SMJ

E-ISSN 2228-8082

Volume 75, Number 6, June 2023

Siriraj Medical Journal

The world-leading biomedical science of Thailand

MONTHLY ORIGINAL ARTICLE

Indexed by

THAILAND SECTION 1954

https://he02.tci-thaijo.org/index.php/sirirajmedj/index

E-mail: sijournal92@gmail.com

By Pramote Euasobhon, et al.

Siriraj Medical Journal SMJ

Volume 75, Number 6, June 2023

ORIGINAL ARTICLE

407 Prevalence and Type of Human Papillomavirus Infection in Thai Males with Anogenital Warts

Sukhum Jiamton, et al.

413 Association between Body Image Focused Social Media Usage (BSMU), Resilience, Attachment and Eating-related Problems among High School Students in Bangkok Nicholas Carriker, et al.

427 Stability of Extemporaneously Prepared Amitriptyline Hydrochloride Topical Preparations for the Treatment of Neuropathic Pain

Piyanuch Rojsanga, et al.

436 Long-term Efficacy of Genicular Nerve Ablation for Chronic Osteoarthritic Knee Pain: A Prospective Observational Longitudinal Study

Thanawut Jitsinthunun, et al.

445 Early Surgical Complications Following Transanal Endorectal Pull-through for Hirschsprung’s Disease

Ravit Ruangtrakool, et al.

454 The Benefit of Unattended Automated Office Blood Pressure Measurement on the White-coat Effect: A Cross-sectional Study

Chavalit Chotruangnapa, et al.

466 Efficacy Evaluation of Smartphone-based Stent Tracking Application in Follow-up Patients with Ureteral Stents: A Prospective Study

Tanapat Pansaksiri, et al.

473 Long-Term Outcomes After Right Ventricular Outflow Tract Conduit Placement

Juthamas Hannarong, et al.

SMJ

SIRIRAJ MEDICAL JOURNAL

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Executive Editor: Apichat Asavamongkolkul Editorial Director: Aasis Unnanuntana

Editor-in-Chief: Thawatchai Akaraviputh, Mahidol University, Thailand

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Adisorn Ratanayotha, Mahidol University, Thailand Chenchit Chayachinda, Mahidol University, Thailand Pornprom Muangman, Mahidol University, Thailand Phunchai Charatcharoenwitthaya, Mahidol University, Thailand

Varut Lohsiriwat, Mahidol University, Thailand

Andrew S.C. Rice, Imperial College London, UK

International Editorial Board

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Anusak Yiengpruksawan, The Valley Robotic Institute, USA Barbara Knowles, The Jackson Laboratory, USA Christopher Khor, Singapore General Hospital, Singapore Ciro Isidoro, University of Novara, Italy

David S. Sheps, University of Florida, USA

David Wayne Ussery, University of Arkansas for Medical Sciences, USA Davor Solter, The Jackson Laboratory, USA

Dennis J. Janisse, Medical College of Wisconsin, USA

Dong-Wan Seo, University of Ulsan College of Medicine, Republic of Korea Folker Meyer, Argonne National Laboratory, USA

Frans Laurens Moll, University Medical Center Ultrecht, Netherlands

G. Allen Finley, Delhousie University, Canada

George S. Baillie, University of Glasgow, United Kingdom

Gregory Bancroft, London School of Hygiene of Tropical Medicine, United Kingdom Gustavo Saposnik, St. Michael’s Hospital, Canada

Harland Winter, Harvard Medical School, USA

Hidemi Goto, Nagoya University Graduate School of Medicine, Japan Ichizo Nishino, National Institute of Neuroscience NCNP, Japan Intawat Nookaew, University of Arkansas for Medical Sciences, USA James P. Doland, Oregon Health & Science University, USA

John Damian Smith, Texas A&M University-San Antonio, USA John Hunter, Oregon Health & Science University, USA

Juri Gelovani, Wayne State University, USA

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

Keiichi Akita, Tokyo Medical and Dental University Hospital, Japan Kym Francis Faull, David Geffen School of Medicine, USA

Kyoichi Takaori, Kyoto University Hospital, Japan Marcela Hermoso Ramello, University of Chile, Chile Marianne Hokland, University of Aarhus, Denmark

Matthew S. Dunne, Institute of Food, Nutrition, and Health, Switzerland 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

Paul James Brindley, George Washington University, USA

Pauline Mary Rudd, National Institute for Bioprocessing Research and Training Fosters Avenue Mount Merrion Blackrock Co., Dublin, Ireland

Peter Hokland, Aarhus University Hospital, Denmark

Philip A. Brunell, State University of New York At Buffalo, USA Philip Board, Australian National University, Australia

Richard J. Deckelbaum, Columbia University, USA Richard W. Titball, University of Exeter, 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

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

Stanlay James Rogers, University of California, San Francisco, USA Stephen Dalton, University of Georgia, USA

Sue Fletcher, Murdoch University, Australia

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

Victor Manuel Charoenrook de la Fuente, Centro de Oftalmologia Barraquer, Spain Vincent W.S. Chan, University of Toronto, Canada

Wen-Shiang Chen, National Taiwan University College of Medicine, Taiwan 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

Yozo Miyake, Aichi Medical University, Japan Yuji Murata, Aizenbashi Hospital, Japan

Ampaiwan Chuansumrit, Mahidol University, Thailand Anuwat Pongkunakorn, Lampang Hospital, Thailand Jarupim Soongswang, Mahidol University, Thailand Nopphol Pausawasdi, Mahidol University, Thailand Nopporn Sittisombut, Chiang Mai University, Thailand Pa-thai Yenchitsomanus, Mahidol University, Thailand Pornchai O-Charoenrat, Mahidol University, Thailand Prapon Wilairat, Mahidol University, Thailand Puttinun Patpituck, Mahidol University, Thailand Rungroj Krittayaphong, Mahidol University, Thailand Saranatra Waikakul, Mahidol University, Thailand

