SMJ

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Volume 77, Number 6, June 2025

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Siriraj Medical Journal

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ORIGINAL ARTICLE

‌ORIGINAL ARTICLE

373 Effectiveness of Different Progestin Modalities Compared to Other Hormonal

Therapies for Endometriosis: A Systematic Review

Siti Azira Putri, Raissa Nurwany, Iche Andriyani Liberty

SMJ

Siriraj Medical Journal

The world-leading biomedical science of Thailand

Volume 77 Number 6

June 2025

392 Predicting Functional Decline in Geriatric Abdominal Surgery Patients: Unveiling Incidence, Risk Factors, and

Innovative Predictive Models in Thailand

Poungkaew Thitisakulchai, Arunotai Siriussawakul, Sunit Jarungjitaree, Nipaporn Sangarunakul, Piyapat Dajpratham

403 Effects of Exercise Through Telerehabilitation on Balance and Walking Speed in Older Adults with Diabetic Peripheral Neuropathy: A Randomized Controlled Trial

Pilipda Chaiwan, Gulapar Srisawasdi, Pannika Prachgosin, Paweena Aekwattanaphol, Nathanit Jirapongpathai

411 Transpore Tape and Transparent Film Dressing on the Incidence of Early-Stage Phlebitis: A Comparative Randomized Trial

Pramote Thangkratok, Krit Pongpirul, Jiruth Sriratanaban

419 Postoperative Pain and Blood Loss of Non-use Compared to Partial-use of a Tourniquet in Bilateral Total Knee Replacement: A Randomized-Controlled Trial

Thada Wipatasinlapin, Surapon Atiprayoon, Peerawin Atiprayoon

427 Outcomes of Vascularized Lymph Node Transfer Treatment in Patients with Lymphedema

Boonyaporn Kotistienkul, Min Yongsuvimol, Nattanit Poungjantaradej, Sitthichoke Taweepraditpol

436 Sonographic Assessment of Fetal Biometric Parameters and Maternal Height Ratio for Prediction of Cesarean Delivery due to Labor Dystocia

Wiarm Wadeng, Wanlaya Onwatanasrikul, Nop Khongthon, Monyada Pleankong, Sinart Prommas, Kornkarn Bhamarapravatana, Komsun Suwannaruk

446 Ergonomic Risks and Musculoskeletal Pain among Office Workers in a Healthcare Setting: A Cross-Sectional Study

Prawit Phoonjaroen, Nitchakan Utaiwattana, Chirathip Thawisuk

456 Enhancing Orbital MRI Quality: Optimization of Saturation Pads for 1.5T

Sujitra Tinnut, Suwimon Nabumrung, Kornthip Jeephet, Kingkarn Aphiwatthanasumet

‌Executive Editor:

SIRIRAJ MEDICAL JOURNAL

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Karl Thomas Moritz, Swedish University of Agricultural Sciences, Sweden Kazuo Hara, Aichi Cancer Center Hospital, Japan

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Matthew S. Dunne, Institute of Food, Nutrition, and Health, Switzerland Mazakayu Yamamoto, Tokyo Women’s Medical University, Japan Mitsuhiro Kida, Kitasato University & Hospital, Japan

Moses Rodriguez, Mayo Clinic, USA

Nam H. CHO, Ajou University School of Medicine and Hospital, Republic of Korea Nima Rezaei, Tehran University of Medical Sciences, Iran

Noritaka Isogai, Kinki University, Japan

Philip A. Brunell, State University of New York At Buffalo, USA Philip Board, Australian National University, Australia Ramanuj Dasgupta, Genome Institution of Singapore

Richard J. Deckelbaum, Columbia University, USA Robert W. Mann, University of Hawaii, USA

Robin CN Williamson, Royal Postgraduate Medical School, United Kingdom Sara Schwanke Khilji, Oregon Health & Science University, USA

Seigo Kitano, Oita University, Japan Seiji Okada, Kumamoto University

Shomei Ryozawa, Saitama Medical University, Japan Shuji Shimizu, Kyushu University Hospital, Japan

Stanlay James Rogers, University of California, San Francisco, USA Stephen Dalton, Chinese University of HK & Kyoto University

Tai-Soon Yong, Yonsei University, Republic of Korea Tomohisa Uchida, Oita University, Japan

Victor Manuel Charoenrook de la Fuente, Centro de Oftalmologia Barraquer, Spain Wikrom Karnsakul, Johns Hopkins Children’s Center, USA

Yasushi Sano, Director of Gastrointestinal Center, Japan Yik Ying Teo, National University of Singapore, Singapore Yoshiki Hirooka, Nagoya University Hospital, Japan

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‌Effectiveness of Different Progestin Modalities Compared to Other Hormonal Therapies for Endometriosis: A Systematic Review

Siti Azira Putri, B.M.1, Raissa Nurwany, M.D., OBGYN2,*, Iche Andriyani Liberty, Ph.D.3

1Medical Profession Education Program, Faculty of Medicine, Sriwijaya University, Palembang, Indonesia, 2Department of Obstetrics and Gynecology, Sriwijaya University, Palembang, Indonesia, 3Department of Public Health and Community Medicine, Sriwijaya University, Palembang, Indonesia.

*Corresponding author: Raissa Nurwany E-mail: raissa.nurwany@fk.unsri.ac.id

Received 18 November 2024 Revised 22 January 2025 Accepted 27 January 2025 ORCID ID: http://orcid.org/0009-0004-5884-7455 https://doi.org/10.33192/smj.v77i6.272256

All material is licensed under terms of the Creative Commons Attribution 4.0 International (CC-BY-NC-ND 4.0) license unless otherwise stated.

Putri et al.

ABSTRACT

Objective: A systematic review was conducted with a study compilation of women with endometriosis in determining the evidence of the use of various progestin modalities compared to other hormonal therapies in improving endometriosis-associated pain, enhancing quality of life (QoL) and minimizing adverse effects and recurrence of disease.

Materials and Methods: This review carried out search strategies on various searching databases to analyze all comparisons of various progestin-only therapies with each other, other types of hormonal therapies, and placebo. The primary outcome is improvement of endometriosis-associated pain. Meanwhile, the secondary outcomes are the impact on QoL or treatment satisfaction, adverse effects, and disease recurrence.

Results: Progestogen (including progestin-only contraceptives) combined oral contraceptives (COC), gonadotropin- releasing hormone (GnRH) agonists, and antagonists are the hormonal therapies that were included in this study. These hormonal therapies significantly decrease the symptoms and increase the patient’s QoL, particularly dienogest, the most used progestogen in the study. The recurrence of the disease was mentioned when progestin- only contraceptives were compared to each other, GnRH agonists and antagonists, which were similar. In addition, almost all of the studies mentioned that irregular bleeding was the most commonly observed adverse effect.

Conclusion: Progestin-only contraceptives are similarly effective and could be more effective than other hormonal therapies in decreasing endometriosis-related symptoms, improving QoL, recurrence rate and minimizing adverse effects. This study also concludes that there is no definite statement on the superiority of specific kinds or administration routes of progestogen to other types of progestin or hormonal therapies.

Keywords: Endometriosis; progestin; hormonal therapy (Siriraj Med J 2025; 77: 373-391)

INTRODUCTION

Endometriosis is a chronic hormone-dependent gynaecological disorder that can be distinguished by the growth and appearance of similar histological components of endometrial glands (epithelial and stromal) outside the anatomical cavity of the uterine. This prevalence of endometriosis in women of reproductive age is approximately 10-15%, although it can rise as high as 70% among women with chronic pelvic pain (CPP).1 The most common clinical manifestations are persistent pelvic pain and impaired fertility. Intermenstrual haemorrhage, dysmenorrhea, and dyspareunia, along with bowel and bladder symptoms such as dyschezia and dysuria, can also present as symptoms of endometriosis.2

Nowadays, there are specific options for treating symptomatic endometriosis, including hormonal therapies, surgical intervention, or a combination of both.3,4 The approach to treating endometriosis requires an individualized-based therapy based on personal preference, efficacy, severity of symptoms, adverse effects, costs, and availability to determine an efficient treatment method. Therefore, hormonal therapy is one of the most frequent and recommended treatments because it suppresses menstruation and ovulation in order to control the disease and clinical manifestations. In endometriosis, hormonal therapy works by disrupting the menstruation cycle in the deactivation of the hypothalamus-pituitary ovary

axis by causing a pseudo-decidual state with consequent amenorrhea, which in turn prevents the progression of the disease.2,5

According to the European Society of Human Reproduction and Embryology (ESHRE) guidelines, progestogen or progestin is a recommended first-line choice of hormonal therapy for endometriosis.4 Progestin has multiple mechanisms in progesterone receptors that induce beneficial effects in reducing the progression of endometriosis and relieving pain.5 This therapy has many options of modalities for patients, so it can be convenient for women with endometriosis who prefer not to worry about daily pill-taking or monthly injections. Also, it is suitable for women with estrogen tolerance due to its side effects and health risks. The most common adverse effects include irregular uterine bleeding, mood swings, weight gain, and decreased density of bone. However, progestin has a lower incidence of side effects than other hormonal therapies and rarely causes treatment abandonment. Approximately two-thirds of patients are satisfied as their symptomatic endometriosis improves to some extent.4

The available progestins that can be administered to patients include oral, intramuscular, subcutaneous, or intrauterine routes. Although there are many different types of progestin, the most frequent progestins that are utilized are dienogest (DNG), norethindrone acetate (NETA), which

is available in the oral route, and medroxyprogesterone acetate (MPA), which is administered via oral, intramuscular, and subcutaneous.2,4 However, as time passes, the excess kinds of progestins have various outcomes in the therapy in treating endometriosis. Furthermore, the necessity of providing better evidence must be attempted. Therefore, this systematic review aims to evaluate the efficacy of various progestin modalities for treating endometriosis. It compares these treatments with other hormonal therapies in reducing symptoms, minimizing adverse effects, and preventing recurrence.

MATERIALS AND METHODS

Literature search

A systematic review of the efficacy of different progestin modalities compared to other therapies in women with endometriosis was conducted using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. The relevant articles were selected through a search in PubMed, Cochrane, Science Direct and Google Scholar. We apply keywords such as “Endometriosis OR Endometrium Ectopic” AND “Progestin OR Progestogen.” The database search was made in March 2024 and included articles from 1 January 2014 to 29 February 2024.

Study selection

The inclusion requirements for this systematic review are randomized controlled trials (RCTs), clinical trials, retrospectives, and observational studies that used progestin modalities compared to other progestin therapies, hormonal therapies, placebos, or without treatment. We selected studies that involved women with surgery-based diagnosis (with or without histopathologic confirmation) and validated radiology-based diagnosis by magnetic resonance or ultrasound of endometriosis. The primary outcome is the improvement of endometriosis- associated pain or symptoms. In addition, the secondary outcomes are the impact on quality of life (QoL), adverse effects, and disease recurrence. Meanwhile, the excluded criteria for this systematic review are non-fully accessible articles, non-English articles, and other study methods not mentioned in the inclusive criteria. The results of assessing the database will be extracted into an extraction table. (Table 1)

Data extraction

The included studies will be extracted to obtain data as follows: (1) Author’s name, year of study, country (2) Type of progestin therapy (3) Study design (4) Diagnosis method of endometriosis (4) Type of intervention comparator

(5) Result of study (6) Included participant (7) Evaluated outcome.

Risk of Bias Analysis

The Cochrane Collaboration’s Risk of Bias Assessment Tool assessed the risk of bias analysis from the included study in the Review Manager 5 application. The overall quality was moderate. The risk of bias assessment was examined by each study’s risk of bias and the overall percentage of each risk of bias component judgment, as shown below.

RESULTS

The predetermined search term identified 367 references published from 1 January 2014 to 29 February 2024. After checking for duplicates, 193 references were removed so that 111 references would be screened for their eligibility. Eighty references were excluded from being included because the studies could not be accessed. These 19 studies fulfilled the inclusion criteria. Fifty-five studies were excluded for the following reasons: irrelevant population, unrelated interventions, different outcomes measured, and incomplete data. (Fig 1)

Progestin, compared to other progestin therapies

In a study conducted by Lee et al., it evaluated dienogest (DNG), levonorgestrel-releasing intrauterine system (LNG-IUS), and untreated women with laparoscopically confirmed endometriosis. Endometriosis-associated pain was significantly lower in the DNG and LNG-IUS than in the untreated group, where the VAS scores were not significantly different after 6- and 12-month interventions. The rate of endometriosis recurrence was higher in the untreated group than in the treated group. Meanwhile, the side effects of both interventions are not substantially different between DNG and LNG-IUS. The most frequent adverse reaction was vaginal bleeding, which is self-limited in most patients.6

Carvalho et al evaluated the efficacy of etonogestrel (ENG)-releasing contraceptive implant compared to LNG-IUS in surgical and histopathological diagnosed endometriosis. Dysmenorrhea and noncyclic pelvic pain were significantly reduced in both groups with no statistical difference from each other. There was an improvement in the patient’s QoL in both groups, but the difference was not shown significantly.7

Meanwhile, a clinical trial that Vahid-Dastjerdi carried out compared the effectiveness of two oral progestins, DNG and medroxyprogesterone acetate (MPA), in surgically confirmed endometriosis. The reduction of pelvic pain was significantly different in contrast to dysmenorrhea

TABLE 1. Summary and results of the included study.

TABLE 1. Summary and results of the included study. (Continue)

Author,

Year, Country

Progestin

Therapy

Type of

Study

Type of Comparator

Diagnosis

Participants

Included

Outcome Evaluated

Result

Pain

QoL

Recurrence

Adverse

Effects

Vahid- Dienogest Randomized Surgical 10 mg MPA 48 vs 53 Yes Yes Yes Dastjerdi, 2 mg / Oral Clinical Trial (Oral)

M et al.,

2023, Iran

• The measured endometriosis-related pain was significantly lower in the dienogest group than in the MPA group (p < 0.001).

• The recurrence incidence of endometriosis between both groups was not different statistically (p = 0.4).

• The drug-related side effects were significantly different between both groups (p < 0.001).

TABLE 1. Summary and results of the included study. (Continue)

TABLE 1. Summary and results of the included study. (Continue)

TABLE 1. Summary and results of the included study. (Continue)

Abdou, A M

et al., 2017,

Egypt

Dienogest

2 mg / Oral

Randomized Surgical

Clinical Trial

Leuprolide Acetate 3.75 mg (Intra Muscular

Injection)

121 vs 121

Yes

Yes

• The VAS score notably reduced pelvic pain, dyspareunia, and back pain (p = 0.000).

• There was no statistically meaningful difference in VAS score reduction between both groups in pelvic pain (p = 0.170), dyspareunia (p = 0,263) and back pain (p = 0.597).

• The most frequent side effect of the dienogest group was vaginal bleeding (64.5%) which was highly substantially different (p = 0.000) between the two groups.

• The most frequent side effects of leuprolide acetate were hot flushes (46.3%), which was highly substantially different (p = 0.00) between the two groups.

• Other observed side effects were vaginal dryness (p = 0.001), weight gain (p = 0.02), which was significantly different, and headache (p = 0.13), which was not

significantly different between both groups.

Progestin vs Gonadotropin-releasing Hormone Agonist (GnRH Agonist)

Purwanto, J Dienogest Randomized Surgical Leuprolide 10 vs 10 Yes Yes

et al., 2020, 2 mg / Oral Clinical Trial Acetate 3.75 mg

Indonesia (Intra Muscular

Injection)

• There was a significantly reduced VAS score in the dienogest and leuprolide acetate groups every four weeks of follow-up until 12 weeks (p = 0.004 and p = 0,003, respectively). However, both groups had a significant difference in VAS scores (p = 1.00).

• The adverse effects of the treatment were vaginal dryness, joint pain, decreased libido, headaches, and hot flashes, which were substantially different between both groups (p = 0.238).

  
  

  TABLE 1. Summary and results of the included study. (Continue)

  
  

  Author, Progestin Type of Type of Comparator Participants Outcome Evaluated Result
  Year,	Therapy	Study	Diagnosis		Included	Pain	QoL	Recurrence	Adverse
  Country									Effects
  Tang, M	Dienogest	Prospective	Surgical	Leuprolide	41 vs 40	Yes		Yes		- The VAS pain score showed improvement
  et al., 2023, China	2 mg / Oral	Clinical Trial		Acetate 3.75 mg (Intra Muscular						and was statistically meaningful between both groups after 3 and 6 months of

  • Dienogest and GnRH agonists reduced endometriosis-related pain significantly (p < 0.001).

  • There were several observed adverse effects, such as amenorrhea (p = 0.05) and hot flushes (p < 0.001), which were substantially different in GnRH agonist than dienogest. Meanwhile, spotting (p < 0.001) was substantially different in dienogest than GnRH agonist.

  					treatment (p < 0.05). - The Kupperman score was statistically
  					meaningful between both groups after 3 and 6 months of treatment (p < 0.05), which
  					assessed the severity of symptoms.
  					- The postoperative recurrence rate was eight patients in the dienogest group and two
  					patients in the GnRH agonist group,
  					significantly different between the two groups (p < 0.05).

  Injection)

  
  

  Ceccaroni, M	Dienogest	Randomized	Surgical	Leuprolide	65 vs 81	Yes	Yes
  et al., 2021,	2 mg / Oral	Clinical Trial		Acetate 3.75 mg
  Italy				(Intra Muscular
  				Injection)

  
  

  Ozaki, R	Dienogest	Prospective	Surgical	Goserelin	35 vs 35	Yes	Yes
  et al., 2020,	2 mg / Oral	Clinical Trial		Acetate 1.8 mg
  Japan				(Subcutaneous
  				Injection)

  • Dienogest reduced endometriosis-related pain more significantly than GnRH agonists (p = 0.006).

