 2.57 vs. 9.76 ± 2.55, p < 0.001 compared to the CP group 3.36 ± 0.60, p > 0.05) or USS (placebo group 2.52 ± 0.67, CP
placebo group). This result revealed the efficacy of CP treatment for the group 2.67 ± 0.54, p > 0.05) at visit 2. We used the minimally important
three OAB symptoms of nocturia, urgency, and incontinence, and the difference (MID) (1 point for PPBC) to evaluate clinically relevant im
effect appeared to maintain rather than having been further change at provements of subjects (Coyne et al., 2006). The results show that the
least 4 weeks (Table 2). number of patients that had achieved recognizable response by visit 3
were 93.9% (31/33) in CP group and 15.2% (5/33) in placebo group.
4
L.-L. Chen et al. Phytomedicine 80 (2021) 153380
Table 2
Comparison of overactive bladder symptom score (OABSS) at visit 2, visit 3 and the 4-week follow-up between the placebo group and the cinnamon patch group
Visit 2 (baseline) Visit 3 (end of treatment) Four-week follow-up
Placebo Cinnamon p Value Placebo Cinnamon p Value Placebo Cinnamon p Value
(n=33) (n=33) (n=33) (n=33) (n=33) (n=33)
OABSS (total score 10.52 ± 2.12 9.70 ± 2.20 1.3 × 9.73 ± 2.52 6.33 ± 2.42 5.1 × 9.76 ± 2.55 6.33 ± 2.57 9.2 ×
1
0~15) 10− 10− 7*** 10− 7***
1
Frequency (score 0~2) 1.18 ± 0.46 1.06 ± 0.35 2.3 × 1.00 ± 0.56 0.97 ± 0.30 7.9 × 10− 0.97 ± 0.53 0.97 ± 0.30 1.0
1
10−
Nocturia (score 0~3) 2.36 ± 0.65 2.45 ± 0.79 6.1 × 2.18 ± 0.77 1.55 ± 0.90 3.1 × 2.21 ± 0.82 1.48 ± 0.91 1.1 ×
1 3
10− 10− ** 10− 3**
Urgency (score 0~5) 4.48 ± 0.57 4.42 ± 0.50 6.5 × 4.18 ± 0.73 2.82 ± 1.24 1.4 × 4.27 ± 0.72 2.85 ± 1.30 1.3 ×
1 6
10− 10− *** 10− 6***
Incontinence (score 2.48 ± 1.79 1.76 ± 1.73 9.8 × 2.12 ± 1.88 1.00 ± 1.37 7.4 × 2.06 ± 1.90 1.03 ± 1.45 1.6 × 10− 2*
1 3
0~5) 10− 10− **
OABSS Score 0~15 (0 = no bother, 15 = maximum restraint). Data are the mean ± standard deviation.
*
p < 0.05
**
p < 0.01
***
p < 0.001, by an independent-sample t-test.
5
L.-L. Chen et al. Phytomedicine 80 (2021) 153380
0.05) (Table 5). In our study, each CP used contained only 0.6% cin AST 26.55 ± 25.82 ± 0.73 24.54 ± 26.41 ± 0.36
namaldehyde, and contact dermatitis was found in 1 patient (3.4%) in 10.93 4.58 8.09 7.56
ALT 25.09 ± 28.06 ± 0.28 23.43 ± 29.66 ± 0.10
the placebo group and in three patients (9.1%) in the CP group.
11.70 10.56 10.90 17.54
Cr 0.87 ± 0.88 ± 0.23 0.91 0.91 ± 0.91 ± 0.33 0.85
Discussion 0.19 0.19
BUN 15.97 ± 15.88 ± 0.94 16.93 ± 16.09 ± 0.51
To the best of our knowledge, this is the first double-blind, ran 4.59 4.88 4.40 5.16
domized, placebo-controlled trial to evaluate the efficacy and applica AST, aspartate aminotransferase; ALT, alanine aminotransferase; Cr. creatinine;
bility of treatment of OAB with a CP through improving changes in BUN, blood urea nitrogen.
urinary behavior, bladder US, and safety. According to TCM principles, Based on an independent-sample t-test. Data are the mean ± standard deviation.