Editorial Board

Sayomporn Sirinavin, Mahidol University, Thailand Suneerat Kongsayreepong, Mahidol University, Thailand Supakorn Rojananin, Mahidol University, Thailand Surapol Issaragrisil, Mahidol University, Thailand

Suttipong Wacharasindhu, Chulalongkorn University, Thailand Vasant Sumethkul, Mahidol University, Thailand

Vitoon Chinswangwatanakul, Mahidol University, Thailand Watchara Kasinrerk, Chiang Mai University, Thailand Wiroon Laupattrakasem, Khon Kaen University, Thailand Yuen Tanniradorn, Chulalongkorn University, Thailand

Journal Manager: Nuchpraweepawn Saleeon, Mahidol University, Thailand

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Office: His Majesty the King’s 80th Birthday Anniversary 5th December 2007 Building (SIMR), 2nd Fl., Room No.207 Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand Tel: 02-419-2888 Fax: 02-411-0593 E-mail: sijournal92@gmail.com

Prevalence and Type of Human Papillomavirus Infection in Thai Males with Anogenital Warts

Sukhum Jiamton, M.D., M.Sc., Ph.D.*, Pattriya Chanyachailert, M.D.*, Nuttagarn Jantanapornchai, M.D.*, Poramin Patthamalai, M.D.*, Jiraporn Jantaravinid, M.Sc., Ph.D.**, Yanisorn Nanchaipruek, M.D.*, Pichaya Limphoka, M.D.*, Yanin Nokdhes, M.D.*

*Sexually Transmitted Disease and HIV Division, Department of Dermatology, Faculty of Medicine Siriraj Hospital,., **Department of Biochemistry,

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

ABSTRACT

Objective: Low-risk (LR) human papillomavirus (HPV) infection is a recognized cause of anogenital warts (AGW). LR-HPV 6 and 11 are the HPV types that were reported to be associated with AGW. However, data specific to the HPV types that associate with AGW in Thailand are scarce. Accordingly, this study aimed to determine the prevalence of HPV in patients with AGW, and to investigate for association between HPV types and AGW among Thai males attending the sexually transmitted disease clinic of Siriraj Hospital – Thailand’s largest national tertiary referral center.

Materials and Methods: This prospective study was conducted at the Department of Dermatology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand during April 2017 to December 2019. Thai males with at least one AGW were included. AGW specimens were obtained, and HPV genotyping was performed at both the genital and perianal areas.

Results: A total of 43 Thai male participants (mean age: 37.3±13.8 years; range: 19-72) with AGW were enrolled. The rate of HPV positive detection at the genital area and the perianal area was 86.0% and 72.1%, respectively. The most common HPV types at the genital area were HPV 6, followed by HPV 11. Alternatively, the most common HPV types at the perianal area were HPV 11, followed by HPV 6.

Conclusion: The findings of this study suggest LR-HPV types 6 and 11 as the culprit pathogenic causes of AGW among males in Thailand. These findings further support and emphasize the importance of HPV vaccination for prophylaxis against both HPV and AGW.

Keywords: Human papillomavirus type; anogenital warts; clinical characteristics; sexually transmitted disease (Siriraj Med J 2023; 75: 407-412)

INTRODUCTION

Human papillomavirus (HPV) is the most common sexually transmitted infection worldwide1, and more than 200 different HPV types have been identified.2 HPV types can also be subcategorized according to their oncogenic potential into high-risk (HR) or low-risk (LR) types. Most HPV infections spontaneously resolve via host immune

response within a couple of years of onset. Persistence of HPV infection is essential for disease progression from latent infection to active infection.3 HR types are strongly associated with malignant disease, such as cervical, anogenital, and oropharyngeal cancers.4 LR types, such as HPV 6 and 11, are the most frequently detected types in anogenital warts (AGW).5,6 HPV induces hyperplasia

Corresponding author: Pattriya Chanyachailert E-mail: pattriya.cht@gmail.com

Received 3 April 2023 Revised 21 April 2023 Accepted 22 April 2023 ORCID ID:http://orcid.org/0000-0002-0928-5650 https://doi.org/10.33192/smj.v75i6.262215

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

and hyperkeratosis, which presents clinically as a wart.7 Perianal warts might occur with genital warts due to either local spread of infection or direct contact during anal coitus.8

The high-risk HPV types 16 and 18 cause approximately 50% of the estimated 26,000 annual cases of penile cancer whereas the low-risk HPV types 6 and 11 carry for about 90% of AGW.9 HPV patients are more likely to suffer from other sexually transmitted infections, such as syphilis, hepatitis B, hepatitis C, gonorrhea, chlamydia and human immunodeficiency virus (HIV).10 Treatment for AGW is normally lengthy and painful, and AGW has a significant adverse impact on quality of life.11 Since the HR HPV types can develop into cervical, anal, vulvar, and penile cancers, the genotyping of HPV infections is clinically important.

Data specific to the HPV types that associate with AGW in Thailand are scarce. Accordingly, the aim of this study was to determine the prevalence of HPV in patients with AGW, and to investigate for association between HPV types and AGW among Thai males attending the sexually transmitted disease (STD) clinic of Siriraj Hospital – Thailand’s largest national tertiary referral center which takes care cases of skin and STD such as syphilis12, herpes simplex virus infections.13

MATERIALS AND METHODS

Study population

This prospective study was conducted at the Department of Dermatology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand during April 2017 to December 2019. Thai males who attended the STD clinic who were aged >18 years, who were willing to enroll in the study and sign the consent form, and who were diagnosed with AGW by clinical manifestation were included. AGW specimens were obtained, and HPV genotyping was performed at both the genital and perianal areas. The protocol for this study was approved by the Siriraj Institutional Review Board (SIRB) (COA no. Si 677/2015).