  • The side effect that occurred more significantly in GnRH agonists than dienogest was hot flashes (p < 0.001).

  • Breast pain and metrorrhagia were the side effects that occurred more significantly in dienogest than GnRH agonists (p = 0.04 and p < 0.001, respectively).

TABLE 1. Summary and results of the included study. (Continue)

TABLE 1. Summary and results of the included study. (Continue)

Abbreviations: LNG-IUS = Levonorgestrel Intrauterine System, MPA Medroxyprogesterone Acetate, EE = Ethinyl Estradiol

and dyspareunia, which were not significantly different in both groups. The recurrence rate between both groups was not consequently different. Adverse effects were notably different between both groups, with the expected effects of DNG being headache in contrast to MPA, which was weight gain.8

Progestin, compared to other hormonal therapies Combined Oral Contraceptive (COC)

Kashi et al conducted a study comparing effects of dienogest, contraceptive oral contraceptive pills (COCP) containing ethinyl-estradiol (EE) and levonorgestrel and placebo. The results was a significant difference in the reduction of pelvic pain and dyspareunia between three groups but there was no significant difference between dysuria and dyschezia. Assessed QoL shows a notable difference in the mean score improvement with no statistical difference post-intervention between the three groups. There was a low adverse effect rate in the DNG and COCP groups. The most common side effects were spotting, hair loss, headache, hot flashes, and nausea, with unmeaningful difference in complications between the two groups.9

Caruso et al randomized women with endometriosis by confirming transvaginal sonography that received dienogest or COCP containing 17b-estradiol (E2) and nomegestrol acetate (NOMAC) to evaluate their effectiveness every 3 months within 12 months. It was reported that DNG had better improvements than E2/NOMAC, with unnoticeable differences. Both intervention groups had improvement in mental and somatic aspects with no statistical difference. However, DNG had a better somatic score than E2/NOMAC in 6 and 12 months, which is statistically meaningful.10

Another clinical trial performed by Niakan et al utilized comparison effects of dienogest, COCP containing EE/Levonorgestrel, and placebo within 12 weeks on

Fig 1. Risk of bias summary: Review authors’ judgements about each risk of bias item for each included study.

Fig 2. Risk of bias graph: Review authors’ judgements about each risk of bias item presented as percentages across all included studies.

Fig 3. Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) criteria of the study.

women with surgical confirmed endometriosis. The mean VAS score of dyspareunia was reduced with no statistical difference between the three groups. Pelvic pain was reduced after 3 months post-intervention following dienogest, COCP and placebo. There is no significant effect of dienogest and COCP in treating dyschezia or dysuria. The mean overall score of QoL was substantially reduced in the three groups. Furthermore, the study discovered a low rate of adverse effects of dienogest and COCP, with the most common complications being hair loss, headache, hot flashes and nausea.11

Piacenti et al managed a study on surgical or radiological confirmed endometriosis with the therapy of oral dienogest or continuous EE/Levonorgestrel for 6 months. It was reported that dyspareunia and CPP significantly decreased, with no statistical difference between the two groups. QoL was improved, especially in the physical component, which decreased substantially, but there was no statistical difference between both groups. In addition, the study reported vaginal bleeding as the most frequent side effects.12

Taha et al. carried out a clinical trial comparing the efficacy of dienogest and COCP-containing EE/ drospirenone. The study discovered that both interventions

significantly improved the mean VAS score on non-cyclic pelvic pain; however, there are notable differences in statistics. Furthermore, CPP had a greater reduction of severity than dysmenorrhea and dyspareunia in both groups. The evaluation of QoL improvement was statistically meaningful, with no statistical differences in both interventions. The adverse effects encountered by patients were abnormal uterine bleeding, mood swings, headache, nausea and breast pain, which is more frequent in COCP than dienogest.13

Gonadotropin-releasing hormone agonist

After performing a surgical procedure to confirm endometriosis, Abdou et al. conducted a clinical trial comparing the effectiveness of dienogest consumed daily to leuprolide acetate (LA) injected monthly for 12 weeks. The alteration of the VAS score on pelvic pain, back pain and dyspareunia is significantly reduced, with no meaningful statistical difference between both interventions. The most frequent adverse effect in dienogest was vaginal bleeding and hot flushes, which were significantly higher than LA. Meanwhile, the most common adverse effect in LA is hot flushes and vaginal dryness, which were also consequently higher than the dienogest.14

Takaesu et al. conducted research on evaluating the efficacy of dienogest consumed daily and goserelin acetate injected monthly for 24 weeks and the group without any treatment assigned. Dysmenorrhea and CPP have significant improvement during progestin administration after 3 months of consumption, whereas it took 6 months for the non-treatment group. The study reported a gradual pain exacerbation in the three groups. The study only shows a substantial difference in recurrence rate between the dienogest and the non- treatment group. The most frequent side effect is irregular bleeding in the dienogest compared to goserelin, a hot flash.15

Purwanto et al. also performed a trial comparing the effect of therapy between dienogest and LA injected monthly within 12 weeks on women with laparoscopy- confirmed endometriosis. There was a decrease of VAS score in every 4 weeks of assessment in both groups with only a significant difference in the dienogest group. The side effects were found after 8 and 12 weeks of therapy. There are no statistical differences in adverse effects on both groups.16

Another research comparing the efficacy of dienogest and LA was conducted by Tang, Yang and Zhang on women with post-laparoscopic surgery in a 6-month observation. The average postoperative VAS score in both groups decreased; however, it only showed a statistically significant decrease in VAS score in the dienogest group. The recurrence incidence was eight patients in the dienogest with a 77.5% effectiveness rate and two patients in the LA group with an 82.9% effectiveness rate.17

Ceccaroni et al. compared two postoperative endometriosis treatments: oral dienogest and injection LA for 6 months for 30 months. It was found that both dienogest and GnRH agonists had noticeable reductions in dysmenorrhea, dyspareunia, dyschezia and CPP. The most frequent adverse effects of the dienogest were hot flushes in contrast to GnRH agonist, which was amenorrhea. Furthermore, there was a significantly lower incidence of amenorrhea and hot flushes in the GnRH agonist group than in the dienogest group. Meanwhile, there was a significantly higher incidence of spotting in the GnRH agonist group than in the dienogest group.18 Ozaki et al. carried out a clinical trial comparing the treatment outcome of post-laparoscopic endometriosis patients with daily oral dienogest and goserelin acetate injected monthly within 3 months. The comparison of preoperative and 4-month postoperative pain related to endometriosis was significantly lower in dienogest- administered patients than in goserelin acetate-injected patients. As for the adverse event, it showed that the

incidence of hot flashes was lower in dienogest than in glycol acetate. In contrast, the incidence of breast pain and metrorrhagia was considerable higher statistically in goserelin acetate than dienogest.19

Gonadotropin-releasing hormone antagonist

Carr et al. conducted a randomized trial study comparing the outcome of depot medroxyprogesterone acetate (DMPA) administered subcutaneously on weeks 1 and 12 of treatment in contrast to oral GnRH agonist administered in two methods of dose (150 mg once daily and 75 mg twice daily). All treatment groups appeared to have a significant reduction of baseline VAS score in endometriosis-associated pain, with elagolix 75 mg twice a day having more pronounced effects compared to elagolix 150 mg every day and DMPA. The most frequent elagolix’s side effects were headache, nausea, and nasopharyngitis, whereas DMPA were headache, nausea, and upper respiratory tract infection.20

Aromatase inhibitor

A clinical study performed by Acien et al. to determine the efficacy of a levonorgestrel-releasing intrauterine device (LNG-IUD) within 6 months and an aromatase inhibitor, which was anastrozole daily on patients with ultrasound-confirmed endometriosis. All endometriosis- related pain significantly improved in all groups during and after 6 months, and the most significant improvements observed were dysmenorrhea and CPP with anastrozole administered to the patient. Nevertheless, there was only a substantial difference between the anastrozole and non-anastrozole groups in the 1-year follow-up. The recurrence rate was similar between both groups (50%), but there was no consequential statistical difference.21

Placebo

A double-blinded, placebo-controlled, randomized study conducted by Tanmahasamut et al. assessed the efficacy of desogestrel daily in reducing endometriosis- associated pain for 6 months. Both groups significantly improved from the baseline VAS score in all types of pain. Desogestrel had a notable statistical difference in the VAS score reduction in overall pain, dysmenorrhea, and non- cyclic pelvic pain. Four patients were observed to have moderate-to-severe pain at 6 months post-treatment, which was significant statistically compared to desogestrel. Alteration of menstruation patterns was found in the desogestrel and the placebo, which was meaningful statistically.22

Another clinical placebo-controlled study was performed by Lang et al. to determine the effectiveness

of dienogest in endometriosis for 24 weeks. The study stated that the VAS score related to endometriosis- associated pelvic pain (EAPP) was an absolute reduction from the baseline, which was different considerably on the statistics after 24 weeks. Also, QoL shows improvement in the physical and mental health of dienogest. The most frequent adverse effect was vaginal haemorrhage.23

Yu et al. also conducted a placebo-controlled study to determine the efficacy of dienogest in endometriosis for 24 weeks. A mean change of VAS score from the baseline in EAPP on the dienogest group was found. On the contrary, the placebo group had a slight decrease in VAS scores. The study reported improvement in QoL in almost all physical and mental health domains. A slight decrease in mental health was observed in the placebo group, which may have affected the overall improvement. The most common adverse effect was vaginal haemorrhage.24

DISCUSSION

Interpretation of findings

Endometriosis is a hormone-dependent chronic inflammatory condition that needs prolonged therapy that corresponds to the efficacy of outcomes with sufficient tolerability. Hormonal therapies are necessary to be given to women with endometriosis by regulating hormones in order to prevent symptoms, progression of severity, and reoccurrence of the disease. Multiple aspects are considered when choosing the most convenient therapy, such as age, reproductive status, pain severity, economic status, possible adverse effects, incidence rate of recurrence, comorbidities, and many other considerations. Discontinuation of hormonal therapies tends to cause disease recurrence. The medication should be focused on long-term effectiveness with minimal adverse effects. Hormonal contraceptive therapies for endometriosis in this systematic review have significant outcomes in relieving endometriosis-associated pain, enhancing quality of life, preventing recurrence, and reducing the incidence of adverse effects.2,4

Among the proposed first-line therapies, progestogens have strong recommendations through their clinical effectiveness in treating endometriosis. In addition, progestogens have various modalities, availability, and affordable costs. Progestin is known for its indication of prolonged treatment. Dienogest is a fourth-generation high-selective progestogen, one of the first-line therapies for endometriosis. It is the first treatment choice due to its safety, efficacy, availability, tolerability, and affordable cost. The disadvantage of consuming dienogest might be the side effects, such as abnormal uterine bleeding;

however, it has a lower side effect than other hormonal therapies in several studies.25,26 Mostly, the studies included dienogest to be compared to other therapies and showed more efficacy than other hormonal treatments discussed below.

Throughout the study, progestogen showed significantly reduced endometriosis-related pain, lower recurrence incidence, minimal side effects, and improved quality of life of patients. Dienogest was compared to LNG-IUS, which both are effective. However, the comparison of efficacy was hardly known in contrast to being compared to oral medroxyprogesterone acetate, in which dienogest was more effective in relieving pain and had a lower incidence of adverse effects while the recurrence rate was similar.6,8 LNG-IUS was also compared to another progestin- only contraceptives, an etonogestrel implant. Both were effective as long-term therapies, but both modalities have no significant difference in therapy outcomes. Therefore, LNG-IUS and etonogestrel implants are good choices for women who do not wish to consume medication daily. However, both modalities need to be administered by medical professionals due to their expensive cost and the possibility of unpredictable bleeding. Furthermore, those modalities may not overcome or control the pain.7,25,27 Three studies were conducted to determine the efficacy

of progestogen: dienogest and desogestrel, which will be compared to placebo. Both dienogest and desogestrel were acceptable and effective as a treatment of endometriosis in reducing clinical symptoms, refining the quality of life and reducing the rate of side effects and recurrence.22–24 Dienogest and desogestrel are selective progestins from nortestosterone derivatives which work specifically in endometrial tissues. Unlike other nortestosterone derivatives, dienogest has a lower androgenic effect with a higher anti-androgenic effect, which is beneficial in minimizing the effects of changes in fat and carbohydrate levels, while desogestrel has an androgenic effect. The selection of the type of progestin used must consider the androgenic effects, anti-mineralocorticoid effects, and glucocorticoid effects to minimise metabolic side effects.28

During the comparison between the progestogens and COC therapies, all of the progestogen treatments that were compared were only diengoest to various COCs. The most COC included in this study was oral ethinyl EE/levonorgestrel. It was an effective COC in treating endometriosis. However, dienogest had significantly reduced pain symptoms and higher quality of life scores than EE/levonorgestrel, but the incidence of side effects was similar in both interventions.9,10,12 Other combinations of COC that were studied were the oral EE/ NOMAC

and EE / Drospirenone, which were also effective, but still, dienogest has a more significant impact in relieving symptoms, lower rate of side effects and better quality of patient life than both COC. COC is safe for long- term consumption, particularly for women who avoid unintended pregnancy.10,13,29

Another widely studied was the comparison between progestogens and GnRH agonists. Four studies used leuprolide acetate injection, which was compared to dienogest. Most of those studies mentioned that both hormonal interventions effectively treat endometriosis. However, dienogest has more advantages, such as it can be used as a long-term therapy with a lower recurrence rate and adverse effects than leuprolide acetate, which was only injected in short-term therapy.14,16–18 Other two studies included goserelin acetate injection, which mentioned that dienogest was more effective than goserelin acetate in reducing endometriosis-associated pain. Regarding sustainability, dienogest is more sustainable than both GnRH agonist therapies.15,19 Meanwhile, a study determined the efficacy of progestogens with GnRH antagonist and aromatase inhibitor, which can be prescribed as a second-line therapy for endometriosis. A clinical trial utilizing oral progestin-only contraceptives containing medroxyprogesterone acetate injected subcutaneously was compared to oral GnRH antagonist containing lanolin, mentioning that both hormonal interventions have a comparable efficacy on endometriosis therapy.20 In addition, it is considered to combine hormone add- back therapy to avoid loss of bone mineral density in prescribing sole GnRH agonist and GnRH antagonists.2,28 This review also included one clinical trial using LNG-

IUS compared to oral aromatase inhibitor anastrozole, which stated that prescribing both hormonal interventions was more effective than using LNG-IUS solely in reducing endometriosis-related symptoms. It is similar to guideline recommendations that aromatase inhibitors should be combined with other endometriosis hormonal therapies, such as progestogens, to reach their maximal efficacy.21 In addition, long-term use of aromatase inhibitors can increase the risk of osteopenia, osteoporosis, and fracture; therefore, requires many considerations in prescribing aromatase inhibitors.28

Practical implications

Nowadays, the recent hormonal therapies include progestogen, combined oral contraceptive pills, aromatase GnRH agonists and antagonists in a variety of routes of administration. guidelines and expert insights have stated progestogen as an option in endometriosis.30 Still, in choosing the suitable treatment options, it is

recommended for clinicians to decide on an individual-based approach.4 From all the proposed therapies, progestogen has appeared to be the foremost option utilized across nations. Progestogen that is prescribed by consideration of clinicians due to its side profile effects to each individual. Among the options of progestogen therapies, dienogest has emerged to be the most used progestogen.4,30

Dienogest, a 19-nortestosterone derivative, has been approved as an endometriosis treatment in several countries. Recently, there have been researches on investigating the safeness of dienogest to be a routine prescription on endometriosis in daily practices.31 The Visanne Post-Approval Observation Study (VIPOS) is the largest non-interventional study conducted in six European countries in 7 years. The study mentioned that dienogest is safe as a long-term treatment for 15 months and longer with no serious side effects.32 Meanwhile, The EffectiveNess of VISanne in Improving quality of life in Asian wOmen (ENVISIOeN), another non- interventional study carried out in six Asian countries concluded that dienogest improve patient’s quality of life and endometriosis-associated pelvic pain in Asian women. The research also distinguished that dienogest can be a favorable first-line non-intervention option in a long-term treatment on alleviating endometriosis- related symptoms.33

Another treatment approach of endometriosis aside from hormonal therapies are non-hormonal therapies and surgery. The widely offered non-hormonal treatment on endometriosis is nonsteroidal anti-inflammatory drugs (NSAID). Although NSAID can be prescribed to patients on reducing endometriosis-associated pain solely or combined with hormonal therapy, it is incapable of reducing the progressivity of endometriosis. Also, several recent guidelines stated a weak recommendation on NSAID due to its gastrointestinal side effects especially in a long-term consumption.4,34

Surgery is as effective as hormonal therapy in relieving endometriosis associated-pain. Indication for surgery includes ovarian endometriomas, superficial peritoneal lesions, and deep infiltrating endometriosis that will decrease ovarian reserve by observing the measured anti-müllerian hormone (AMH) and ultrasonography measured total of the antral follicles.35,36 In addition, undergoing surgery on endometriosis improves fertility outcomes by repairing the anatomical abnormalities caused by the ectopic endometrial implants.37 Nowadays, one of the most common gynecological intervention, which is laparoscopy approach has been widely performed on endometriosis with its lower incidence of post surgery complications compared to laparatomy.38,39 Aside from

its therapeutic function to endometriosis, laparoscopy approach also assists clinicians in diagnosing endometriosis along with MRI.39,40 Hormonal therapy is suggested to be prescribed after the surgical intervention to enhance the outcome of the endometriosis-associated symptoms and prevent recurrence if the patient would not intend to get pregnant immediately. Meanwhile, in presurgical hormone treatment does not improve the surgery outcome but it is offered to reduce pain symptoms in a waiting interval as an adjunct before proceeding to surgical intervention.4

Limitations of study

The limitations of our systematic review are the limited number of studies carried out on each comparison of progestogens to other hormonal therapies due to our strict data inclusion requirement. The evidence of measured endometriosis-associated pain is diverse in every study included; therefore, it is challenging to compare. Furthermore, medication-related decrease in baseline parameters of pain is an important statement. However, it can be misleading to the placebo effect due to producing a high response rate, especially in a short- term study. A small-scale of populations might lead into a patient-based preference treatment and homogenous patients such as age, preference, socioeconomic status that can affect the interpretation of the investigations which also can be biased. Meanwhile, a brief follow-up research, could also influence the final interpretation mainly by only focusing on symptom improvement which might overshadow symptoms relapse, adverse effects and quality of life in the time ahead. A diverse and long-term follow-up could improve the conclusion more than previous.