an unbalanced constitution can represent an individual’s susceptibility
to and recurrence of specific diseases, especially chronic diseases and antimuscarinic treatment of OAB patients resulted in a considerable
their complications (Huang et al., 2019). Coyne’s team reported that as 58.24% (3.64 to 1.52) reduction in USS (Liu et al., 2009). Adjusted mean
people get older, they are at an increased risk of developing OAB (Coyne differences in PPBC (-1.21 at visit 3 and -1.12 at follow-up) were sta
et al., 2011). They are also at higher risk of getting diseases and disor tistically significantly greater than the MID in PPBC, which produced
ders which lead to polypharmacy, such as depression, visual or auditory clinically significant effects in response to OAB treatment (Fig. S3). In
hallucinations, and anxiety (Dagli and Sharma, 2014). To prevent addition, our study showed no significant change in the PVR volume,
problems of polypharmacy from the oral intake of multiple medications, which is the same result as previous research (Chughtai et al., 2013; Liu
there are some third-line treatments of choice, such as peripheral tibial et al., 2009). Overall, 18.2% of patients were found to have a PVR
nerve stimulation and sacral neuromodulation (Corcos et al., 2017). volume which was not normal (normal PVR < 50 ml) in our trial. The
Previous studies showed that increased dosages of cinnamon in pre population of OAB patients enrolled in our study displayed relatively
scribed decoctions can increase bladder circulation and urine elimina smaller impacts on the PVR volume, and the changes in the PVR volume
tion (Wiseman et al., 2009). The formula containing Cinnamomi in patients between the placebo and CP treatment groups were statisti
Ramulus, Aconiti Lateralis Radix, and Asari Radix decoction was pre cally insignificant.
scribed to treat symptoms of nocturia in patients diagnosed with a yang Cinnamon contains about 1%~2% essential oils which are mainly
deficiency pattern (Pan et al., 2006). Therefore, we use CP treatment, comprised of 65%~80% cinnamaldehyde, with a lesser amount of
based on TCM principles, by topical application instead of oral admin eugenol (Bansode, 2012). In this study, crude cinnamon powder con
istration to reduce the complexity of polypharmacy. tains 2.16 ± 0.03 mg/g cinnamaldehyde (supplement 2). Aromatic
The study showed significant improvements in urgency, nocturia, aldehyde and phenol volatile oils exhibited potential neuroprotective
and urinary incontinence compared to the placebo group after 2 weeks effects via inhibition of neuroinflammation through attenuating induc
of treatment, which reduced the overall OABSS. In this study, CP ible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 expres
treatment revealed a 34.69% (9.70 to 6.33) decline in OABSSs. After sions and the nuclear factor (NF)-κB signaling pathway after ischemic
ceasing CP treatment, the beneficial effects apparently lasted 4 weeks. stroke in a previous study (Chen et al., 2016). Cinnamaldehyde, the most
Because of improvements in OAB symptoms, patients’ overall sensations specific transient receptor potential ankyrin 1 (TRPA1) agonist, excites a
of the bladder and urgency also statistically significantly decreased. The subset of sensory neurons highly enriched in cold-sensitive neurons and
results are in accord with the results of previous studies (Chughtai et al., elicits nociceptive signals. The transient receptor potential (TRP) su
2013; Garely et al., 2007; Xiao et al., 2016). Results of a study by perfamily contains relatively non-selective cation channels, and some of
Chughtai et al. indicated that administration of Gosha-jinki-gan, them are expressed in the bladder, especially in primary afferent neu
composed of cinnamomi cortex and nine other herbs, in OAB patients rons and the urothelium, and their modulators were found to have
decreased OABSSs by 34.67% (7.5 to 4.9) (Chughtai et al., 2013). Xiao therapeutic potential for OAB in animal studies (Fry et al., 2019).
et al. reported that treatment with Weng-li-tong plus tolterodine caused a Around 9.1% (3/33) of patients in the CP group and 3.4% (1/29) of
statistically significant decrease in OABSSs by 40.62% (9.6 to 5.7) (Xiao patients in the placebo group reported a mild skin allergy, such as
et al., 2016). In this study, the CP treatment group revealed a 36.01% redness, swelling, burning, bumps, and a rash at the application site. In
(3.36 to 2.15) decline in PPBC and a 38.58% (2.67 to 1.64) decline in our study, each CP contained only 0.6% cinnamaldehyde, which was
USS. Garely et al. demonstrated that solifenacin treatment for OAB with less than a 3% concentration of cinnamaldehyde which produced irri
incontinence resulted a statistically significant 36.96% (4.6 to 2.9) tation on volunteers’ skin in a previous study (Bickers et al., 2005).
reduction in PPBC (Garely et al., 2007). The findings of the current study Besides contact dermatitis, there was no liver or renal toxicity or other
are in agreement with those of Liu et al. who demonstrated that SAE was found in this study. However, the lack of directly measured
Table 4
Comparison of the post-voiding residual (PVR) volume at visits 2 and 3 between the placebo group and the cinnamon patch group.
Visit 2 (baseline) Visit 3 (end of treatment)
Placebo(n=33) Cinnamon(n=33) p Value Placebo(n=33) Cinnamon(n=33) p Value
PVR Volume (ml)a 24.02 ± 24.13 26.15 ± 41.98 0.80 21.72 ± 28.16 20.74 ± 24.61 0.88
normal (No. [%])b 27 (81.8) 27 (81.8) 1.00 26 (78.8) 30 (90.9) 0.17
abnormal 6 (18.2) 6 (18.2) 7 (21.2) 3 (9.1)
6
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