Procedure

History taking and physical examination were performed in each participant. Specimens from lesions at the perianal and genital area were collected and stored at -80°C. A Roche Linear Array HPV Genotyping Test (Roche Diagnostics, Basel, Switzerland) was used to detect 37 HPV types, including 13 HR HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 66), and 24

LR HPV types (6, 11, 26, 40, 42, 53, 54, 55, 61, 62, 64, 67-

73, 81-84, IS39, and CP6108). A follow-up appointment

was made 2 weeks later to inform the study patient of the results of testing, and to decide upon a treatment plan. Each participant was treated at our center’s STD clinic.

Statistical analysis

Descriptive statistics were used to summarize patients’ characteristics and HPV types (mean plus/minus standard deviation for normally distributed continuous data; and number and percentage for categorical data). Statistical analysis was performed using PASW Statistics for Windows, version 18.0 (SPSS Inc, Chicago, IL, USA).

RESULTS

A total of 43 Thai male participants (mean age(sd): 37.3(13.8) years; range: 19-72) with AGW were enrolled. Table 1 shows the sociodemographic, behavioral/lifestyle, and clinical characteristics of study AGW patients. More than half (60.5%) of patients reported having more than one sexual partner, and most participants reported being single. Almost half (48.8%) of participants reported having a bachelor’s degree and being employed as an office worker. Regarding reported sexual preference, 72.1% were heterosexual, 18.6% were homosexual, and 9.3% were bisexual.

Some participants reported having a history of other STDs. The most commonly reported disease was gonorrhea (11.6%), followed by syphilis (6.9%). The other STDs reported was non-gonorrhea (2.3%), chancroid (2.3%), and Lymphogranuloma venereum (2.3%).

All 43 participants developed at least 1 genital or perianal wart. The most common site of lesion was the genitalia (67.4%), followed by the perianal area (23.3%). Only 9.3% of participants had AGW on both areas. More than three-quarters (83.7%) of lesions were verrucous papules, and 14% were flat lesions.

The HPV positive detection rate at the genital area and perianal area was 86.0% and 72.1%, respectively (Table 2). In this study, the incidence of individual HPV types was counted regardless of whether the patient had a single-type infection or a multiple-type infection. The most common HPV types at the genital area were HPV 6, followed by HPV 11, HPV 55 and HPV 51 as shown in Fig 1A. The most common HPV types at the perianal area were HPV 11, followed by HPV 6, HPV 18 and HPV 62, as shown in Fig 1B. The prevalence of HR HPV at the genital area and perianal area was 32.6% and 34.9%, respectively.

The rate of single-type infection was 37.2% at the genital area, and 34.9% at the perianal area. The rate of dual-type (2 HPV types) infection was 14.0% at the

TABLE 1. Sociodemographic, behavioral/lifestyle, and clinical characteristics of study anogenital wart patients (N=43).

Characteristics (%) N (%)

Marital status Single Married

Divorced/Widowed/Separated

28 (65.1)

9 (20.9)

6 (14.0)

Age (years) mean ± SD, (range) 37.3 ± 13.8, (19-72)

Highest education

TABLE 2. HPV positive rate and prevalence of low-risk and high-risk HPV types at the genitalia and perianal areas in study anogenital wart patientsa (N=43).

Location HPV types N (%)

Genitalia Positive 37 (86.0)

Low riskb 23 (53.5)

HPV, human papillomavirus

a HPV types were counted regardless of the status of single- or multiple-type infections.

b HPV type 6, 11, 40, 42, 53, 54 ,55, 61, 62, 67, 68, 73, 81, 82, 84,

CP6108, and IS39

c HPV type 16, 18, 39, 51, 52, 58, and 59

Fig 1. (A) The percentage for each type of HPV in genital area. The most common HPV types at the genital area were HPV 6, followed by HPV 11, HPV 55 and HPV 51. Others HPV typing included: HPV 39, 40, 42, 53, 54, 58, 59, 61, 62, 67, 81, 82, 84 and IS39.

Fig 1. (B) The percentage for each type of HPV in perianal area. The most common HPV types at the perianal area were HPV 11, followed by HPV 6, HPV 18 and HPV 62. Others HPV typing included: HPV 53, 54, 59, 67, 68, 73, 81, 84 and CP6108.

genital area, and 18.6% at the perianal area. The rate of three or more HPV type coinfections was 34.9% at the genital area, and 18.6% at the perianal area (Table 3).

TABLE 3. Frequency of single and multiple HPV type infections in anogenital wart patients.

Abbreviation: HPV, human papillomavirus

DISCUSSION

AGW is widely regarded as a benign disease that is caused by LR HPV. However, studies about HPV genotype distribution in Thai patients with genital warts are limited. To the best of our knowledge, this is the first study to evaluate the distribution pattern of HPV types at 2 anatomic sites in Thailand.

The average age of participants affected by AGW in our study was 37.3 years. This mean age is consistent with the age of manifestation of AGW reported by Clanner- Engelshofen, et al.10; however, adolescents are exposed to HPV earlier, and may develop AGW earlier due to a higher frequency of sexual activity and more sexual partners.