Despite the various kinds of hormonal therapies that were compared, the distinct number of studies in every comparison of hormonal therapies made it challenging to assume the superiority of a specific, especially the lack of comparison of progestogen with progestogen itself, GnRH antagonist, and aromatase inhibitor. In addition, the progestogen that is compared to the placebo is only dienogest, which is now currently the most widely used progestogen in most countries. This made other progestogen effects to treat endometriosis unexplained well in comparison to placebo.

In terms of future research, identifying more studies in comparing progestin-only therapies to other hormonal therapies that might be used as endometriosis treatment with flexible criterias. By using more adjustable requirements of study such as a confined measured outcome could gain more studies than before that can be

beneficial in concluding the findings. Furthermore, more investigations can be conducted regarding comparing progestins to other hormonal medications. It is also acceptable to any other aspect that could be analyzed to know the distinct superiority of hormonal contraception in endometriosis treatment, such as laboratory findings (hormone levels), radiological findings (endometrioma size), bone mineral density and others.

CONCLUSION

Based on the systematic review, progestogens are similarly effective or could be more effective than other hormonal treatments in decreasing endometriosis-associated pain, improving patients’ life qualities, restraint relapse, and reducing adverse effects of endometriosis. There is no well-defined evidence of specific administration routes of progestogens that are more effective than another method of administration.

Data Availability Statement

Thisarticle reviewhasprovidedallrelevantpublications.

ACKNOWLEDGEMENT

We would like to extend our sincere appreciation to all colleagues from Faculty of Medicine, Sriwijaya University for providing support and contributions.

DECLARATIONS

Grants and Funding Information

None.

Conflict of Interest

All authors acknowledge that there is no conflict of interest.

Registration Number of Clinical Trial

None.

Author Contributions

Conceptualization and methodology, S.A.P., R.N., and I.A.L. ; Investigation, S.A.P., R.N., I.A.L. ; Formal

analysis, S.A.P., R.N., and I.A.L. ; Validation, R.N., I.A.L. ; Visualization and writing – original draft, S.A.P; Writing – review and editing, S.A.P. ; Supervision, R.N., I.A.L. ; All authors have read and agreed to the final version of the manuscript.

Use of Artificial Intelligence

There is no involvement of the artificial intelligence usage.

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‌Predicting Functional Decline in Geriatric Abdominal Surgery Patients: Unveiling Incidence, Risk Factors, and Innovative Predictive Models in Thailand

Poungkaew Thitisakulchai, M.D.1, Arunotai Siriussawakul, M.D.2,3, Sunit Jarungjitaree, M.Sc.3, Nipaporn Sangarunakul, B.NS.3, Piyapat Dajpratham, M.D.1,*

1Department of Rehabilitation Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand, 2Department of Anesthesiology,

Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand, 3Integrated Perioperative Geriatric Excellent Research Center, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.

*Corresponding author: Piyapat Dajpratham E-mail: piyapat.daj@mahidol.ac.th

Received 18 November 2024 Revised 21 January 2025 Accepted 22 January 2025 ORCID ID:http://orcid.org/0000-0002-6067-0319 https://doi.org/10.33192/smj.v77i6.272262

All material is licensed under terms of the Creative Commons Attribution 4.0 International (CC-BY-NC-ND 4.0) license unless otherwise stated.

INTRODUCTION

The aging of the global population has become a growing concern in recent years. One of the most prevalent issues among older adults is functional decline,1 which is characterized by a decreased ability to perform activities of daily living. This condition poses significant challenges, adversely impacting their independence, social interactions, overall life satisfaction, and quality of life.2

In addition, older individuals often battle diverse illnesses, including some that may require surgical intervention. For those in advanced age, undergoing major surgery represents a critical event that can expose them to various complications. It can result in both short-term and sustained functional decline, which can shorten their survival, increase healthcare utilization, or even lead to institutionalization after surgery.3-5

Several studies have sought to identify risk factors associated with postoperative functional decline and poorer surgical outcomes in older individuals across various circumstances.4–14 Researchers have also attempted to predict this decline using predictive indices that encompass a range of parameters and screening tools with varying degrees of accuracy.15-18 However, for elective abdominal surgery, which accounts for approximately 40% of all surgical procedures performed on older patients in our institution, the frequency and determinants of postoperative functional decline remain unclear. Furthermore, a simple

and effective method to predict and identify at-risk individuals has yet to be established.

Against this background, our research aims to identify the incidence rate and risk factors of functional decline following elective abdominal surgery in older adults. Additionally, we aim to utilize these factors to formulate simple equations that predict its occurrence. We believe these findings will offer valuable insights into patient care by aiding in the identification of individuals at risk, enabling healthcare providers to implement appropriate interventions, and potentially improving patient outcomes and recovery trajectories.

MATERIALS AND METHODS

Study design

This prospective cohort study was conducted at a tertiary care center in Thailand between August 2019 and March 2021. Corresponding to the statutory retirement age in Thailand, the inclusion criteria comprised individuals aged 60 years and older who were undergoing elective abdominal surgery. The exclusion criteria included patients scheduled solely for gastrostomy or jejunostomy, as well as those already in a state of dependence (Barthel Index

< 10).

Measurements

The ASA Physical status serves as a classification system for assessing the preoperative health status of

individuals. The scale comprises five classes, ranging from ASA 1 to ASA 5. Notably, an ASA status of 3 or higher is reported to be related to poorer postoperative outcomes.13-15

Physical condition was assessed using the Medical Research Council sum score and a 30-second chair stand test. The sum score comprises the combined scores from 6 muscle groups in the upper and lower extremities on both sides.19 The score ranges from 0 to 60, and is typically used to evaluate global peripheral muscle strength. The 30-second chair stand test involves recording the total number of completed chair stands executed in 30 seconds. The test assesses lower body strength and endurance in older adults.20

Functional status was measured by evaluating Basic Activities of Daily Living (BADLs) and Instrumental Activities of Daily Living (IADLs) using the Barthel Index and the Lawton IADL scale, respectively. The Barthel Index evaluates a patient’s functionality across 10 BADL items (feeding, grooming, transfer, toilet use, mobility, dressing, stairs, bathing, and bowel and bladder control) with a final score ranging from 0 to 100,while the Lawton IADL scale was used to assess 5 IADL items (ability to use telephone, shopping, transportation, managing medications, and managing finances), with an overall score ranging from 0 to 5. 21,22 ,23 For both indices, scores are assigned based on the ability to perform each task independently, and lower scores indicate a higher level of dependency.

Cognitive function was evaluated using the Thai Mental State Examination (TMSE). With the maximum score of 30, a higher score represents better cognitive function. A cutoff score of < 24 is used to signify the presence of cognitive impairment.24

Nutritional status was evaluated by the Mini Nutritional Assessment short-form (MNA-SF), a validated tool designed to assess nutritional status in older adults. The score can range from 0 to 14, with higher scores indicating better nutrition. Patients with a score of 7 or lower were considered malnourished.25

Depression was evaluated through the Patient Health Questionnaire-9 (PHQ-9), which comprises 9 items assessing the frequency of depressive symptoms experienced by patients. Each item is scored on a scale from 0 to 3, resulting in an overall score ranging from 0 to 27. A cutoff score of ≥ 9 is applied to identify the presence of depression.26

Quality of life was assessed using the EQ-5D- 5L questionnaire, which covers 5 dimensions with 5 items each. Responses were converted into an index value, known as the utility score, utilizing standard

values specific to Thailand. The maximum utility score is 1, with a higher value indicating a better health state. Additionally, participants were asked to rate their self- perceived current health status using the EQ Visual Analogue Scale (EQ-VAS), which ranges from 0 (worst) to 100 (best health).

Data collection

Before surgery, a research assistant, uninvolved in any therapeutic procedures, collected data on patient demographics, physical condition, functional status, cognitive function, depressive symptoms, nutritional status, and quality of life. Preoperative laboratory tests were conducted to measure hemoglobin, albumin, and vitamin D levels. After discharge, another research assistant retrospectively reviewed medical records to collect perioperative details, including the type of surgery (upper abdominal, lower abdominal, or urological), surgical technique (open or laparoscopic), surgery duration, estimated blood loss (EBL), and length of stay (LOS). Postoperative complications, such as infectious, surgical, cardiovascular, respiratory, renal, and neurological issues, were documented according to established criteria from previous studies.13,27 One month after surgery, the initial research assistant conducted a telephone follow-up to reassess each patient’s functional status, depressive symptoms, and quality of life. Of all participants, only one remained hospitalized and was reassessed directly in the ward. The participants were then divided into 2 groups (functionally stable and functionally declined) based on changes in their functional capacity between baseline and follow-up. In line with a preceding study, functional decline was defined as a decrease of ≥ 10 points in BADLs on the Barthel Index or ≥ 2 points in IADLs on the Lawton IADL scale between the 2 assessments.12

Statistical analyses

Continuous variables with normal distributions are presented as means ± standard deviations, while non- normally distributed variables are shown as medians (IQR). Categorical data are expressed as numbers and percentages. As cut-off points for continuous variables, such as LOS, EBL, and surgery duration, are typically determined based on clinical context or operation category, we employed Receiver Operating Characteristic (ROC) analyses to define optimal thresholds. These cut-off values were selected to achieve the best balance between sensitivity and specificity, as determined by the Youden index.28 The corresponding area under the ROC curve (AUC) values for the selected thresholds are as follows: LOS > 7 days (0.725), EBL > 550 ml (0.586), and surgery

duration > 165 minutes (0.598). Associations between variables and outcomes in the univariable analysis were assessed using independent t-tests, chi-square tests, or Mann–Whitney U tests, as appropriate. Comparisons of BADLs and IADLs within groups were analyzed using paired t-tests, while comparisons between groups were analyzed using independent t-tests. A p-value of less than

0.05 was considered significant for all analyses. Factors showing statistical significance in the univariable analysis were introduced into a multivariable logistic regression model to control for potential confounding factors. These significant factors were also used to formulate predictive equations for postoperative functional decline. Model discrimination was assessed by the AUC of each equation. All analyses were conducted using PASW Statistics for Windows, version 18.0 (SPSS Inc, Chicago, IL, USA).

RESULTS

A total of 190 patients scheduled for elective abdominal surgery and meeting the inclusion criteria were approached. Of these, 100 provided informed consent to participate in the study. However, 2 were not operated on due to unstable medical conditions, and 1 died after surgery. Consequently, these 3 were excluded from the final study cohort (Fig 1). The remaining 97 participants had a mean age of 70.2 ± 6.6 years, with 64.9% being male. 37.1% had an ASA classification of 3, while the rest had a classification of 2. The mean TMSE score was 25.1 ±

3.9, while the mean BADL and IADL scores were 92.8

± 11.1 and 4.1 ± 1.5, respectively. The mean MNA-SF score, blood albumin, and vitamin D levels were within normal ranges and no statistical significance was observed between the groups (Table 1).

Regarding the operation, 71.1% were open surgeries, while 28.9% were performed laparoscopically. 69.1% of the surgical procedures exceeded a duration of 165 minutes. The median LOS was 7 days (IQR 5–10), with 44.3% of participants staying more than 7 days (Table 2). Nearly one-third of participants (28.9%) had 1 or more postoperative complications during admission. The most common complications were infectious, surgical, cardiovascular, renal, neurological, and respiratory (10.3%, 7.2%, 6.2%, 6.2%, 5.2%, and 4.1%) respectively.

At the one month follow-up, the incidence of functional decline, as defined previously, was 61.9%. Within the decline group, 31.7% showed a decrease in BADLs only, 46.7% in IADLs only, and 21.7% in both BADLs and IADLs. The BADL items significantly impacted were mobility, stair climbing, bathing, toilet use, and bladder control, while all aspects of IADL except telephone usage were affected. No statistically significant improvement in EQ-5D-5L utility score was observed for both the functionally stable and the functionally declining group. However, the stable group reported a significantly higher EQ-VAS (self-perceived health) score post operation than the declining group (77.6 ± 12.3 vs.

Fig 1. Flow diagram of the study.

TABLE 1. Baseline characteristics of patients and preoperative laboratory findings.

Continuous data were analyzed using independent t-tests, and categorical data were analyzed using chi-square tests.

• Significant at p-value < 0.05

  Abbreviations: ASA, American Society of Anesthesiologists; BADL, Basic Activities of Daily Living; BMI, Body Mass Index; IADL, Instrumental Activities of Daily Living; M, mean; MNA-SF, Mini Nutritional Assessment short-form; MRC, Medical Research Council; SD, standard deviation; TMSE, Thai Mental State Examination

  
  

  TABLE 2. Surgery-related variables

  
  

  Variables	Total n = 97	Stable n = 37	Functional decline n = 60	p-value
  Type of surgery, n (%) Upper abdominal	33 (34.0)	16 (43.2)	17 (28.3)	0.132
  Lower abdominal	29 (29.9)	12 (32.4)	17 (28.3)	0.668
  Urological procedures	35 (36.1)	9 (24.3)	26 (43.3)	0.058
  Method of surgery, n (%) Open surgery	69 (71.1)	21 (56.8)	48 (80.0)	0.014*
  Laparoscopic surgery	28 (28.9)	16 (43.2)	12 (20.0)
  Surgery duration, median (IQR)	205 (155,285)	185 (150,260)	207.5 (170,322.5)	0.106
  > 165 minutes, n (%)	67 (69.1)	21 (56.8)	46 (76.7)	0.039*
  EBL, median (IQR)	150 (400,1100)	300 (100,700)	490 (150,1280)	0.158
  > 550 ml, n (%)	37 (38.1)	10 (27.0)	27 (45.0)	0.077
  ≥ 1 complication, n (%)	28 (28.9)	7 (18.9)	21 (35.0)	0.090
  LOS (days), median (IQR)	7 (5,10)	6 (4,7)	8 (6,12.5)	< 0.001*
  > 7 days, n (%)	43 (44.3)	7 (18.9)	36 (60.0)	< 0.001*

  Categorical data were analyzed using chi-square tests. Non-normally distributed data are presented as median (IQR) and analyzed using Mann–Whitney U tests.

• Significant at p-value < 0.05

Abbreviations: IQR, interquartile range; LOS, length of stay; EBL, estimated blood loss; ml, milliliter; M, mean; SD, standard deviation

72.8 ± 14.9, p=0.023). The stable group also presented a lower postoperative PHQ-9 score (fewer depressive symptoms) than the declining group (2.8 ± 3.2 vs. 3.9 ± 3.7, p=0.051; Table 3).

Factors found to be associated with functional decline from the univariable analysis were age ≥ 70, ASA

≥ 3, open surgery technique, surgery duration > 165 minutes, and LOS > 7 days. After a multivariable analysis adjusting for other variables in the model, the factors significantly associated with postoperative functional decline were age ≥ 70 (adjusted odds ratio [OR] 3.18, 95% confidence interval [CI] 1.11–9.06) and LOS > 7

days (adjusted OR 5.04, 95% CI 1.75–14.42; Table 4). Other variables, including laboratory testing, physical condition, and nutritional status, showed no significant association with functional changes after surgery.

The five factors showing statistical significance from the univariable analysis were used to develop four predictive equations. These equations incorporated either two, three, four, or all five factors in order of their significance. To predict the risk of functional decline, each factor present

in a patient was assigned a value of 1, and its absence a value of 0. This value was then multiplied by a coefficient derived from the β coefficient of each factor, representing its association with decline. If the resulting value from each equation met or exceeded the cut-off, it indicated a risk of postoperative functional decline. The predictive accuracy increased with the number of factors used, yielding AUCs of 0.766, 0.788, 0.805, and 0.814 for the two-, three-, four-, and five-factor formulas, respectively. The five-factor formula showed the best performance, with an accuracy of 74.2%, a positive predictive value of 83.0%, a negative predictive value of 63.6%, a sensitivity of 73.3%, and a specificity of 75.7% (p<0.001) (Table 5).

DISCUSSION

This study examined the incidence rate and risk factors associated with postoperative functional decline following elective abdominal surgery in older patients. Our findings revealed that nearly two-thirds of the patients experienced a decline in function one month after surgery. Age ≥ 70 and LOS > 7 days were identified as the factors

TABLE 3. Comparison of pre- and postoperative outcome scores.