Most participants (72.1%) in our study reported their sexual orientation as heterosexual, which is consistent with the 76.0% rate reported by Dhumale, et al. (76%).8 Our prevalence of men who have sex with men (MSM) was 18.6%, which was similarly reported by Jiamton, et al.14

In the present study, HPV was identified in 86% (37/43) and 72% (31/43) of genital and perianal samples,

respectively. The most commonly isolated HPV genotype was HPV 6, followed by HPV 11 either alone or in combination with another HPV type. This result is similar to those from previous studies in Thailand, China, Mexico, Brazil, and the United States.15-18 Approximately 90% of anal squamous cell carcinoma can be attributed to HPV, especially HR-type (HPV 16 and 18).19 A screening program for high-risk patients can help to prevent or early detect anal cancer.20 HR HPV types at the anal area were also found in our study. Therefore, these high-risk cases were referred to a colorectal surgeon for clinical evaluation and follow-up.

In this study, we found multiple-type HPV infection to be common among patients with AGW. A study from Shanghai, China found the prevalence of multiple LR HPV infection to be relative low, but multiple HR HPV infection was common.21 A study from Italy reported that multiple HPV infections occurred by chance, and no evidence supporting higher tendency of coinfections in the specific HPV types.22

We swabbed both the genital and anal areas of patients who had a wart in either area. Our findings showed that even though some participants did not have a lesion at the anal area, they still showed as HPV positive at the anal area. The explanation for this is that AGW are often asymptomatic. Transmission can occur via skin-to-skin contact during sexual intercourse, oral sex, anal sex, or other contact involving the genital area.23 The burden of this disease could be lowered by increased HPV vaccination. Bivalent HPV vaccine covers HPV 6 and 11, quadrivalent HPV vaccine covers HPV 6, 11, 16, and 18, and 9-valent HPV vaccine covers

HPV types 6, 11, 16, and 18, 31, 33, 45, 52, and 58. All types of the vaccines can prevent the two predominant genital wart-associated HPV types (HPV 6 and HPV 11) in this study. According to our results, we implied that quadrivalent vaccines could prevent HPV infection at genital and perianal area at 44% and 51%, respectively. Moreover, the prevention rates increased to 50% for genital and 59% perianal area by the 9-valent HPV vaccine. However, this study was based on a very limited number of patients. We could not imply for the whole Thai population. Further studies in larger population in Thailand are needed.

In this study, we found a low prevalence of HPV 16 in AGW compared to other studies that recommended the use of quadrivalent HPV vaccine to protect against AGW.16, 21 However, the bivalent HPV vaccination might be suitable for prevention of AGW in Thai males. Future study is needed to evaluate cost-effectiveness compared between bivalent and quadrivalent HPV vaccines relative

to their impact in protecting against HPV-related diseases like cervical cancer and anal cancer.

AGW is a disease that is associated with both psychological and financial burden.24 Studies from Taiwan and the Philippines reported negative psychosocial impact of AGW on both well-being and health-related quality of life.25,26

Limitations

The notable limitation of this study was the lack of histologic confirmation to rule out intraepithelial lesion or squamous cell carcinoma (SCC), both of which can coexist with or appear similar to AGW.

CONCLUSION

The findings of this study suggest LR-HPV types 6 and 11 as the culprit pathogenic causes of AGW among males in Thailand. These findings further support and emphasize the importance of HPV vaccination for prophylaxis against both HPV and AGW.

ACKNOWLEDGMENTS

The authors gratefully acknowledge the patients that generously agreed to participate in this study.

Conflict of interest statement:

All authors have no conflicts of interest to declare relevant to the contents of this article.

Funding:

This study was supported by a grant from the Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand (grant no. [IO] R015933018).

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    Association between Body Image Focused Social Media Usage (BSMU), Resilience, Attachment and Eating-related Problems among High School Students in Bangkok

    
    

    Nicholas Carriker*, Sirichai Hongsanguansri, M.D.**, Chosita Pavasuthipaisit, M.D.***, Komsan Kiatrungrit, M.D.**

    *Master of Science Program in Child, Adolescent and Family Psychology, Affiliate Program Between Faculty of Medicine Ramathibodi Hospital, Faculty of Medicine Siriraj Hospital and National Institute for Child and Family Development, Mahidol University, Bangkok 73170, Thailand, **Department of Psychiatry, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand, ***Child and Adolescent Mental Health Rajanagarindra Institute, Department of Mental Health, Ministry of Public Health of Thailand, Chiangmai 50200, Thailand.

    
    

    ABSTRACT

    Objective: This study aimed to find the association among body image focused social media usage (BSMU), resilience, attachment, and eating-related problems among Thai adolescents.

    Materials and Methods: Cross-sectional descriptive research was conducted with a sample of 495 high school students from three schools in Bangkok. The participants answered an online questionnaire comprised of age, sex, height/weight, BSMU, Body-esteem Scale for Adolescents and Adults, Eating Attitudes Test, Inventory of Parent and Peer Attachment for Children, and the Thai Resilience Quotient. Descriptive statistics were used to analyze demographic information, body satisfaction, resilience, attachment, and eating-related problems. T-tests, chi-square, and multivariate logistic regression analysis were performed to explore the associations between these variables. Results: Mean (SD) age was 17.06 (0.805), with 307 female participants (62%). Time spent on social media was found to be associated with increased risk of binging (AOR (CI) = 1.71 (1.14-2.56)). BSMU was associated with increased risk of inappropriate eating attitudes, binging, purging and using laxative (AOR (CI) = 1.14 (1.03-1.27), 1.14 (1.06- 1.22), 1.20 (1.04-1.40), and 1.21 (1.09-1.34) respectively). Higher resilience was found to associated with lower risk in binging (AOR (CI) = 0.45 (0.21-0.97)). However, attachment is not associated with any of eating-related problems. Conclusion: BSMU usage was associated with inappropriate eating attitudes and behavior. Findings also suggest that higher resilience and stronger attachment were associated with lower risk of eating-related problems. The effectiveness of resilience and attachment improvement programs should be explored to help protect against eating problems.