* Significant at p-value < 0.05

Abbreviations: BADL, Basic Activities of Daily Living; IADL, Instrumental Activities of Daily Living; M, mean; PHQ-9, Patient Health Questionnaire-9; SD, standard deviation

most closely associated with the decline, while other factors, such as ASA ≥ 3, surgery duration > 165 minutes, and the use of open surgery techniques, showed a lower level of association. These findings emphasize the need for evaluations that address not only surgical risk but also strategies to mitigate postoperative functional decline, while highlighting the importance of incorporating geriatric considerations into surgical care to optimize

patient-centered outcomes. By combining these factors, we developed a predictive model that integrates commonly available clinical variables to estimate the likelihood of functional decline following surgery. This approach underscores the potential for individualized patient management and proactive planning, ultimately aiming to reduce the burden of postoperative morbidity in older populations.

TABLE 4. Results of multivariable logistic regression analysis to determine predictive factors for postoperative functional decline.

* Significant at p-value < 0.05

Abbreviations: ASA, American Society of Anesthesiologists; LOS, length of stay. Each variable was adjusted for other variables included in the model.

TABLE 5. Receiver operating characteristics of the predictive formulas.

Abbreviations: AUC, area under the receiver operating characteristic curve; PPV, positive predictive value; NPV, negative predictive value; LOS, length of stay

Two-factor formula: LOS (> 7 days) x 18 + Age (≥ 70 years) x 11, cut-off value ≥ 11

Three-factor formula: LOS (> 7 days) x 16 + Age (≥ 70 years) x 13 + Open surgery x 10, cut-off value ≥ 15

Four-factor formula: LOS (> 7 days) x 16 + Age (≥ 70 years) x 13 + Open surgery x 10 + Surgery duration (> 165 min) x 10, cut-off value

≥ 28

Five-factor formula: LOS (> 7 days) x 16 + Age (≥ 70 years) x 12 + Open surgery x 10 + Surgery duration (> 165 min) x 10 + ASA (≥3) x 6, cut-off value ≥ 27

The presence or absence of each factor is assigned a value of 1 or 0, respectively.

Age has consistently been identified by numerous studies as a predictor of worse surgical outcomes,5-7, 13-17 with some research also reporting a significant association between longer LOS and functional decline after surgery.7,15 Conversely, while higher ASA classification, longer operation time, and the distinction between major and minor operations have been recognized by certain studies as factors linked to functional decline or undesirable surgical results,13,14 other studies have found no such association.29,30 For instance, a study by Yamaguchi et al. on postoperative functional decline identified higher ASA score and major surgery as contributing factors but found no significant relation between longer operation time and this outcome.15 In contrast, a study by Zattoni et al. reported no significant association between major operations or higher ASA scores and functional decline.17 Nonetheless, a combination of these factors can effectively predict functional decline. Patients of advanced age, particularly those with multiple comorbidities or scheduled for open surgery, should be thoroughly prepared for the physiological stress of surgery. Moreover, patients undergoing prolonged surgeries or extended hospital stays require close monitoring for functional changes to ensure timely interventions and mitigate potential decline. Employing our developed predictive equations can further aid in the early identification of at-risk individuals,

enabling the implementation of preventive strategies.

Examining the specific ADLs affected can provide valuable insights for delivering effective strategies to prevent such declines. In the decline group, several BADLs showed significant deterioration, particularly in stair climbing, mobility, bathing, toilet use, and bladder control (Table 3). While surgeries involving the urological system may impact bladder function, the broader decline in other areas indicates challenges related to overall physical mobility. Therefore, implementing strategies to maintain patients’ physical capabilities, such as early mobilization, is crucial. Early mobilization is also a core component of the ERAS pathways and has been shown to offer numerous postoperative benefits, including improved physical function, reduced risk of complications, and shorter hospital stays.31-36

In terms of IADLs, all aspects except telephone usage were negatively impacted. While this too could partly be attributed to the aforementioned difficulties in mobility, which is reported to be one of the significant predictors of IADLs function,37 postoperative delirium (POD) might be other aspect to be considered. POD is reported to be one of the factors associated with decreased IADL functionality after surgery.38-40 However, in our study, through the

reviews of medical records we identified only 4 cases (4.1%) of POD, with no statistically significant differences between the functional stable and the decline groups. Future studies with larger sample sizes and standardized POD identification protocols are needed to clarify the relationship between POD and IADL functionality and to establish effective preventive strategies.

As for predicting postoperative functional decline, several strategies have been proposed across different surgical scenarios. Yamaguchi et al. used total psoas muscle volume measured by CT scans to predict decline following emergency abdominal surgery, achieving a good predictive value (AUC = 0.802 from ROC analyses).15 Another study by Fukuda et al. utilized multiple routine medical data to create complex predictive equations for decline after hip fracture surgery.16 Two other studies by Zattoni and Hoogerduijn employed screening tools—the Flemish version of the Triage Risk Screening Tool (fTRST) and the Identification of Seniors at Risk-Hospitalized Patients (ISAR-HP)—to predict decline in emergency and cardiac surgery, with AUCs of 0.72 and 0.73, respectively.17,18

Nevertheless, to the best of our knowledge, no published study has specifically addressed the prediction of decline following elective abdominal surgery. Based on the risk factors for postoperative functional decline identified in this population, our predictive equations can effectively forecast its occurrence without requiring additional investigations or complex calculations. Given the limited resources, these formulas are valuable tools for healthcare providers. By identifying patients at higher risk of postoperative functional decline, clinicians can prioritize resources for those who are most likely to benefit. This targeted approach could help optimize patient outcomes and enhance overall care quality and efficiency for patients undergoing elective abdominal surgery.

However, our study has several limitations. First, postoperative complications were identified exclusively through medical record reviews, which may limit the completeness of the data. Additionally, participants were reassessed only one month after surgery. Extending the follow-up period could provide valuable insights into the long-term trajectory of patients’ functional capacities post-surgery. Third, the data for this study were collected prior to the full implementation of the ERAS pathway at our institution. Future research conducted after its full adoption could provide a clearer picture of how these strategies impact both the incidence and prognosis of functional decline. Lastly, while the developed formulas demonstrated good performance within the studied sample, further validation is necessary to confirm their

broader applicability.

CONCLUSION

More than 60% of Thai older adults undergoing elective abdominal surgery are likely to experience functional decline one month after the procedure. Age

≥ 70 and LOS > 7 days were found to be the factors most strongly associated with this decline. The predictive formulas developed using these factors could be useful for early postoperative risk stratification and guiding timely interventions. These findings highlight the need for proactive measures to mitigate this deterioration and emphasize the importance of tailored strategies to preserve functionality in this population.

Data Availability Statement

The data supporting the findings of this study are not publicly available but can be obtained from the corresponding author upon reasonable request.

ACKNOWLEDGEMENTS

The authors sincerely thank the volunteers who agreed to participate in this study. We acknowledge the invaluable contributions of the Siriraj Integrated Perioperative Geriatric Excellent Research Center. We would also like to thank Mr. Suthipol Udompunthurak and Ms. Julaporn Pooliam, of the Research Group and Research Network Division, Research Department, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand, for providing assistance with statistical analysis.

DECLARATIONS

Grants and Funding Information

This study was funded by a grant from the Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand (Grant Number R016232013).

Conflict of Interest

The researchers claim no conflicts of interest.

Ethics approval

Ethics approval was obtained from the Medical Ethics Committee of the Human research protection unit of the hospital (COA no. 202/2018). All participants gave their written consent to participate.

Author Contributions

Conceptualization: PT, PD; Data curation: PT, SJ, NS; Funding acquisition: PT; Methodology: PT, PD, AS; Project administration: PT; Supervision: PD; Writing – original draft: PT; Writing – review & editing: PT, PD.

All authors have read and agreed to the final version of the manuscript.

Use of Artificial Intelligence

ChatGPT-4o was used to check for grammatical errors and improve the readability of this manuscript. The content was subsequently reviewed and edited as needed. The authors take full responsibility for the final version of this publication.

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‌Effects of Exercise Through Telerehabilitation on Balance and Walking Speed in Older Adults with Diabetic Peripheral Neuropathy: A Randomized Controlled Trial

Pilipda Chaiwan, M.Sc.1, Gulapar Srisawasdi, M.D.1,*, Pannika Prachgosin, M.D.2, Paweena Aekwattanaphol, M.Sc.1, Nathanit Jirapongpathai, M.Sc.1

1Sirindhorn School of Prosthetics and Orthotics (SSPO), Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand, 2Department

of Rehabilitation Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.

*Corresponding author: Gulapar Srisawasdi E-mail: gulapar.pho@mahidol.edu

Received 11 December 2024 Revised 9 February 2025 Accepted 9 February 2025 ORCID ID: http://orcid.org/0009-0002-0053-6684 https://doi.org/10.33192/smj.v77i6.272555

All material is licensed under terms of the Creative Commons Attribution 4.0 International (CC-BY-NC-ND 4.0) license unless otherwise stated.

INTRODUCTION

According to the International Diabetes Federation 2021, diabetes is a rapidly escalating global health crisis in the 21st century. The report estimated that around 537 million adults (20-79 years) were living with diabetes in 2021, which is estimated to increase to 643 million by 2030, and 783 million by 2045.1 Type 2 diabetes (T2DM) is the most prevalent type of diabetes, representing about 90% of all diabetes cases worldwide.2 One of the most prevalent chronic complications of diabetes is diabetic peripheral neuropathy (DPN), characterized by paresthesia, especially in the feet and hands.3 DPN can lead to decreased proprioception4, reduced foot-ankle range of motion, and diminished muscle strength5,6, resulting in impaired postural stability, functional gait, and balance. These impairments significantly increase the risk of falls, especially in older adults. Moreover, DPN is a major cause of foot ulceration and amputation.7-10 Exercise has been an essential aspect of non- pharmacological treatment for DPN.11 Evidence suggests that exercise programs, including walking, balance training, and lower limb strengthening exercises, can decrease the risk of falls in older adults with DPN.12-16 However, many patients are unable to participate in the offered exercise programs due to barriers such as long-distance travel or work commitments.17 During the COVID-19 pandemic, physical therapists (PTs) adapted their practices to maintain rehabilitation services while

adhering to healthcare safety measures. Some PTs began implementing telerehabilitation (TR).18 TR, a system to manage or monitor remote rehabilitation through communication technologies might be an option.19 This approach not only saves time and resources in healthcare, but also provides convenience and flexibility, allowing information to reach a broader audience, including those in remote areas.19,20

Therefore, we developed an exercise program for balance and gait training, amid the COVID-19 pandemic. This program was delivered through TR and supervised by a PT. Thus, this study aimed to analyze effects of TR- based exercise program on balance and walking speed in older adults with DPN compared to no intervention.

MATERIALS AND METHODS

Research design

This observer-blinded randomized controlled trial was conducted at the Sirindhorn School of Prosthetics and Orthotics (SSPO), Faculty of Medicine Siriraj Hospital, Mahidol University, Thailand, between October 2021 and January 2024. The study conformed to the guidelines of the Declaration of Helsinki was approved by the Siriraj Institutional Review Board with a certificate of approval (COA) no. Si 821/2021. After informed consent participants were randomly assigned to an intervention group or a control group. Randomization was conducted by an independent researcher using a computer-generated

randomization list to ensure allocation concealment. Participants were assigned to their respective groups based on the sequential order of the randomization list.

Participants

Patients with T2DM were recruited from the diabetic foot clinic at SSPO and the Siriraj Diabetes Center of Excellence, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok by clinical staff. Included were people, 1) diagnosed with T2DM and DPN at moderate or high risk of developing diabetic foot ulcers (DFU) as diagnosed by physicians21; 2) 60 years or older; 3) capable of walking and exercising independently without the need for assistive devices; 4) having a caregiver or someone present while exercising at home; 5) capable of using a smartphone or laptop for the TR program. Excluded were people with 1) an active foot ulcer; 2) baseline Berg Balance Scale (BBS) score below 45; 3) history of amputations; 4) orthopedic or surgical issues in the lower extremities such as fractures, malformations, or severe osteoarthritis; 5) presence of other neurological impairments, central nervous system problems, or vestibular system disorders; 6) severe retinopathy and/or nephropathy;

7) severe cardiopulmonary conditions or abnormal electrocardiogram results; 8) postural hypotension or uncontrolled hypertension; 9) poor vision; 10) intellectual disabilities or psychiatric disorders.

Intervention

All exercises included in the training program are described in Supplementary Material (https://doi. org/10.6084/m9.figshare.27991079.v3). The training program, partly based on previous studies15,16, was developed by our team to enhance balance and gait training in a TR setting. Two PTs participated in this study. An observer, blinded to group allocation assessed pre- and post-intervention outcomes. A PT administered the exercises through TR. Participants in the intervention group received logbook that included the home-based exercise program as well as educational materials for self-care. Individuals accessed TR services through an online platform (LINE application) with the PT. Training time was 60 minutes, twice a week for 8 weeks on non- consecutive days. During training, the participants wore sport shoes or therapeutic shoes, which are custom-made to protect sensitive feet, reduce pressure, and provide support for patients’ conditions, prescribed by a physician and worn with socks. The standardized training equipment consisted of 1) a training mat, 2) a sensory massage ball, diameter of 7.5 cm, 3) a lightweight elastic band, and 4) a step board size 28x78x20 cm. The training program

was structured into three components: warming-up, balance and gait training, and cooling-down (Table 1). Participants in the control group did not receive an exercise program, but received usual hospital medical care. In addition, both groups received pamphlets written by interdisciplinary teams at Siriraj Diabetes Center of Excellence covering topics such as diabetic foot care,

diabetic diet, and diabetes complications.

Outcome measures

All participants were assessed using the Berg Balance Scale (BBS) and the 10 Meter Walk Test (10MWT) by the observer at baseline (T0) and after an 8-week follow- up (T1). Furthermore, during the final evaluation, the intervention group filled in a satisfaction questionnaire. The BBS assesses static and dynamic balance capabilities and it consists of 14 items, each item is graded on a five-point scale (0 to 4) based on the quality of the performance of the item. The maximum score is 56. A score below 45 indicates a higher risk of falling.8,22 The tool demonstrates responsiveness to changes in balance.

The 10MWT measures the time needed to walk a distance of 10 meters on a 14-meter walkway. The participants walked at a comfortable speed. The mean time (in seconds) of three trials was analyzed, with a 2-minute rest between each trial.23

Assessment of satisfaction concerning the exercise program, included six items (1) How would you rate the appropriateness of the duration of each training session, around 1 hour?, (2) How would you rate the quality of the training and equipment?, (3) Did the physical therapist explain the exercises in a way that was easy to understand?, (4) Do you feel that the physical therapist treated you with respect and dignity?, (5) Would you recommend this exercise program to a friend or family member?, (6) How would you rate the overall quality of the program delivered via an online platform? These items could be rated as; 1 = unsatisfied, 2 = poor, 3 = fair, 4 = good, or 5 = excellent.

Sample size calculation

The sample size calculation for this study was calculated using G*Power software, based on a randomized controlled trial with a 1:1 ratio of intervention group and control group.16 That study reported a mean change of 2.1 for the intervention group and 0.1 for the control group in BBS outcomes, with standard deviations (SD) of 2.3 for both groups Assuming a power of 80% and an alpha of 0.05, the resulting effect size was 0.87. The required sample size was 44 participants, with 22 participants per group.

TABLE 1. Outline of the Siriraj Exercise Protocol.

Balance and gait training

(40 minutes)

Part 1: Balance training on a training mat

• Bipedal heel and toe raise (10 reps/3 sets)

• One-leg stance (10 seconds/3 reps/side)

  Rest: Sitting on a chair with a resistance band exercise (10 reps/3 sets)

• Chest press

• Middle back band pull-apart

  Part 2: Progressive balance and gait training on a training mat

• Tandem stance (10 seconds/10 reps/side)

• Backward walking (10 reps)

• Sideways walking (10 reps/side)

  Part 3: Exercises on a step board (10 reps/direction/side)

• Step-ups: front step-ups and side step-ups

• Weight shifting: forward and side-to-side

Warming-up (10 minutes) Stretching: Neck muscles, posterior shoulder, triceps brachii stretch with side bend, hamstrings, gluteus and lower back, quadriceps, calf (10 seconds/3reps/side)

Cooling-down - Sensory ball massaging (10 reps/side)

(10 minutes) - Foot writing the number 1 to 10 in the air (10 reps/side)

• Towel curl (10 reps/3 sets)

• Deep breathing (5 reps)

Abbreviation: Reps = repetitions

Statistical analysis

Statistical analyzes were performed using IBM SPSS Statistics, Version 29.0.2.0. The Shapiro-Wilk test was employed to assess the normality of the distribution for all parameters. Baseline differences between groups were evaluated using Student’s t test or the Mann-Whitney U test for continuous variables and the Chi-square test for categorical variables. Differences in changes between groups were analyzed using an independent samples t-test or Mann-Whitney U test depending on data distribution. A significance level of P < 0.05 was considered statistically significant for all tests.

RESULTS

Forty-eight individuals were assessed for eligibility, and a total of forty-four participants were randomized into either the intervention group (n=22) or the control group (n=22). Finally, 18 participants in the intervention group and 21 participants in the control group were analyzed (Fig 1). There were no significant differences

in the baseline characteristics between the two groups (P>0.05) (Table 2). No serious adverse events of the programs were reported.