    
    

    Keywords: Social media; body image; inappropriate eating behaviors; resilience; adolescent-parent relationship (Siriraj Med J 2023; 75: 413-426)

    
    

    INTRODUCTION

    Social media (SM) has revolutionized communication and relationships, but it has also been linked to negative consequences for mental health, including eating problems in adolescents.1,2 The issue of eating problems in adolescents

    is of significant importance and interest to the scientific community. Eating disorders are prevalent in adolescence and can have severe consequences for mental and physical health.3,4 Previous studies have shown that significant SM use predicts increased body dissatisfaction and can

    
    

    Corresponding author: Komsan Kiatrungrit E-mail: komsan.kei@gmail.com

    Received 1 February 2023 Revised 4 April 2023 Accepted 10 April 2023 ORCID ID:http://orcid.org/0000-0002-6975-114X https://doi.org/10.33192/smj.v75i6.261124

    
    

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

    
    

    lead to inappropriate eating behaviors such as binging and purging.1,5-7 However, most studies only found an association between general SM use and eating-related problems, such as number of SM platforms2,8, time spent on SM1, frequency of SM usage6,8, visiting or commenting on others’ profile9, general smartphone activities which might not related to body-image (e.g., browsing websites, sending and receiving text messages/e-mailing, watching TV shows).5 Additionally, not all aspects of SM are associated with eating-related problems, and internalization and appearance comparison may be responsible for the maladaptive effects of SM use.1,10,11

    Previous studies have examined the association between body image-related SM usage and eating-related problems, but have only focused on some body image- related SM activities such as photo-related activities (e.g., posting selfies, photo manipulation before posting, comments or likes on others’ selfies)12,13, and finding information related to body image on SM.14 However, people engage in various body image-focused social media usage (BSMU) activities (e.g., number of selfie posts, how important of like or comments on their pictures, how often they photoshop their pictures before posting, how their profile picture looks) which might affect eating-related problems.15-17

    SM usage has been found to have negative effects on eating-related problems, and identifying protective factors against these effects is important. Resilience is an important protective factor against many mental health problems18,19, and studies have shown that individuals with greater resilience have fewer body image issues.20-22 Emotional regulation, which is a components of resilience, has been found to plays a mediating role in the relationship between body image disturbance and disordered eating behavior.23 Healthy adolescent-parent attachment has also been identified as an important protective factors against problematic eating behaviors.24 However, spending more time on electronic media has been associated with lower quality attachment between adolescents and parent25-27, and growing up in a dysfunctional family type has been linked to a higher risk of developing eating disorders in. female adolescents.28 Berge et al., suggest that high quality family relationships and a sense of connection with parents may protect against problematic eating behaviors.29 However, few studies have examined protective effect of these factors against negative effect of SM use, particularly on eating-related problems.30,31

    There are many studies that found an association between SM activities and eating problems. However, most of them usually found an association between a few specific SM activities and eating-related problem as

    previously mentioned. Moreover, there are also limited studies on the protective effect of resilience and attachment against these problems. In this study, the researcher decided to explore 1) the association between BSMU and eating-related problems, 2) the association among resilience, attachment, and eating-related problems among high school students.

    
    

    MATERIALS AND METHODS

    Cross-sectional descriptive research was conducted to investigate the social media use behaviors, attachment, and resilience of students in grades 10 – 12 in the Thai educational system in Bangkok, and the effect on eating- related problems. The data were collected after the study received full approval from the institutional ethical review board of the Faculty of Medicine Ramathibodi Hospital, Mahidol University under the code MURA 2020/366. Participants and procedure

    Purposive sampling was used to choose three schools, two government schools and one international school following an international curriculum within Thai educational system in Bangkok, to be included in this study. Participants were in grades 10-12 in the 2nd semester of educational year 2020 and were selected in accordance with the teachers’ convenience. Sample size was calculated using the G*Power32,33 where effect size = 0.03, α error probability = 0.05, Power = 0.95 and number of predictions = 10. The total sample size required from the result of this calculation was 436. Students who could not read Thai, would not give assent to participating in the research, and those who did not complete the questionnaire were excluded. The data was collected from 15 to 31 October 2020 through an online questionnaire. After researchers provided details of the study and inform and consents were obtained, a QR code link to the online questionnaire was provided to participants. There were 529 questionnaires returned with 34 incomplete responses (6.43% of returned responses) resulting in a total of 495 participants (93.57%) (Fig 1).

    
    

    Measurement

    The survey consisted of six parts. The first part is demographic data which comprise questions regarding age, sex, weight/height, and grade in school.

    The BSMU questionnaire was developed by the researcher to investigate BSMU. This self-reported questionnaire consisted of 10 questions and was based on a review of studies on body image-related SM usage.1,5,7,8,9,34,35 The draft questionnaire was evaluated for face validity by three experts in psychiatry with experience in adolescent media use, and was revised based on their feedback. The

    
    

    
    

    Fig 1. Participant selection for the study

    
    

    questionnaire was then pilot-tested with ten students in Bangkok, and the questionnaire was revised based on feedback from the pilot test such as added a fill-in- the-blank option for the question about which social media platforms participants use most often, and the instructions for how to respond to the questions was modified to minimize confusion. The first question asked, “Which of the following SM platforms do you use most often?” The 11 most popular platforms from the website Digital 2020: Thailand36 and a fill in the blank choice for “others” were possible replies and more than one reply was permitted. Question 2 asked how much time the respondent spent on SM following superstars/ models and topics such as weight gain/loss and beauty. This response was fill in the blank. The next question (question 3) asked what the participant’s profile picture was (e.g., waist-up, full body, someone/thing besides the participant). The next six questions (question 4-9) asked, within the last month how often participants conducted body image focused activities such as, posting selfies, photoshopping, and tagging/un-tagging themselves in pictures. Response options ranged from never (0) to every time (3). The final question (question 10) asked how important likes received on selfies or pictures were to the respondent. The results from last seven questions, which have responses option ranged from not at all