Berg balance scale

The improvement in the BBS were significantly larger in the intervention group, (median change [IQR]:

6.5 [4.8, 5.2] than the control group (median change

[IQR]: -1 [-1, -2]), P<0.001, MWU test (Table 3).

10 Meter walk test

The improvements in 10MWT were significantly larger in the intervention group (mean change -1.9 seconds [95% CI: -2.5, -1.3]) than the control group

(mean change -0.1 seconds [95% CI: -0.5, 0.4]), P<0.001, independent t-test) (Table 3).

The satisfaction with the exercise program

Among the 18 participants who completed the survey, 17 rated the duration of each training session as

Fig 1. Flow diagram of the study.

excellent. 16 rated the quality of training and equipment as excellent, and 17 reported that the PT explained the exercises in a way that was easy to understand with excellent. All participants felt they were treated with respect and dignity by the PT. Additionally, 16 of participants would recommend this exercise program to a friend or family member, and 17 rated the overall quality of the program through the online platform as excellent.

DISCUSSION

This exercise program delivered by a PT via TR resulted in significant improvements in balance and walking speed in older adults with DPN. In the control group BBS score deteriorated highlighting the negative impact of physical inactivity or insufficient exercise. This result is consistent with previous findings that older adults with T2DM rapidly decline in leg muscle strength and muscle quality.24

Throughout the 8-week of training, no serious adverse events or diabetic foot ulcers were observed among participants in the intervention group. This finding challenges the historical advice for people with DPN to reduce weight-bearing activity.25 However, lack of physical activity can result in deterioration of

skin health and decrease in total body tolerance.26,27 A previous study confirmed that weight-bearing exercises significantly improved daily step count and 6-minute walk test compared to non-weight-bearing exercises.28 Moreover, increased weight-bearing activity did not lead to an increased risk of re-ulceration in diabetic foot.29

In this study, we selected an 8-week, twice-weekly training program based on the findings of a previous study, which reported significant improvements in balance and trunk proprioception were found following an on- site training.16 We delivered our program through TR, highlighting the potential of remote training to achieve similar benefits.

To improve balance performance, balance exercises should be performed 2-3 days a week to enhance postural ability and gait, thereby reducing the risk of falling. Stretching exercises should be performed to the point of tightness for 10-30 seconds with 2-4 repetitions to improve joint range of motion.30 The American Diabetes Association31 guidelines emphasize the importance of regular exercise for older adults managing T2DM to promote overall physical function and prevent mobility- related complications.

TABLE 2. Baseline characteristics of both groups.

• Result of Student t test.

  † Result of Mann-Whitney U test; otherwise by Chi-square test.

  
  

  TABLE 3. Results of the Berg Balance Scale (BBS) and the 10 Meter Walk Test (10MWT) evaluated baseline and 8-week follow-up within the group.

  
  

  Outcomes	Intervention group	Control group	Intervention group	Control group	P Value of difference in change between groups
  	T0 T1	T0 T1	Change	Change
  BBS (score) (median [IQR])	48.5 [47, 50.8] NS 55 [51.8, 56]	47 [46, 50] NS 46 [45, 48]	6.5 [4.8, 5.2]	-1 [-1, -2]	<0.001†
  10MWT (second) (mean ± SD)	11.8 ± 3.6 NS 9.9 ± 3.3	12.8 ± 3.4 NS 12.8 ± 3.5	-1.9 [95%CI: -2.5, -1.3]	-0.1 [95%CI: -0.5, 0.4)	<0.001*

  T0 = at baseline, T1 = at 8 weeks of follow-up, BBS = Berg Balance Scale, 10MWT = 10 Meter Walk Test. NS = Not significant difference at baseline between groups (P > 0.05).

  † Result of the Mann-Whitney U test.

• Result of Student's paired t test.

Improved walking speed is critical to maintaining functional mobility and independence in older adults. Brisk walking (4-8 km/hour) significantly increases the chance of maintaining in functional mobility and independence in T2DM compared to slower paces.32 In this study, the intervention group showed an improvement in walking speed (10MWT) from 3.1 km/hour to 3.6 km/hour but that is still speed that is less than the desirable speed of 4 km/hour.

Our study utilized TR intervention delivered through real-time video conferencing, allowing participants to receive direct supervision and feedback from the PT. This approach enabled participants to maintain social distancing during the pandemic while continuing supervised exercise at home. The program is simple and uses affordable equipment, easy to implement, and suitable for home- based settings. Furthermore, the high satisfaction reported in the survey supports the feasibility and acceptability of this exercise program among participants. Similarly, a recent study reported that a 6-week (3 times/week) supervised home-based TR program combining aerobic and resistance exercises significantly improved glycemic control, six-minute walk test performance, muscle strength, and quality of life in patients with T2DM. TR addresses barriers to exercise participation by being accessible, making it a viable alternative to traditional in-person programs.33

This study has several limitations. First, the sample size was below the estimated target. The inclusion criteria required older adults to be able to use a smartphone for TR, which posed challenges for some participants due to technological difficulties and the COVID-19 situation, caused temporary research pauses. Second, the study duration was limited to 8 weeks, which may not capture the long-term effects of the intervention. Future studies should include larger sample sizes and longer follow- up periods to assess the sustainability of the observed improvements. Third, the control group received only standard hospital care. Future studies should consider another intervention such as those participating in alternative home-based exercise programs (e.g., cycling on a home trainer), to assess whether similar improvements could be achieved with other intervention designs.

CONCLUSION

This exercise program through TR increases balance and walking speed in older adults with DPN. The high levels of participant satisfaction further support its feasibility and acceptability. These findings suggest that TR could be a valuable tool in the management of DPN, offering a flexible and accessible approach to rehabilitation.

Data Availability Statement

The data of this study and details regarding the exercise program are available on Figshare at https:// doi.org/10.6084/m9.figshare.27991079.v3.

ACKNOWLEDGMENTS

The authors sincerely thank the patients and families for their vital participation. Appreciation also goes to the Siriraj Diabetes Center of Excellence, Faculty of Medicine Siriraj Hospital for participant recruitment support and to Miss Nerisa Thornsri for her invaluable help with statistical analyses.

DECLARATION

Grants and Funding Information

This study was supported by Siriraj Research Fund, Faculty of Medicine Siriraj Hospital, Mahidol University, Grant Number (IO) R016531010 and Partial Funding Proposal for Research Grant 2021 by Graduate Studies of Mahidol University Alumni Association and Faculty of Graduate Studies.

Conflict of Interest

No potential conflict of interest was reported by the authors.

Registration Number of Clinical Trial

This study protocol was not registered in a trial registry.

Author Contributions

Conceptualization and methodology, P.C., G.S., P.P., and P.A. ; Provision of patients, N.J. ; Data collection and data acquisition, P.C. and P.A. ; Formal analysis,

P.C. and G.S. ; Visualization and writing – original draft,

P.C. ; Writing – review and editing, G.S. ; Supervision,

G.S. and P.P. All authors - Final approval of the version to be published.

Use of Artificial Intelligence

No artificial intelligence tools were used in the writing of this research.

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2. Liu J, Bai R, Chai Z, Cooper ME, Zimmet PZ, Zhang L. Low- and middle-income countries demonstrate rapid growth of type 2 diabetes: an analysis based on Global Burden of Disease 1990-2019 data. Diabetologia. 2022;65(8):1339-52.

3. Win MMTM, Fukai K, Nyunt HH, Linn KZ. Hand and foot exercises for diabetic peripheral neuropathy: A randomized

   controlled trial. Nurs Health Sci. 2020;22(2):416-26.

4. Ahmad I, Verma S, Noohu MM, Shareef MY, Hussain ME. Sensorimotor and gait training improves proprioception, nerve function, and muscular activation in patients with diabetic peripheral neuropathy: a randomized control trial. J Musculoskelet Neuronal Interact. 2020;20(2):234-48.

5. Monteiro RL, Sartor CD, Ferreira JS, Dantas MG, Bus SA, Sacco IC. Protocol for evaluating the effects of a foot-ankle therapeutic exercise program on daily activity, foot-ankle functionality, and biomechanics in people with diabetic polyneuropathy: A randomized controlled trial. BMC Musculoskelet Disord. 2018;19:1-12.

6. Martinelli AR, Mantovani AM, Nozabieli AJ, Ferreira DM, Barela JA, Camargo MR, et al. Muscle strength and ankle mobility for the gait parameters in diabetic neuropathies. Foot (Edinb). 2013;23(1):17-21.

7. Venkataraman K, Tai BC, Khoo EYH, Tavintharan S, Chandran K, Hwang SW, et al. Short-term strength and balance training does not improve quality of life but improves functional status in individuals with diabetic peripheral neuropathy: a randomised controlled trial. Diabetologia. 2019;62(12):2200-10.

8. Timar B, Timar R, Gaiță L, Oancea C, Levai C, Lungeanu D. The impact of diabetic neuropathy on balance and on the risk of falls in patients with type 2 diabetes mellitus: a cross-sectional study. PloS One. 2016;11(4):e0154654.

9. Vongsirinavarat M, Kraiwong R. Falls among Older People with Type 2 Diabetes Mellitus with Peripheral Neuropathy. Siriraj Med J. 2021;73(2):92-8.

10. Selvarajah D, Kar D, Khunti K, Davies MJ, Scott AR, Walker J, et al. Diabetic peripheral neuropathy: advances in diagnosis and strategies for screening and early intervention. Lancet Diabetes Endocrinol. 2019;7(12):938-48.

11. de Oliveira Lima RA, Piemonte GA, Nogueira CR, Dos Santos Nunes-Nogueira V. Efficacy of exercise on balance, fear of falling, and risk of falls in patients with diabetic peripheral neuropathy: a systematic review and meta-analysis. Arch Endocrinol Metab. 2021;65(2):198-211.

12. Allet L, Armand S, de Bie RA, Golay A, Monnin D, Aminian K, et al. The gait and balance of patients with diabetes can be improved: a randomised controlled trial. Diabetologia. 2010; 53(3):458-66.

13. Richardson JK, Sandman D, Vela S. A focused exercise regimen improves clinical measures of balance in patients with peripheral neuropathy. Arch Phys Med Rehabil. 2001;82(2):205-9.

14. Gu Y, Dennis SM. Are falls prevention programs effective at reducing the risk factors for falls in people with type-2 diabetes mellitus and peripheral neuropathy: A systematic review with narrative synthesis. J Diabetes Complications. 2017;31(2): 504-16.

15. Lee K, Lee S, Song C. Whole-body vibration training improves balance, muscle strength and glycosylated hemoglobin in elderly patients with diabetic neuropathy. Tohoku J Exp Med. 2013; 231(4):305-14.

16. Song CH, Petrofsky JS, Lee SW, Lee KJ, Yim JE. Effects of an exercise program on balance and trunk proprioception in older adults with diabetic neuropathies. Diabetes Technol Ther. 2011;13(8):803-11.

17. Duruturk N. Telerehabilitation intervention for type 2 diabetes. World J Diabetes. 2020;11(6):218-26.

18. Buabbas AJ, Albahrouh SE, Alrowayeh HN, Alshawaf H.

    Telerehabilitation during the COVID-19 Pandemic: Patients and Physical Therapists’ Experiences. Med Princ Pract. 2022;31(2): 156-64.

19. Seron P, Oliveros M-J, Gutierrez-Arias R, Fuentes-Aspe R, Torres- Castro RC, Merino-Osorio C, et al. Effectiveness of Telerehabilitation in Physical Therapy: A Rapid Overview. Phys Ther. 2021;101(6): pzab053.

20. Connelly J, Kirk A, Masthoff J, MacRury S. The use of technology to promote physical activity in Type 2 diabetes management: a systematic review. Diabet Med. 2013;30(12):1420-32.

21. Sarinnapakorn V, Sunthorntepwarakul T, Deerochanawong C, Niramitmahapanya S, Napartivaumnuay N. Prevalence of diabetic foot ulcers and risk classifications in type 2 diabetes mellitus patients at Rajavithi Hospital. J Med Assoc Thai. 2016;99(2):S99-S105.

22. Bogle Thorbahn LD, Newton RA. Use of the Berg Balance Test to predict falls in elderly persons. Phys Ther. 1996;76(6):576- 83; discussion 84-5.

23. Steffen TM, Hacker TA, Mollinger L. Age- and Gender-Related Test Performance in Community-Dwelling Elderly People: Six-Minute Walk Test, Berg Balance Scale, Timed Up & Go Test, and Gait Speeds. Phys Ther. 2002;82(2):128-37.

24. Park SW, Goodpaster BH, Strotmeyer ES, Kuller LH, Broudeau R, Kammerer C, et al. Accelerated loss of skeletal muscle strength in older adults with type 2 diabetes: the health, aging, and body composition study. Diabetes Care. 2007;30(6):1507-12.

25. Sigal RJ, Kenny GP, Wasserman DH, Castaneda-Sceppa C, White RD. Physical activity/exercise and type 2 diabetes: a consensus statement from the American Diabetes Association. Diabetes Care. 2006;29(6):1433-8.

26. Mueller MJ, Maluf KS. Tissue adaptation to physical stress: a proposed “Physical Stress Theory” to guide physical therapist practice, education, and research. Phys Ther. 2002;82(4):383- 403.

27. Dajpratham P, Thitisakulchai P, Pongratanakul R, Prapavanond R, Haridravedh S, Muangpaisan W. Effectiveness of Personalized Multifactorial Fall Risk Assessment and Intervention in Reducing Fall Rates Among Older Adults: A Retrospective Study. Siriraj Med J. 2025;77(1):64-72.

28. Mueller MJ, Tuttle LJ, Lemaster JW, Strube MJ, McGill JB, Hastings MK, et al. Weight-bearing versus nonweight-bearing exercise for persons with diabetes and peripheral neuropathy: a randomized controlled trial. Arch Phys Med Rehabil. 2013;94(5): 829-38.

29. Lemaster JW, Reiber GE, Smith DG, Heagerty PJ, Wallace C. Daily weight-bearing activity does not increase the risk of diabetic foot ulcers. Med Sci Sports Exerc. 2003;35(7):1093-9.

30. Colberg SR, Sigal RJ, Yardley JE, Riddell MC, Dunstan DW, Dempsey PC, et al. Physical Activity/Exercise and Diabetes: A Position Statement of the American Diabetes Association. Diabetes Care. 2016;39(11):2065-79.

31. Standards of Care in Diabetes-2023 Abridged for Primary Care Providers. Clin Diabetes. 2022;41(1):4-31.

32. Jayedi A, Zargar MS, Emadi A, Aune D. Walking speed and the risk of type 2 diabetes: a systematic review and meta-analysis. Br J Sports Med. 2024;58(6):334-42.

33. Blioumpa C, Karanasiou E, Antoniou V, Batalik L, Kalatzis K, Lanaras L, et al. Efficacy of supervised home-based, real time, videoconferencing telerehabilitation in patients with type 2 diabetes: a single-blind randomized controlled trial. Eur J Phys Rehabil Med. 2023;59(5):628-39.

‌Transpore Tape and Transparent Film Dressing on the Incidence of Early-Stage Phlebitis: A Comparative Randomized Trial

Pramote Thangkratok, Ph.D.1,*, Krit Pongpirul, Ph.D.1,2,3,4,5,6, Jiruth Sriratanaban, Ph.D.1

1Department of Preventive and Social Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand, 2Center of Excellence in Preventive and Integrative Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand, 3School of Global Health and Department of Preventive and Social Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand, 4Clinical Research Center, Bumrungrad International Hospital, Bangkok, Thailand, 5Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA, 6Department of Infection Biology & Microbiomes, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK.

*Corresponding author: Pramote Thangkratok E-mail: pramot_computer@hotmail.com

Received 14 December 2024 Revised 22 January 2025 Accepted 22 January 2025 ORCID ID: http://orcid.org/0000-0001-8169-411X https://doi.org/10.33192/smj.v77i6.272715

All material is licensed under terms of the Creative Commons Attribution 4.0 International (CC-BY-NC-ND 4.0) license unless otherwise stated.

INTRODUCTION

Peripheral intravenous catheters (PIVCs) are a standard invasive nursing procedure used for administering fluids, medications, and blood components.1 In the United States alone, annual usage ranges between 200 to 300 million,2 and global estimates indicate approximately 2 billion catheters are utilized annually.3 A substantial proportion, between 50% to 90%, of hospitalized patients undergo catheter implantation. Despite its necessity, this procedure can lead to complications such as phlebitis.

Phlebitis, the inflammation of veins, can result from the chemical properties of administered substances or bacterial infection.3-5 The reported incidences of phlebitis range between 0.1% and 63.3%, with symptoms including fever, redness, swelling, pain, localized warmth or coldness, pus formation, and more severe complications like reduced fluid flow, visible vein tracks, tissue damage, organ dysfunction, and blood clots.6-8 The choice of cannula insertion practices, including the selection of appropriate devices and dressings, is critical in preventing phlebitis.9 Previous studies have shown divergent outcomes regarding the effectiveness of different dressing types, with some suggesting that transparent film dressings could reduce complications,10 while others indicate no significant difference or even superiority of gauze and tape dressings.11,12 To the best of our knowledge, there is no evidence indicating a direct association between the use of transpore tape or transparent film dressing and the incidence of phlebitis. However, further investigation is necessary to confirm this finding.

Given the conflicting evidence and the absence of specific data comparing transpore tape and transparent

film dressing in early phlebitis, this study aims to bridge this gap. Additionally, considering the varied costs of these dressings, a comprehensive cost-effectiveness analysis is essential.13 This study seeks to evaluate the efficacy of transpore tape and transparent film dressing on the incidence of early-stage phlebitis in patients with peripheral venous catheters, potentially offering new insights and strategies for early management of the phlebitis.

MATERIALS AND METHODS

Study design

This study was a randomized controlled trial with a parallel-group design, conducted on inpatients in the internal medicine wards of a community hospital in Thailand. The trial spanned from November 2020 to March 2021.

Ethical considerations

All participants provided written informed consent. The study received ethical approval from the Institutional Review Board of the Faculty of Medicine, Chulalongkorn University (COA No.1037/2020, IRB No.332/63) on August 27, 2020. The trial was officially registered in the Thai Clinical Trial Registry (TCTR20210801004).

Participants

The study included adult patients over the age of 18 years who underwent IV therapy with osmolality less than 820 mOsm/L via a PIVC during their hospital stay. Participants were required to have a body mass index (BMI) ranging from 18.50 to 22.90 kg/m2 and be

communicative, cooperative, and willing to engage in the study. The study excluded patients on immunosuppressive therapy, those with hypercoagulability disorders, patients experiencing diaphoresis, those with peripheral nervous system disorders, or a known allergy to transparent dressings.

Randomization

Participants were divided into two groups through block randomization, utilizing blocks of two based on a table of random numbers. The groups were 1) the transpore tape dressing group, and 2) the transparent film dressing group. Enrollment and assignment of participants to each group were conducted by a registered nurse (RN). Participants could not be blinded to the intervention due to the nature of the dressing types, as they were able to visibly identify the type of dressing applied.

Interventions

The PIVCs were administered by an RN to patients meeting the inclusion criteria. To minimize the risk of phlebitis, the smallest gauge and shortest length PIVC compatible with the prescribed therapy were selected.14 Preferred sites for catheter insertion included the basilic, cephalic, dorsal metacarpal, and dorsal venous arch veins on the dorsal forearm.14,15

The PIVC insertion followed a strict aseptic protocol. This process began with routine hand hygiene, a practice repeated as necessary, especially after handling any invasive medical devices.14 Skin preparation for catheter insertion involved using a 70% alcohol solution for antiseptic purposes.16 After PIVC insertion, a separate RN, who was not involved in the initial procedure, applied the dressing. In the transpore tape group, a transpore tape was used to secure the catheter.

Outcome measures

The primary outcome of this study was the incidence of early-stage phlebitis, assessed using the Visual Infusion Phlebitis Scale. Post-insertion of the catheter, an RN conducted evaluations at least every eight hours. The outcome assessment was performed by an independent registered nurse (RN). The RN was not involved in the clinical trial procedures or group allocation, ensuring that the assessment of phlebitis outcomes was unbiased. The phlebitis grading at the insertion site was independently reviewed by two researchers, who then collaborated to reach a consensus on the visual infusion phlebitis score. Early-stage phlebitis was defined as a level 2 on a scale ranging from 0 to 5, where 0 represents no signs of phlebitis and 5 indicates an advanced stage, characterized

by the presence of two or more symptoms such as pain, erythema, or swelling.17

Sample size calculation

The sample size for this non-inferiority or superiority trial was calculated using a specific statistical formula. This calculation resulted in a requirement of 138 participants per group. To accommodate potential dropouts and other unforeseen contingencies, an additional 10% was factored in, bringing the total to 308 patients. Consequently, the study included 154 patients in the transpore tape dressing group and 154 in the transparent film dressing group, each with attached peripheral venous catheters.

Statistical analysis

The data were analyzed using the Statistical Package for Social Sciences (SPSS) version 23.0 for Windows. This included descriptive statistics, chi-square tests, and Fisher’s exact test. Fisher’s exact test was used to analyze categorical data because it is particularly appropriate when sample sizes are small or when the expected frequencies in any of the cells of a contingency table are below 5. In our study, certain subgroups had relatively small frequencies, which could have violated the assumptions of the Chi-square test (i.e., expected frequencies should be at least 5 in each cell). As a result, Fisher’s exact test was chosen because it is more reliable for determining the significance of associations in these cases, without the risk of invalid conclusions due to small sample sizes. We performed a multivariable analysis to control for potential confounding factors that could influence the comparison of the two interventions. This analysis allowed us to adjust for relevant determinants, such as patient characteristics (e.g., age, gender, comorbidities) and baseline conditions that could impact the outcomes related to early state of phlebitis. Relative risk (RR) was calculated using SPSS 23.0. The threshold for statistical significance was set at a p-value of less than 0.05. The relative risk (RR), or risk ratio, is the ratio of the risk of an event in the transpore tape dressing group (e.g., exposed group) versus the risk of the event in the transparent film dressing group (e.g., nonexposed group) and the confidence interval (CI). A p-value of less than 0.05 in this analysis indicated a statistically significant association between the groups. In addition to the intention-to-treat (ITT) analysis, a per-protocol analysis was conducted as a secondary approach. The per-protocol analysis included only those participants who adhered strictly to the assigned intervention protocol and completed the study as per the predefined procedures. This analysis was performed to assess the outcomes based on the

participants who followed the treatment plan without any deviations.

RESULTS

Participant characteristics

Between November 2020 and March 2021, 1,219 adult inpatients from the internal medicine wards of a Community Hospital were evaluated for eligibility. Of these, 403 were excluded due to IV therapy with osmolality <820 mOsm/L via PIVC and having a BMI below 18.5 or above 22.90 kg/m2. Additionally, 508 chose not to participate. Consequently, 308 adult patients were recruited and evenly divided into two groups of 154 each (Fig 1).

Table 1 reveals that both transpore tape dressing group and the transparent film dressing group were comparable in terms of gender, average age, highest level of education, presence or absence of chronic diseases, smoking habits, number of insertion attempts, PIVC site, use of IV medication, and IV fluid utilization. No significant differences were observed between the two groups.

Table 2 presents the incidence of early-stage phlebitis between the groups. The transpore tape dressing group exhibited a 77.92% incidence, while the transparent film dressing group showed a 66.88%. A statistically

Fig 1. CONSORT 2010 flow diagram of the clinical trial.

significant difference in phlebitis incidence between the groups was observed. The group using transpore tape had a 1.16 times higher risk of early-stage phlebitis than the group using transparent film dressing (RR = 1.16, 95% CI = 0.116-0.452).

Table 3 shows the comparison of data for catheter dwell time. In this table, 53.25% of catheters in the transpore tape dressing group had a catheter dwell time of 49–72 h, whereas 61.69% of catheters in the transparent film dressing group had a dwell time of 73-96 h. The analysis showed that catheter dwell time of 49–72 h and 73-96 h varied by the groups, which was statistically significant (p < 0.001)

DISCUSSION

Peripheral Intravenous Catheter (PIVC) administration, globally used to deliver fluids, medications, or blood components, frequently results in phlebitis due to the procedure’s invasive nature. Therefore, ensuring the catheter’s stability is vital to reduce complications. This research compared the effectiveness of transpore tape and transparent film dressing on the incidence of early- stage phlebitis in patients with a PIVC. We found that early-stage phlebitis developed in 77.92% of the transpore tape group, in contrast to 66.88% in the transparent film dressing group. A statistically significant difference in the

TABLE 1. Participants characteristics.

TABLE 2. Comparison of data for early state of phlebitis.

TABLE 3. Comparison of data for catheter dwell time.

incidence of phlebitis was observed between the groups.18 Despite these variations, both investigations underscore a significant difference in complication rates between the groups. Transparent film dressing is an adhesive dressing made of thin, transparent film placed over the PIVC. It is designed to be breathable and waterproof, allowing for easy wound monitoring without needing to remove the dressing. Transpore tape, on the other hand, is a perforated medical tape with strong adhesive properties, making it ideal for securing thicker dressings and tubing. It is hypoallergenic, latex-free, and customizable in width, often used for covering PIVC.10,19

Our results align with previous studies,10,19 which advocate for the use of transparent film dressings in PIVC applications due to fewer complications. The consistency across these studies suggests that the enhanced catheter stabilization capabilities of transparent film dressings play a pivotal role in reducing the incidence of phlebitis. Transparent film dressings act as a protective barrier against external contaminants and pathogens, reducing the need for frequent dressing changes, thereby preserving skin integrity and minimizing the risk of infection.12,20-24 The ease of use associated with these

dressings reduces complications such as skin damage from repeated changes, leading to reduced pain and lower infection probabilities.10,19,25 The study results revealed a statistically significant difference between the group that received the transparent film dressing and the group that received the transpore tape. This suggests that the transparent film dressing was more effective in securing PIVC than the transpore tape. It is important to note that the study was conducted under controlled conditions and may not necessarily reflect real-world scenarios.

In the study comparing catheter dwell times between the transpore tape dressing group and the transparent film dressing group, it was found that 53.25% of catheters in the transpore tape dressing group had a dwell time of 49–72 hours, while 61.69% of catheters in the transparent film dressing group had a dwell time of 73-96 hours. The analysis revealed a statistically significant variation in catheter dwell times between the two groups. This discrepancy in dwell times suggests that the type of dressing used has an impact on how long catheters remain in place. Specifically, a higher percentage of catheters in the transparent film dressing group had a longer

dwell time of 73-96 hours compared to the transpore tape dressing group, where more catheters had a dwell time of 49–72 hours. The statistical significance of this difference indicates that it is unlikely to have occurred by chance alone. It may be attributed to the properties of the dressings and their influence on catheter stability and adhesion.26,27

These findings have implications for clinical practice and may inform decisions regarding the selection of dressing types for catheter securement. Healthcare providers should consider the potential impact of dressings on catheter dwell times when making choices about patient care. Additionally, these results contribute to the body of knowledge in catheter-related research and may guide future studies investigating optimal catheter management strategies. One limitation of our research was its limited scope, involving a small participant pool from a single hospital clinic. Future studies should expand the sample size and encompass multiple settings for a more comprehensive analysis.

CONCLUSION

The early-stage phlebitis incidence was 77.92% in the transpore tape dressing group and 66.88% in the transparent film dressing group. This difference was statistically significant, suggesting transparent film dressing may reduce phlebitis occurrence when attaching peripheral venous catheters. The study compared catheter dwell times between two groups, one using transpore tape dressing and the other using transparent film dressing. Statistical analysis demonstrated a significant difference in catheter dwell times between the two groups, suggesting that the type of dressing used influences how long catheters stay in place.

Data Availability Statement

The data supporting this study are available from the corresponding author upon reasonable request.

ACKNOWLEDGEMENTS

We would like to express our sincere gratitude to all participants for their time and cooperation in this study. Your kindness and commitment have been invaluable to the success of this research.

DECLARATION

Grants and Funding Information

None.

Conflict of Interest

All authors declare no conflicts of interest.

Registration Number of Clinical Trial

The trial was officially registered in the Thai Clinical Trial Registry (TCTR20210801004).

Author Contributions

Conceptualization and methodology, P.T and K.P.

; Investigation, P.M., K.P., J.S. ; Formal analysis, P.T. and K.P. ; Visualization and writing – original draft,

P.T. ; Writing – review and editing, P.T., K.P., J.S. ; Supervision, P.T. All authors have read and agreed to the final version of the manuscript.

Use of Artificial Intelligence

Not applicable.

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3. Zingg W, Pittet D. Peripheral venous catheters: an under- evaluated problem. Int J Antimicrob Agents. 2009;34 Suppl 4:S38-42.

4. Campbell L. IV-related phlebitis, complications and length of hospital stay: 1. Br J Nurs. 1998;7(21):1304-12.

5. Collin J, Constable F, Collin C, Johnston I. Infusion thrombophlebitis and infection with various cannulas. Lancet. 1975;306(7926): 150-3.

6. Laudenbach N, Carie AB, Klaverkamp L, Hedman-Dennis S. Peripheral IV stabilization and the rate of complications in children: an exploratory study. J Pediatr Nurs. 2014;29(4):348- 53.

7. Helm RE, Klausner JD, Klemperer JD, Flint LM, Huang E. Accepted but unacceptable: peripheral IV catheter failure. J Infus Nurs. 2015;38(3):189-203.

8. Enes SM, Opitz SP, Faro AR, Pedreira Mde L. Phlebitis associated with peripheral intravenous catheters in adults admitted to hospital in the Western Brazilian Amazon. Rev Esc Enferm USP. 2016;50(2):263-71.

9. Higginson R, Parry A. Phlebitis: treatment, care and prevention. Nurs Times. 2011;107(36):18-21.

10. Atay S, Yilmaz Kurt F. Effectiveness of transparent film dressing for peripheral intravenous catheter. J Vasc Access. 2021;22(1): 135-40.

11. Forni C, Loro L, Tremosini M, Trofa C, D'Alessandro F, Sabattini T, et al. Effectiveness of sterile transparent dressing than the standard for attaching peripheral venous catheter (CVP) on the incidence of phlebitis: randomized controlled trial. Assist Inferm Ric. 2012;31(2):63-9.

12. Bausone-Gazda D, Lefaiver CA, Walters SA. A randomized controlled trial to compare the complications of 2 peripheral intravenous catheter-stabilization systems. J Infus Nurs. 2010;33(6):371-84.

13. Marsh N, Webster J, Mihala G, Rickard CM. Devices and dressings to secure peripheral venous catheters to prevent complications. Cochrane Database Syst Rev. 2015;(6):CD011070.

14. Gorski LA, Hadaway L, Hagle ME, Broadhurst D, Clare S, Kleidon T, et al. Infusion therapy standards of practice. J Infus Nurs. 2021;44(1S Suppl 1):S1-S224.

15. Alexandrou E, Ray-Barruel G, Carr PJ, Frost SA, Inwood S, Higgins N, et al. Use of short peripheral intravenous catheters: characteristics, management, and outcomes worldwide. J Hosp Med. 2018;13(5).

16. Boyce JM. Best products for skin antisepsis. Am J Infect Control. 2019;47(S):A17-A22.

17. Doesburg F, Smit JM, Paans W, Onrust M, Nijsten MW, Dieperink W. Use of infrared thermography in the detection of superficial phlebitis in adult intensive care unit patients: a prospective single-center observational study. PLoS One. 2019;14(3):e0213754.

18. Atay S, Sen S, Cukurlu D. Phlebitis-related peripheral venous catheterization and the associated risk factors. Niger J Clin Pract. 2018;21(7):827-31.

19. Gabriel J. Vascular access devices: securement and dressings. Nurs Stand. 2010;24(52):41-6.

20. Bernatchez SF. Care of peripheral venous catheter sites: advantages of transparent film dressings over tape and gauze. J Assoc Vasc Access. 2014;19(4):256-61.

21. De Bono S, Heling G, Borg MA. Organizational culture and its implications for infection prevention and control in healthcare institutions. J Hosp Infect. 2014;86(1):1-6.

22. Ezzelarab MH, Nouh O, Ahmed AN, Anany MG, Rachidi NGE, Salem AS. A randomized control trial comparing transparent film dressings and conventional occlusive dressings for elective surgical procedures. Open Access Maced J Med Sci. 2019;7(17): 2844-50.

23. Chunhasuwankul R, Owattanapanich N, Somcharit L, Pantheepo H, Prasanrat S, Yiengpruksawan A. A prospective randomized controlled trial comparing infection rates of the daily dressing and scheduled dressing of sutured traumatic wounds. Siriraj Med J. 2018;70(5):377-81.

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‌Postoperative Pain and Blood Loss of Non-use Compared to Partial-use of a Tourniquet in Bilateral Total Knee Replacement: A Randomized-Controlled Trial

Thada Wipatasinlapin, M.D.1,*, Surapon Atiprayoon, M.D.1, Peerawin Atiprayoon2

1Queen Savang Vadhana Memorial Hospital, Chonburi, Thailand, 2Triam Udom Suksa School, Bangkok, Thailand.

*Corresponding author: Thada Wipatasinlapin E-mail: fighter.thada@gmail.com

Received 11 September 2024 Revised 18 February 2025 Accepted 19 February 2025 ORCID ID: http://orcid.org/009-0002-0067-4470 https://doi.org/10.33192/smj.v77i6.271055

All material is licensed under terms of the Creative Commons Attribution 4.0 International (CC-BY-NC-ND 4.0) license unless otherwise stated.

INTRODUCTION

Currently, total knee arthroplasty (TKA) has become increasingly common, due to its efficacy to improve patients’ quality of life and reduce pain1 allowing those patients with knee osteoarthritis who failed conservative treatment, to regain their ability to walk normally again. In TKA surgeries, the use of a tourniquet has been employed to aid in the reduction of blood loss during the procedure, and improving intraoperative visualization for the operating surgeon.2-4

However, the use of a tourniquet in TKA surgeries remains a topic of debate. There are research studies supporting its use, and some supporting operations without using a tourniquet.5,6 While TKA with a tourniquet may reduce the operating time, it has been found to be associated with more complications. These complications include deep vein thrombosis, and an increase in occurrences of surgical-site infection, or bruising with signs of bleeding.7 Moreover, several research studies have also found that patients - in the group using a tourniquet - experience more postoperative pain.8 This is believed to be due to the tourniquet causing metabolic waste to accumulate in the thigh muscles, and in blood vessels around the area where it is applied.2

Latest evidence suggests that the most debating tourniquet-use technique is between NTU (Non-tourniquet usage) and BOO (Before Osteotomy in Operation), which involves using a tourniquet before starting the bone cutting, until wound closure. Despite numerous

meta-analyses, and randomized-control trials (RCTs), there is still no conclusive evidence on the most effective, and efficient method of using a tourniquet especially between these two techniques.9 This is because the data come from various experimental designs, with most of previous research data, being captured from studies of the outcomes of tourniquet usage in unilateral total knee arthroplasty. Hence, these studies often lack a crossover design, which could introduce confounding variables. Therefore, we designed a protocol which was a randomized-control trial with a crossover design, specifically studying the outcomes of tourniquet use in the bilateral total-knee arthroplasty of each limb in the same patient, aiming to provide clearer insights into the benefits of different tourniquet techniques.