    (0) to very important (3), were summed together and resulted in a possible total score of 0 – 21 points, with higher scores indicating greater engagement in body

    image-focused social media usage. The reliability for this scale was questionable (Cronbach’s alpha = 0.64). (the full version of BSMU questionnaire can be seen in supplementary material 1)

    
    

    Eating-related problems were measured with three instruments as following:

    1. The weight group was assessed using the “Nutrition Computation Program” (INMU-NutriStat), which was developed by Chittchana U and the Nutrition Institute of Mahidol University. This program computerized the nutrition of populations aged 1 day up to 19 years, and gave the results of nutrition status based on weight for age (w/a), height for age (h/a), and weight for height (w/h) for both genders. This program was widely used in a study about the weight status of children and adolescents in Thailand.37 In this study we used only w/h because they are relevant to our outcomes. The results for each nutritional status based on w/h were divided into 3 categories which are underweight (under -1.5 SD), average weight (-1.5 to +1.5 SD), and overweight (more than

       +1.5 SD) compared with norms for Thai children.37,38

    2. Body-esteem was collected using the 23-question Body-esteem Scale for Adolescents and Adults (BESAA) developed by Mendalson et al.39, and translated into Thai by Gunta A. (Cronbach’s Alpha = 0.9).40 Response options ranged from never agree (0) to always agree (4). Scores for each question were summed and divided into three ranges, low (0.0 – 30.6), medium (30.7 – 61.3), and high

       
       

       satisfaction (61.4 – 92.0) based on class interval analysis. Participants who had medium or high body satisfaction were grouped together to compare with those who had low body satisfaction. The reliability for this scale was excellent (Cronbach’s alpha = 0.9) and validity was assessed with two experts on woman health.40

    3. To evaluate eating attitudes and behaviors the EAT-26 (Eating Attitudes Test – 26 Questions) developed by Garner et al., and translated by Kaewpornsawan, (Cronbach’s Alpha = 0.7) 41,42 was used. Eating attitudes was evaluated with first twenty-six items of the questionnaires (e.g., I Am terrified about being overweight, I Avoid eating when I am hungry) with response options ranged from never (0) to always (3). Inappropriate eating behaviors was assessed using five additional questions which asked how often participants binge, purge, use laxatives/drugs for weight control, exercise longer than 60 minutes, and have participants lost/gained more than 9 kilograms in the past 6 months. Choices were, never, once/month or less, 2-3 times/month, once/week, 2-6 times/week, and once/day or more often. For binging, anything more than once/month, and answers other than never for purging and laxative/drug use were considered at risk. Exercising more than 60 minutes/ day was only considered at-risk if the reply was once/day or more. Weight fluctuation was a simple yes or no reply and participants would be considered at risk if they reply with “yes”. The first 26 questions were summed with scores over 12 indicating that the respondent was at risk for developing an eating disorder. The reliability of the scale was excellent (Cronbach’s alpha=0.86).

To analyze resilience, the Thai Resilience Quotient Questionnaire (RQ), developed by the Thai Ministry of Public of Mental Health43, was utilized and demonstrated good reliability (Cronbach’s alpha = 0.749). The RQ contains 20 questions with response options ranging from not true

(1) to very true (4). There were 3 subscales, emotional stability (questions 1-10), willpower (11-15), and problem- solving (16-20). Each subscale was graded separately and then a total RQ score was summed. Emotional stability was scored as, lower-than- (< 27), normal (27-34), and higher-than-normal (> 34). Willpower was scored as, lower-than- (< 14), normal (14-19), and higher-than- normal (> 19), and problem-solving as, lower-than- (< 13 normal (13-18), and higher-than-normal (> 18). Total RQ score was scored as, lower-than- (< 55), normal (55-69), and higher-than-normal (> 69). The Cronbach’s alpha value for this scale was 0.83 which indicate excellent reliability and face validity was evaluated with experts on mental health and psychology.43

Adolescent-parent relationship was evaluated using

only the parent part (28 questions) of the Inventory of Parent and Peer Attachment – Revised (IPPA-R).44 The questionnaire was translated into Thai by Lucktong, and demonstrated good reliability (Cronbach’s alpha = 0.88) and face validity was evaluated by psychology experts.45 Responses ranged from never (1) to always true (3). Questions were grouped into 3 subscales, communication (7), trust (8), alienation (8), and non-categorized (5 questions) which were negatively worded and reversed scored. Communication subscale included questions regarding seeking parent’s viewpoints, telling parents about problems, and parental support. Trust subscale was made up of questions related to parents respecting their child’s opinions, parental acceptance, trust, and understanding. Alienation questions concerned being ashamed around parents, getting easily upset and angry with parents, and lack of parental understanding. The higher the score on each subscale, the greater that attribute, and for total IPPA-R score, the higher the score the stronger the relationship.

Statistical analysis

Statistical analyses were performed using SPSS version

23.0 software (IBM, Armonk, NY USA). Descriptive statistics were used to detail demographics (sex, age, grade, weight group), and BSMU, BESAA, EAT-26, IPPA-R, and RQ. T-tests were used to analyze the number of SM accounts classified by sex, grade level, and weight group. Chi-square (X2) was used to analyze the association among BSMU and weight group, body- esteem, and inappropriate eating behaviors, and to analyze the association between resilience and attachment, and body-esteem, and inappropriate eating behaviors.