MATERIALS AND METHODS

Inclusion and exclusion criteria

Patients diagnosed with bilateral severe knee osteoarthritis, meeting the inclusion criteria, were recruited at our institution from November 2022 to August 2024. We obtained an approval from the Institutional Review Board (IRB) of the Queen Savang Vadhana Memorial Hospital. This trial had been registered in clinical trial registry before participant enrollment (NCT06815445). The inclusion criteria were patients diagnosed with bilateral severe knee osteoarthritis, over 50 years of age. The exclusion criteria were patients having undergone previous knee surgery, being subject to uncontrolled

hypertension, coagulopathy, or recent knee sepsis, with an ASA physical status grade > 2, inability to use patient- controlled analgesia (PCA), such as communication, or cognitive issues, or those patients who were allergic to medications used in the treatment process.

Patients

20 patients (40 knees) were randomized into two groups with an allocation ratio of 1:1, determined by the various block randomization method employing a computer-generated program. Ten patients underwent NTU in the first operation and BOO in 3 months later. On the other hand, ten patients underwent BOO in the first operation and NTU in 3 months later. The two operations were spaced more than 3 months apart, as previous research indicates that this can significantly reduce morbidity and mortality, particularly concerning cardiovascular risk.10

On the day of the surgery, the orthopedic resident conducted the sampling method by opening a sealed envelope before the operation to determine which patients would undergo surgery without the use of a tourniquet (NTU) and which patients would have partial use of a tourniquet (BOO). Communication in the operating room would be taken place in the patient waiting area to prevent patients hearing the method of tourniquet use during that time.

Surgical technique and postoperative evaluation

The operations were performed by a single surgeon, an experienced orthopedic surgeon sub-specializing in knee arthroplasty. The surgeries involved several steps. Firstly, performance of spinal anesthesia, was carried out by an anesthesiologist. Next, was the application of an appropriately-sized, and positioned tourniquet to the patient’s thigh. Then, prophylactic antibiotics were administered intravenously, being given 30 minutes prior to surgery. This was followed by the intravenous administration of ketorolac, 30 mg and Tranexamic acid 1 g, being given 30 minutes before the skin incision was made. The surgeon made a midline incision on the skin, adopting a sub-vastus approach, using an intramedullary guide wire for femur, and extramedullary guide wire for the tibia cuts. A cemented prosthesis of Zimmer Nextgen was used – as it was in every operation. A tourniquet was inflated to the systolic blood pressure (SBP), plus 100 mmHg in the leg of patients undergoing partial-use of a tourniquet (BOO), at the time of the start of the bone osteotomy until skin closure. Finally, a compressive dressing was applied, and covered with a Robert Jones bandage.

The postoperative care included an adductor canal block, with 0.25% Marcaine 20 ml, applied by an anesthesiologist in the patient recovery room to alleviate knee pain on the side operated on. Prophylactic antibiotics were administered for 48 hours post-surgery. The intravenous pain medication was given through patient-controlled analgesia (PCA), along with opioid drugs as pain relief, for the first 3 days post-surgery. The same oral pain control medications were administered for all patients. A redivac drain was removed on first postoperative day. On the second, and third postoperative days, an occlusive dressing was applied to the wound, and the patient was encouraged to ambulate with a walker. All postoperative outcomes were performed by a single orthopedic resident. The primary outcome was the presence of postoperative pain, assessed in terms of the amount (mg) of opioid consumption, using the patient-controlled analgesia (PCA) machine at 24, 48, and 72 hours postoperative. The visual analog scale (VAS) score - ranging from 0-10 (0-2 was minimal pain, 2-4 was mild pain, 4-7 was moderate and 7-10 was severe pain) was also obtained at postoperative day 1 to day 3.

3. For the secondary outcomes, blood loss was calculated by comparing the maximal hematocrit drop between preoperative hematocrit levels and the postoperative levels on either the first or the fourth postoperative day. The time to ambulation, complications, including deep vein thrombosis (DVT), wound complications were recorded.

Sample size calculation

Calculated using STATA Version 14.0 with a power of 80% and an alpha of 0.05, the mean (SD) differences were referenced from the study by Kumar et al. (2015),

(11) which examined postoperative pain using VAS for pain with different tourniquet methods in patients undergoing knee replacement surgery. This resulted in a total population of 36 knees, divided into 18 knees per group. Factoring in a 10% dropout rate, the total population needed is 40 knees, with 20 knees per group.

RESULTS

The study collected data from patients with bilateral knee osteoarthritis who underwent staged bilateral total knee arthroplasty, with at least a 3-month interval between operations. In the first group of 20 patients, the initial surgery was performed without a tourniquet (NTU), and the second surgery used a partial tourniquet (BOO) applied to the other knee. In the second group of 20 patients, the initial surgery used a partial tourniquet (BOO), while the second surgery to the other knee was

Randomized (20 patients; n=40 knees)

Fig 1. CONSORT Diagram

performed without tourniquet (NTU). Thus, the study analyzed a total of 20 patients (40 knees). (Table 1)

There were no cases of loss to follow-up in the study. There was 1 case with a serious complication, being Deep Vein Thrombosis (DVT) in a knee operated on with BOO with statistically significant difference, and

5 cases of wound complications in BOO group, and 1 case in NTU group with statistical significance.

The primary outcome of interest in this study was the difference in pain levels during the early postoperative period, from day 1 to day 4 before the patients were discharged, assessed in terms of the morphine consumption.

TABLE 1. Baseline characteristics.

It was hypothesized that less pain would result in faster recovery, and earlier initiation of physical therapy, as well as greater patient satisfaction.

Results showed that the NTU group had a morphine consumption of 14.8 ± 8.3 mg in the first 24 hours after surgery, while the BOO group had a morphine consumption of 24.6 ± 10.8 mg during the same period. (Fig 2) The NTU group used significantly less morphine in the first 24 hours post-surgery with statistical significance (P value < 0.05). The following day, morphine consumption in the NTU group remained lower as shown in Table 2, but this difference was not statistical significance.

Consistent with these findings, the Visual Analog Scale (VAS) scores showed that the mean VAS score in the NTU group was 3.2, 3.9, 3.5, and 2.3 on postoperative

days 1, 2, 3, and 4 respectively. In the BOO group, the

mean VAS score was 4.3, 5.6, 4.8, and 4.1 on the same days. (Table 3 and Fig 3) There was a significant difference

in pain scores between the NTU and BOO groups on postoperative days 1-4 (P value < 0.05).

No significant differences were found in postoperative blood loss, as assessed by decrease in the maximum hematocrit, between the two groups. (Table 4)

No significant differences were found in time to ambulation between two groups.

DISCUSSION

Until now, based on a recent systematic review, and on a meta-analysis conducted by Cao et al. in 2021, there are six techniques of using a tourniquet in total knee arthroplasty surgery.9 The objective was to determine which tourniquet technique provides the best outcomes for patients undergoing surgery, and results in reduced postoperative complications, as well as facilitating early postoperative ambulation without pain. These techniques are:

Fig 2. Morphine consumption between groups during hospital stays.

TABLE 2. Comparison of morphine consumption between groups

TABLE 3. Comparison of VAS for pain between groups.

Fig 3. VAS for pain between groups during hospital stays

TABLE 4. Comparison of blood loss between groups.

1. Non-tourniquet usage (NTU): No tourniquet is used throughout the surgery.

2. Mid-way into the operation (MO): Tourniquet is used only during the period of cement implantation.

3. During the first half of operation (FHO): Tourniquet is used from skin incision until bone osteotomy is finished.

4. During the second half of operation (SHO): Tourniquet is used from cement implantation until wound closure is finished.

5. Before osteotomy in operation (BOO): Tourniquet is used from bone osteotomy until wound closure is finished.

6. Throughout the operation (TTO): Tourniquet is used from skin incision until wound closure is finished.

This recent systematic review and meta-analysis suggests that the best recommended technique is BOO (Before Osteotomy in Operation), which involves using a tourniquet before starting the bone cutting, until wound closure. This technique has been found to be the most effective in reducing blood loss, shortening the duration of surgery, and minimizing postoperative complications, based on comparative analysis.9

Despite the numerous meta-analyses and randomized- control trials (RCTs) conducted, a definitive conclusion on the most beneficial and effective use of tourniquets remains inconclusive.9,12-14 This is because the available data comes from studies with various methodologies, including many that have focused on the effect of tourniquets in unilateral total knee arthroplasty (TKA), rather than crossover studies. Such studies may be prone to confounding factors. Therefore, to better understand the benefits, research needs to be conducted using randomized-control trials with a crossover design, specifically examining the effect of tourniquets in patients undergoing bilateral total knee arthroplasty (TKA).

Currently, there are only three RCTs that have studied the effect of tourniquets in bilateral TKA. In 2015, Kumar et al. compared NTU with TTO, and found that patients in the NTU group experienced significantly less postoperative pain compared to those in the TTO group.11 Then, in 2016, Wang et al. compared FHO with MO, and found that the MO group had significantly less postoperative pain and blood loss compared to the FHO group, leading to better recovery, and physical therapy outcomes.3 Most recently, in 2017, Liu et al. conducted another study comparing NTU with TTO, and again found that the NTU group had experienced significantly less postoperative pain compared to the TTO group.8

However, none of these studies have compared NTU with BOO to determine which method is more effective, and has better outcomes. This is the rationale for the current study, which aims to compare non-use of

the tourniquet (NTU) with partial use of the tourniquet (BOO) in the context of bilateral TKA performed on the same patient with at least a 3-month interval between surgeries.

Therefore, the conclusion from this crossover RCT is that NTU provides better pain relief compared to BOO. The NTU group did not experience more blood loss than the BOO group, and the BOO group had one serious complication (DVT), and four wound complications (ecchymosis). Thus, this study supports that performing total knee arthroplasty without a tourniquet is more effective than other methods. The strength of this research lies in its use of a crossover RCT design to minimize confounding factors, and in its objective measurement of pain through morphine consumption, in milligrams. A limitation of this study is the sample size, which could be increased. Future research could focus on comparing the most effective tourniquet methods by conducting crossover design studies in bilateral total knee arthroplasty. Another limitation was the crossover design itself, the study might have inherent risks of carry- over effects, especially related to differences in recovery post-first surgery that could influence the outcomes of

the second surgery.

CONCLUSION

Performing total knee arthroplasty (TKA) without using a tourniquet, can reduce particularly the magnitude of the difference in pain and opioid consumption better than using the tourniquet as well as lack of significant differences in blood loss. This will allow for future clinical implications to determine that NTU may be preferable due to reduced postoperative pain and fewer postoperative wound complications.

Data Availability Statement

Data are available on reasonable request. Data may be obtained from a third party and are not publicly available. Data are available upon request to the authors.

ACKNOWLEDGEMENTS

I would like to thank Queen Savang Vadhana Memorial Hospital Institute for providing the necessary resources and funding for this project. Special thanks to my colleagues, Varissara Chatyanan and Chalathorn Kulthonchalanan, for their assistance with data collection and analysis.

DECLARATIONS

Grants and Funding Information

Queen Savang Vadhana Memorial Hospital Institute

Conflict of Interest

The authors declare no conflicts of interest.

Registration Number of Clinical Trial

NCT06815445

Author Contributions

Conceptualization and methodology, T.W., and

S.A. ; Investigation, T.W. ; Formal analysis, T.W., and P.A.; Visualization and writing – original draft, T.W. ; Writing – review and editing, T.W., and S.A. ; Funding acquisition, T.W., and S.A. ; Supervision, S.A. All authors have read and agreed to the final version of the manuscript.

Use of Artificial Intelligence

Not applicable .

REFERENCES

1. Luansritisakul C. Quality of Life after Total Knee Replacement at Siriraj Hospital, Thailand. Siriraj Med J. 2016;68(2):72-78.

2. Vandenbussche E, Duranthon LD, Couturier M, Pidhorz L, Augereau B. The effect of tourniquet use in total knee arthroplasty. Int Orthop. 2002;26(5):306-9.

3. Ozkunt O, Sariyilmaz K, Gemalmaz HC, Dikici F. The effect of tourniquet usage on cement penetration in total knee arthroplasty: a prospective randomized study of 3 methods. Medicine (Baltimore). 2018;97(4):e9668.

4. Arthur JR, Spangehl MJ. Tourniquet use in total knee arthroplasty. J Knee Surg. 2019;32(08):719-29.

5. Alexandersson M, Wang EY, Eriksson S. A small difference in recovery between total knee arthroplasty with and without tourniquet use the first 3 months after surgery: a randomized

   controlled study. Knee Surg Sports Traumatol Arthrosc. 2019; 27(4):1035-42.

6. Jawhar A, Stetzelberger V, Kollowa K, Obertacke U. Tourniquet application does not affect the periprosthetic bone cement penetration in total knee arthroplasty. Knee Surg Sports Traumatol Arthrosc. 2019;27:2071-81.

7. Matar HE, Platt SR, Gollish JD, Cameron HU. Overview of randomized controlled trials in total knee arthroplasty (47,675 patients): what have we learnt? J Arthroplasty. 2020;35(6):1729- 36.e1.

8. Liu Y, Si H, Zeng Y, Li M, Xie H, Shen B. More pain and slower functional recovery when a tourniquet is used during total knee arthroplasty. Knee Surg Sports Traumatol Arthrosc. 2020;28: 1842-60.

9. Cao Z, Guo J, Li Q, Wu J, Li Y. Comparison of efficacy and safety of different tourniquet applications in total knee arthroplasty: a network meta-analysis of randomized controlled trials. Ann Med. 2021;53(1):1816-26.

10. Wang KY, LaVelle MJ, Gazgalis A, Bender JM, Geller JA, Neuwirth AL, Cooper HJ, Shah RP. Bilateral total knee arthroplasty: current concepts review. JBJS Rev. 2023;11(1):e22.

11. Kumar K, Railton C, Tawfic Q. Tourniquet application during anesthesia: “What we need to know?” J Anaesthesiol Clin Pharmacol. 2016;32(4):424-30.

12. Tai TW, Lin CJ, Jou IM, Chang CW, Lai KA, Yang CY. Tourniquet use in total knee arthroplasty: a meta-analysis. Knee Surg Sports Traumatol Arthrosc. 2011;19:1121-30.

13. Alcelik I, Pollock RD, Sukeik M, Bettany-Saltikov J, Armstrong PM, Fismer P. A comparison of outcomes with and without a tourniquet in total knee arthroplasty: a systematic review and meta-analysis of randomized controlled trials. J Arthroplasty. 2012;27(3):331-40.

14. Deering EM, Hu SY, Abdulkarim A. Does tourniquet use in TKA increase postoperative pain? A systematic review and meta-analysis. Clin Orthop Relat Res. 2019;477(3):547-58.

‌Outcomes of Vascularized Lymph Node Transfer Treatment in Patients with Lymphedema

Boonyaporn Kotistienkul, M.D., Min Yongsuvimol, M.D., Nattanit Poungjantaradej, M.D., Sitthichoke Taweepraditpol, M.D.*

Division of Plastic Surgery, Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.

*Corresponding author: Sitthichoke Taweepraditpol E-mail: ntdclub13@gmail.com

Received 3 January 2025 Revised 28 January 2025 Accepted 28 January 2025 ORCID ID: http://orcid.org/0009-0008-1706-8032 https://doi.org/10.33192/smj.v77i6.272983

All material is licensed under terms of the Creative Commons Attribution 4.0 International (CC-BY-NC-ND 4.0) license unless otherwise stated.

ABSTRACT

Objective: This study aimed to evaluate the postoperative outcomes of patients with lymphedema treated with vascularized lymph node transfer (VLNT).

Materials and Methods: A retrospective chart review was conducted on 28 patients who underwent VLNT procedures at Siriraj Hospital between 2010 and 2020. Data collected included patient demographics, underlying diseases, previous cancer treatments, duration of lymphedema, etiology of lymphedema, donor and recipient sites, operative time, and limb circumference measurements were taken pre-operatively and at 1, 3, 6, and 12 months postoperatively. Additionally, postoperative complications were documented and analyzed.

Results: The review identified various underlying diseases associated with lymphedema, mostly linked to cancer. Noteworthy cancer treatments included node dissection, radiotherapy, and chemotherapy. The etiology of lymphedema varied, with multiple donor and recipient sites used for VLNT procedures. Postoperative limb circumference measurements showed significant percentage reduction in limb circumference, particularly in patients with upper limb lymphedema (p<0.05), while the lower limb showed no statistical significance. Postoperative complications included flap necrosis, flap congestion, flap hematoma, and cellulitis.

Conclusion: Our retrospective analysis underscores the effectiveness of VLNT procedures in managing lymphedema at Siriraj Hospital. Despite the diverse etiologies and prior treatments, VLNT demonstrated favorable outcomes in terms of limb circumference reduction, particularly in upper extremities. Further prospective analytic studies are warranted to validate these findings and optimize treatment protocols.

Keywords: Vascular lymph nodes transfer (VLNT); lymphedema; limb circumference; postoperative reduction; postoperative complication (Siriraj Med J 2025; 77: 427-435)

INTRODUCTION

Lymphedema is a chronic condition characterized by impaired lymphatic drainage, leading to limb swelling and tissue changes such as adipose tissue deposition and skin thickening.1,2 Lymphedema is classified into two etiological groups: primary and secondary lymphedema. While primary lymphedema is typically caused by congenital abnormalities or developmental defects in the lymphatic system, secondary lymphedema often results from surgical interventions, trauma, or underlying medical conditions that disrupt lymphatic flow, such as cancer.3-5

Common symptoms of lymphedema include pain, heaviness, swelling, decreased limb function, decreased quality of life, skin changes and recurrent infections. Diagnosis is often based on limb circumference or volume measurements, with differences of 2 cm or more in limb circumference compared to the contralateral limb, or volume differences of 200 mL or 10% from baseline, considered diagnostic.6

Management of lymphedema consists of nonoperative and surgical treatment. The nonoperative treatment started with decongestive therapy (CDT), while surgical treatment is mostly second-line therapy, offered after unsuccessful CDT. The surgical treatment can be classified into debulking procedures; direct excision (Charles or Sistrunk procedure) and liposuction, and physiologic procedures; lymphatic bypass and lymph node

transplants.7 The emerging surgical procedure including lymphaticovenous anastomosis (LVA), vascularized lymph node transfer (VLNT), liposuction and Charles procedure.8 VLNT involves transferring lymphatic tissue to an area of lymph obstruction to reconstruct the affected part. Lymph nodes for VLNT can be harvested from various donor sites, including the groin, submental region, supraclavicular, area, thoracodorsal region, lateral thoracic region, internal mammary region, deep inferior epigastric, lateral intercostal artery region, gastroepiploic, jejunal mesentery, mesoappendix and ileocecal area.9-15 The mechanism of VLNT consist of 2 main actions, of which are lymphatic pump, which is an immediate action and lymphangiogenesis which requires time. Therefore, VLNT is indicated for patients whose lymphatic vessels are impaired, higher stage of ISL, or failure of prior LVA.7 This study focuses on the surgical outcomes of patients treated with VLNT at Siriraj Hospital between 2010 and 2020. The analysis includes postoperative limb circumferences, complications, and percentage reduction

in limb circumference.

MATERIALS AND METHODS

A case series study was conducted with approval from the Institutional Review Board (IRB) of the Faculty of Medicine Siriraj Hospital No. 073/2566, COA No. Si 187/2023. The study focused on patients diagnosed

with lymphedema who underwent VLNT using lymph nodes harvested from the supraclavicular, submental, omentum, or other donor sites between 2010 and 2020. Demographic data, including age, sex, weight, height, and underlying disease(s) were collected. Patients were graded according to ISL staging, primary or secondary lymphedema, and the location of affected limb(s). Operational data included the donor site location and the duration of the operation were collected.

Limb circumferences were measured using a standardized approach with five anatomical reference points. For the upper extremities, measurements were taken at 20 cm above the olecranon (Site 1), 10 cm above the olecranon (Site 2), 10 cm below the olecranon (Site 3), 20 cm below the olecranon (Site 4), and mid palm (Site 5). For the lower extremities, measurements were taken at 20 cm above the patella (Site 1), 10 cm above the patella (Site 2), 10 cm below the tibial tuberosity (Site 3), 10 cm above the medial malleolus (Site 4), and the mid-arch of the foot (Site 5).

The outcomes were evaluated by comparing pre- operative and postoperative limb circumferences at 1, 3, 6, and 12 months. Results were calculated as the percentage of limb circumference reduction. Additional postoperative complications, including flap loss, flap congestion, hematoma, lymphocele, and infection were assessed and compared across donor site areas.

Baseline data were summarized using descriptive statistics, presented as medians with percentile 25 and percentile 75 (Q1, Q3), mean with standard deviations (SD), or frequencies with percentages as appropriate. Due to repeated measures of outcomes over time and missing data, generalized estimating equations (GEE) was employed. The dependent variable was percentage reduction in limb circumference from baseline and independent variable was time as a factor. To assess change over time, only subjects with at least two values of percentage reduction were included in GEE model. The correlation among repeated outcomes was tested using corrected quasi likelihood under the independent model criterion (QICC) and resulted in exchangeable correlation structure. Results from GEE were presented as estimated mean, standard error (SE) and p-value. A p-value of <0.05 was considered statistically significant. All statistical analyses were performed using IBM SPSS 29.

Ethical considerations were upheld throughout the study in accordance with the principles of the Declaration of Helsinki. Patient confidentiality was rigorously maintained by anonymizing patient data during both analysis and reporting.

RESULTS

Demographic Data

A retrospective analysis was conducted on 43 patient charts. Fifteen patients were excluded due to missing data or insufficient data. Thus, the final analysis included 28 patients, consisting of 26 females (92.9%) and 2 males (7.1%). This examination provided valuable insights into the complex management of lymphedema. The mean age of the patients was 61.1 ± 12.9 years the mean BMI was 27.4 ± 5.6 kg/m2. Gynecological cancer was the most common underlying condition, affecting 13 patients (46.4%), followed by breast cancer, which accounted for 8 cases (28.6%). Additionally, 6 patients (21.4%) were diagnosed with primary lymphedema, and one patient (3.6%) presented with lymphedema caused by other factors, such as trauma (Table 1).

Among patients with cancer-related lymphedema, prior treatments played a significant role in disease progression and management. The analysis revealed that 14 patients had undergone radiotherapy, 12 had received chemotherapy, and seven had undergone node dissection. These findings highlight the prevalence of these treatments and intricate relationship between cancer therapies and the development of secondary lymphedema, emphasizing the importance of comprehensive preoperative assessments and tailored surgical interventions to optimize patient outcomes.

The average duration of lymphedema before diagnosis by a specialized professional was 3.5 years. Concurrently, patients experienced an average of 1 episodes of infection. Among the 28 patients, 11 had undergone LVA prior to VLNT, one had a failed outcome from a prior VLNT procedure, and another had undergone liposuction before VLNT. Patients were also categorized based on their ISL staging. Seven patients (25.0%) were classified as ISL stage 1, 18 patients (64.3%) as ISL stage 2, and three patients (10.7%) as ISL stage 3. Regarding the location of lymphedema, 19 patients were diagnosed with lower extremity lymphedema, of whom 12 (42.9%) had lymphedema in the left leg and seven patients (25.0%) in the right leg. Additionally, nine patients presented with upper extremity lymphedema, with four patients (14.3%) experiencing lymphedema in the left arm and five patients (17.9%) in the right arm.

Surgical Outcomes and Parameters

The mean operative duration for VLNT procedures was 6.8 ± 1.5 hours, highlighting the complexity of microsurgical techniques employed. The average hospital stay was 11.0 days with mean follow-up time of 18.9 months. Among the 28 patients who underwent VLNT,

TABLE 1. Demographic Characteristics of Patients Who Received VLNT.

23 (85.2%) were categorized as having successful outcomes, while 4 patients (14.8%) were classified as failed surgeries, with one additional patient lost to follow-up. Postoperative complications were delineated into four categories: flap congestion, flap necrosis, hematoma, and cellulitis, affecting three, two, two and five patients, respectively. Overall, 14 patients (51.9%) experienced postoperative infections, while 13 patients (48.1%) remained infection- free. Additionally, patients were categorized based on donor and recipient sites. Donor sites included the supraclavicular (7 patients, 25%), submental (7 patients,

25%), and omental (14 patients, 50%) area. Recipient sites

included the axilla (1 patient, 3.6%), wrist (8 patients,

28.6%), thigh (3 patients, 10.7%), calf (8 patients,

28.6%), ankle (6 patients, 21.4%), and dorsum of the foot (2 patients, 7.1%) (Table 2).

Quantitative measurements, including preoperative and postoperative limb circumference assessments, were essential for evaluating treatment efficacy and tracking disease progression longitudinally. We calculated the percentage reduction in limb circumference by comparing preoperative measurements to postoperative results at 1, 3, 6, and 12 months, respectively. The findings revealed that patients with upper extremity lymphedema patients showed the highest percentage reduction in limb circumference at 12 months postoperatively, particularly at site 3, with a reduction of 9.68%. Conversely, patients with lower extremity lymphedema demonstrated the greatest

TABLE 2. Surgical Outcomes and Parameters of Lymphedema Patients Who Received VLNT.

percentage reduction in limb circumference at site 1, 6 months postoperatively, with a reduction of 3.56%. For upper extremity lymphedema patients, the percentage reduction in limb circumference progressed from most reduction to least at 12, 1, 6, and 3 months postoperatively, respectively. For lower extremity lymphedema patients, the percentage reduction in limb circumference, the order was 6, 3, 1, and 12 months, respectively, from most to least reduction. Fig 1 and 2 illustrate the postoperative percentage reduction in limb circumference relative to preoperative measurements, where a negative value indicates a decrease in limb circumference, while a positive value indicates an increase in limb circumference compared to the baseline.

The table below showed the mean percentage limb reduction with standard error (SE) in relation to the follow-up time at 1, 3, 6, and 12 months post-operatively (Table 3). The p-value showed significantly reduction in the upper extremities especially in 12 months post- operative (Table 3a), while the lower extremities showed most reduction at 6 months post-operative (Table 3b). The table illustrated that the upper extremities benefit from the VLNT treatment the most, with the significant reduction shown in most of the site and follow-up month, while the lower extremities showed no statistical significance in the percentage reduction. However, the dynamic and trend of the outcome can still be seen from the outcomes.

Fig 1. Postoperative Percent Reduction in Limb Circumference Among Upper Extremity Lymphedema Patients Compared to Preoperative Measurements

Upper extremities landmarks starting at 20 cm above olecranon (Site 1), 10 cm above olecranon (Site 2), 10 cm below olecranon (Site 3), 20 cm below olecranon (Site 4), and mid palm (Site 5). The (*) in the graph indicated statistical significance at the point of time and site.

Fig 2. Postoperative Percent Reduction in Limb Circumference Among Lower Extremity Lymphedema Patients Compared to Preoperative Measurements

Lower extremities landmarks starting at 20 cm above patella (Site 1), 10 cm above patella (Site 2), 10 cm below tibial tuberosity (Site 3), 10cm above medial malleolus (Site 4), and mid-arch of the foot (Site5)

DISCUSSION

The comprehensive retrospective analysis of 28 patient charts demonstrated the complexities of lymphedema management. The predominance of female patients in our study (92.9%) aligns with the higher prevalence of lymphedema among women, emphasizing the need for gender-specific considerations in lymphedema management. The mean age of our patient cohort (61.07 years) underscores the significance of lymphedema as a condition commonly affecting older individuals, necessitating age-appropriate strategies in treatment planning and care. Cancer also was a major contributor to lymphedema, with up to 75.0% of patients having cancer including gynecological cancers, particularly breast cancer.

The comparison of postoperative and preoperative limb circumference measurements provides valuable insights into the effectiveness of surgical interventions in reducing limb volume and managing lymphedema. Our findings highlight the dynamic nature of lymphedema management, with significant differences observed across various measurement sites and time points. Notably,

the findings revealed significant reduction in upper limb circumference with the highest percentage at 12 months postoperatively, with a reduction of 11.063%. Conversely, the greatest percentage reduction in lower limb circumference at 6 months postoperatively, with a reduction of 7.029%. These findings underscore the efficacy of surgical interventions, such as vascularized lymph node transfer (VLNT), in restoring lymphatic function especially in the upper extremities.

The variation in response to surgical interventions between upper and lower extremity lymphedema patients underscores the importance of tailoring treatment strategies to individual patient characteristics and disease severity. Furthermore, the calculated percentage reduction in limb circumference provides quantitative evidence of treatment efficacy, with upper extremity lymphedema patients demonstrating the highest percentage reduction at 12 months postoperatively and lower extremity lymphedema patients exhibiting the greatest reduction at 6 months postoperatively.

Compared to prior research, Brown et al. (2023) conducted an extensive review of studies evaluating

TABLE 3. Estimated mean of percent reduction at each month and site by Generalized Estimating Equations (GEE).

(a) Upper Extremities Circumference

Lower extremities landmarks starting at 20 cm above patella (Site 1), 10 cm above patella (Site 2), 10 cm below tibial tuberosity (Site 3), 10 cm above medial malleolus (Site 4), and mid-arch of the foot (Site 5)

outcomes following VLNT, addressing factors such as limb measurements, bio-impedance, Patient-Reported Outcome Measures (PROMs), cellulitis, and complications.22 While our study primarily focuses on limb circumference measurements and percentage reduction, our findings aligned with the broader consensus that VLNT offered significant advantages in managing lymphedema. The observed improvements in postoperative complications further validate the effectiveness of VLNT as a therapeutic approach for managing lymphedema. Similarly, Ciudad et al.

(2019) performed a comparative examination of clinical outcomes in upper and lower extremity lymphedema, suggesting potential benefits of VLNT, particularly in upper extremity cases.24 Our findings supported these findings, demonstrating favorable outcomes in upper extremity lymphedema, including significant reductions in limb volume over the follow-up period. However, our research not only showed the similar outcome, but also showed the dynamic nature of the limb reduction, where the circumferences can vary with time. This highlights

the potential advantages of VLNT in addressing upper extremity lymphedema and emphasizes the importance of tailoring treatment strategies to specific anatomical considerations.

Numerous studies have investigated lymphedema treatment, including comprehensive reviews of VLNT outcomes,16,17 complications,18-20 and meta-analysis of VLNT efficacy in lymphedema treatment.21-23 Meuli et al. (2023) conducted a meta-analysis of microsurgical treatments for lymphedema, concluding that both LVA and VLNT are effective in reducing the severity of secondary lymphedema.21 Brown et al. (2023) reviewed studies that evaluated outcomes such as limb-measurement, bio-impedance, Patient-Reported-Outcome-Measures (PROMs), cellulitis and complications at 1 and 2 years post-VLNT.22 Similarly, Ciudad et al.24 compared clinical outcomes between upper and lower extremity lymphedema, finding that VLNT may provide greater benefits for upper extremities, a result consistent with Ward et al.’s meta-analysis.23

A limitation of this study is the relatively small number of VLNT cases at Siriraj Hospital. Lymphedema is not the most common cause of limb edema and is often misdiagnosed,25 resulting in a limited number of lymphedema cases, and an even smaller cohort receiving VLNT treatment. Despite this limitation, our research focused specifically on patients with VLNT at Siriraj Hospital and included sequential follow-up evaluations. This approach provided more detailed insights into the progression of postoperative outcomes compared to methods used in previous studies.

These findings highlight the importance of longitudinal assessment and monitoring in evaluating treatment outcomes and guiding therapeutic decision-making in lymphedema management. By employing objective metrics such as limb circumference measurements and percentage reduction, clinicians can track disease progression, assess treatment response, and optimize patient care strategies. Moving forward, further research should explore the long-term efficacy and durability of surgical interventions, as well as identify predictive factors associated with treatment success across different patient subgroups. Overall, our study underscored the dynamic nature of lymphedema management and emphasized the importance of individualized, multidisciplinary approaches to optimize patient outcomes and enhance quality of life.

CONCLUSION

Our study underscores the importance of a multidisciplinary approach to lymphedema care, integrating

surgical expertise with comprehensive assessment and rehabilitation. Tailored interventions, such as VLNT, demonstrated significant potential in reducing limb volume and managing complications. The VLNT showed better result in reducing upper extremities lymphedema than in lower extremities lymphedema. The study also showed the dynamic result compared to time of follow- up. Therefore, the study suggests VLNT as a surgical option for upper extremities lymphedema patients. However, further analytic research is suggested to refine treatment strategies, identify predictive factors, and enhance patient care. By advancing our understanding and refining approaches, we can improve outcomes and enhance the quality of life for individuals living with lymphedema.

Data Availability Statement

The authors confirm that the data supporting the finding of this study are available within the article and its supplementary materials.

ACKNOWLEDGEMENTS

We are thankful for Chulaluk Komoltri, DrPH for assisting with the revision of the statistical analysis.

DECLARATIONS

Grants and Funding Information

None.

Conflict of Interest

The authors declare no conflict of interest.

Registration Number of Clinical Trial

Not applicable.

Author Contributions

Conceptualization and methodology, N.P, and S.T.

; Investigation, N.T., and S.T. ; Formal analysis, B.K., and

M.Y. ; Visualization and writing – original draft, B.K., M.Y., and S.T. ; Writing – review and editing, B.K., and

S.T. ; Supervision, S.T. All authors have read and agreed to the final version of the manuscript.

Use of Artificial Intelligence

The study does not use artificial intelligence for the manuscript.

Human Ethics Approval Declaration

The study was conducted with approval from the Institutional Review Board (IRB) of the Faculty of Medicine Siriraj Hospital No. 073/2566, COA No. Si 187/2023.

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‌Sonographic Assessment of Fetal Biometric Parameters and Maternal Height Ratio for Prediction of Cesarean Delivery due to Labor Dystocia

Wiarm Wadeng, M.D.1, Wanlaya Onwatanasrikul, M.D.1,*, Nop Khongthon, M.D.2, Monyada Pleankong, M.D.1, Sinart Prommas, M.D., Ph.D.1, Kornkarn Bhamarapravatana, Ph.D.3, Komsun Suwannaruk, M.D.4