Multivariate logistic regression analysis was performed at a 5% level of significance. The associations between demographic data (sex and age), BSMU, IPPA-R, and RQ and outcomes such as weight status, body esteem, eating problems were analyzed using a multivariate logistic regression model. Adjusted Odd Ratio (AOR) was presented for determining the impact of those factors and outcome, while body weight was analyzed by linear regression as a continuous outcome. The model was used to find the association between demographic characteristics, BSMU, resilience, attachment, and eating-related problems.

RESULTS

Demographics, eating-related problems, resilience, and attachment

Out of the 495 participants, 307 were female (62%), and the mean age of all respondents was 17.01 (SD = 0.92). Participants were grouped into under-, average,

and overweight, resulting in a total of 140 overweight (28.3%) and 49 underweight (9.9%). The BESAA found 66 participants (13.3%) had low body-esteem. There were 56 participants (11.3%) in the EAT-26 high-risk group. There was a greater percentage of females admitting to binging (47.6% and 41.0%), purging (6.2% and 5.9%), and laxatives/drug use, (16.9% and 5.3%) at p-value <

0.001. A greater percentage of males excessive exercised (12.2% and 2.6%; p-value < 0.001) and had 9-kilogram

weight fluctuations (19.1% and 10.7%; p-value = 0.009). One hundred and eighty-two participants (36.8%) were in low total RQ group. Mean score on the IPPA-R was

58.45 (SD = 5.14). (Table 1)

Body image focused social media usage and association with eating-related problems

Female participants had a greater number of SM accounts (3.20 and 2.83), spent more time on SM (5.38 and 3.82 hours/day), and their overall BSMU score was higher than males (6.84 and 5.31 all at p-value < 0.001). The mean number of SM accounts and time spent on SM were 3.07 (SD = 1.20) and 4.79 hours/day (SD = 4.35) respectively (Table 1). BSMU mean scores of the overweight group (5.78; SD = 2.87) were significantly lower than average weight group (6.48; SD = 3.12) at p-value = 0.024, but not for the under- and the average weight group. Mean BSMU was higher for the EAT-26 high-risk group (7.09 and 61.5) at p-value = 0.029 and for those admitting to binging and laxative/drug use (6.87 and 5.76; 7.77 and 6.04; at p-value < 0.001) and purging (7.40 and 6.18) at p-value = 0.33. Those with binging behaviors spent more time on SM (mean = 5.36 hours) than those who did not (4.32 hours) at p-value =

0.008. Those admitting to laxative/drug use spent more time on SM (mean = 6.50 hours) than those who did not (4.54) at p-value = 0.008 (Table 2).

Association among resilience, attachment, and eating- related problems

Participants in lower RQ group (both total RQ and every subscale) tended to significantly have low body- esteem. Moreover, lower-than-normal willpower scores tended to be in the binging, purging, and laxative/drug use groups (p-value < 0.001, p-value = 0.046 and 0.015, respectively). Lower-than-normal RQ problem-solving subscale scores were mostly in the laxative/drug use group at p-value = 0.005, while those with lower-than-normal total RQ scores tended to be in the binging and laxative/ drug use groups at p-value = 0.005 and p-value < 0.001 (Table 3). As for attachment, higher parental alienation and IPPA-R total scores tended to be in the low body-

esteem group at p-value = 0.044 and 0.024 respectively (Table 2). Moreover, higher IPPA-R total scores tended to be in the purging group at p-value = 0.026 (Table 3).

Regression analysis for BSMU, resilience, attachment, and eating-related problems

The results found that increased time spent on SM is associated with being in the over-weight group (AOR =

1.07 (1.02-1.12)). However, the BSMU and total IPPA-R scores were associated more with a decreased risk for being in over-weight group (AOR = 0.93 (0.86-0.99) and 0.62 (039-099), respectively). The number of SM accounts is not associated with weight group and low BESAA. Additionally, Resilience (RQ) and IPPA-R are not associated with BESAA. (Table 4)

The higher number of SM accounts is associated with lower risk of purging (AOR 0.62, CI 0.42-0.93), while both time on SM and BMSU scores are associated with higher risk of binging (AOR 1.71, CI 1.14-2.56 and AOR 1.14, CI 1.06-1.22, respectively). In addition to binging, BMSU scores are also associated with being in the EAT-26 high-risk group (AOR 1.14, CI 1.03-1.27), risk of purging (AOR 1.20, CI 1.04-1.40), and risk of drug/ laxative use (AOR 1.21, CI 1.09-1.34). While participants who are in high willpower RQ subscale and normal total RQ groups tended to have lower risk of binging (AOR

= 0.18 (0.03-0.98) and 0.45 (0.21-0.97), respectively). Participants who are in high emotion RQ subscale tended to have higher risk for excessive exercise (AOR = 16.6 (1.63-169.1)). However, IPPA-R is not associated with any of those factors when analyzed by regression analysis. (Table 5)

DISCUSSION

The result of this study found that having multiple social media accounts, spending more time on SM and having higher BSMU was associated with an increased risk of inappropriate eating attitudes and inappropriate eating behaviors such as binging, purging, using laxative drugs. These findings supported our aims to find that not just overall social media usage, but specifically body-image focused social media usage which have effects on eating-related problems. Moreover, the study found that having higher resilience had a lower risk of binging. However, higher emotional stability (which is a subscale of resilience) associated with an increased risk of overexercise.

In this study, we found that 9.9% of participants were underweight and 28.3% were overweight. While the prevalence of overweight students was similar to a previous study in Thailand, which reported 29.3%

TABLE 1. Descriptive analysis of demographics, eating-related problems, resilience, and attachment.

Abbreviations: SM = social media, BSMU = body image focused social media usage, BESAA = Body Esteem Scale for Adolescents and Adults, EAT-26 = Eating Attitudes Test-26 item, kg = kilograms, RQ = Resilience Quotient, IPPA-R = Inventory of Parent and Peer Attachment – Revised, a = mean (SD), * = p-value < 0.05, ** = p-value < 0.01, *** = p-value < 0.001

Original Article SMJ

TABLE 2. Analysis of body image focused social media usage, resilience, parental attachment and association with weight group, and body-esteem

Abbreviations: BESAA = Body Esteem Scale for Adolescents and Adults, SM = social media, BSMU = body image focused social media usage, RQ = resilience quotient, IPPA-R = Inventory of Parent and Peer Attachment, a = mean (SD) and independent t-test was used to analyze, b = n (%) and chi-square test was used to analyze, c = statistically significant between frequencies or means of participants in underweight group and average weight group, d = statistically significant between frequencies or means of participants in overweigh, * = p-value < 0.05, ** = p-value < 0.01, *** = p-value < 0.001

https://he02.tci-thaijo.org/index.php/sirirajmedj/index Volume 75, No.6: 2023 Siriraj Medical Journal 419

Inappropriate eating attitudes

Inappropriate Eating Behaviors

Low

High

Binging

Purging

Laxative/Other Drug Use

Excessive Exercise

lost/gained weight > 9 kg/6 months

TABLE 3. Analysis of body image focused social media usage, resilience, attachment and association with inappropriate eating attitudes and behaviors (EAT-26)

Abbreviations: SM = social media, BSMU = body image focused social media usage, RQ = Resilience Quotient, a = mean (SD) and independent t-test was used to analyze, b = n (%) and chi-square test was used to analyze, * = p-value < 0.05, ** = p-value < 0.01, *** = p-value < 0.001

TABLE 4. Multivariate logistic regression testing association between BSMU, resilience, attachment and weight group, and body esteem (BESAA)

Abbreviations: SM Accts = social media accounts, Tm on SM = time on social media, BSMU = body image focused social media usage, RQ

= Resilience Quotient, Emo Stab = emotional stability, Prob Sol = problem solving, Comms = communication, Alien = alienation; Data were adjusted for sex and age; * = p-value < 0.05, ** = p-value < 0.01, *** = p-value < 0.001

overweight participants, the prevalence of underweight students was unexpectedly high. Our study found a rate two times greater than previous studies, which reported only 5.2% of participants as underweight.46 Further investigation is necessary to understand the reasons behind this discrepancy. One possible explanation could be the demographic differences between our sample and previous studies, as our sample had a higher mean age. Our study found that participants had a mean of 3.07 SM accounts, which is lower than previous studies.36,47 This could be due to the difference in ages of the respondents as studies have shown that the number of SM accounts increases with age (up to age 34).48 However, the mean number of hours spent on SM was higher, at 4.79 hours/ day, consistent with other studies reporting adolescents

spending 3–5 hours/day on SM.1,49,50 Our study also found that females had higher body image-related SM activities than males. which aligns with previous research on self- objectification.51,52 However, the COVID-19 pandemic and resulting regulations have led to an increased reliance on technology for social interactions and entertainment, which could have influenced the results of this study. Previous studies have shown an increase in social media use during the pandemic, particularly among adolescents.53,54 In addition, the pandemic might effect on various mental health problems among adolescents which might affect the results of eating-related problems in our study.

The current study found a lower prevalence of low body-esteem (13.3%) compared to previous study in Western countries, which have reported up to 27% of

TABLE 5. Multivariate logistic regression testing association between BSMU, resilience, attachment and inappropriate eating attitudes/behaviors (EAT-26)

High risk eating attitudes

p

Binging

AOR (CI)

p

Purging

AOR (CI)

Drug/Laxative use E

p

AOR (CI)

p

xcessive Exercise

AOR (CI)

Weight Fluctuation

AOR (CI)

p

AOR (CI)

p

SM Accts 1.10 (0.85-1.43) 0.477 0.98 (0.83-1.15) 0.783 0.62 (0.42-0.93) 0.020* 1.05 (0.82-1.34) 0.723 0.98 (0.68-1.40) 0.905 0.86 (0.68-1.10) 0.234

Time on SM 0.76 (0.40-1.45) 0.408 1.71 (1.14-2.56) 0.010* 0.59 (0.25-1.37) 0.217 1.01 (0.53-1.93) 0.997 2.08 (0.82-5.26) 0.120 1.17 (0.65-2.09) 0.599

RQ

Emotional low

Ref

Ref

Ref

Ref

Ref

Ref

Stability normal 0.88 (0.34-2.30) 0.800 1.67 (0.89-3.14) 0.110 0.93 (0.29-2.97) 0.906 0.66 (2.73-1.59) 0.352 1.60 (0.31-8.22) 0.572 0.47 (0.19-1.15) 0.099

high 1.19 (0.21-6.82) 0.841 2.05 (0.63-6.65) 0.233 0.34 (0.01-13.6) 0.565 0.80 (0.10-6.22) 0.833 16.6 (1.63-169.1) 0.018* 1.01 (0.22-4.59) 0.991

Willpower low

Ref

Ref

Ref

Ref

Ref

Ref

normal 1.11 (0.47-2.61) 0.819 0.93 (0.54-1.57) 0.776 0.69 (0.24-1.97) 0.493 0.88 (0.41-1.90) 0.749 2.30 (0.72-7.39) 0.162 1.46 (0.67-3.17) 0.337

high 1.88 (0.32-11.03) 0.485 0.18 (0.03-0.98) 0.047* 0.92 (0.54-1.57) 0.998 3.77 (0.28-51.5) 0.320 0.69 (0.05-9.95) 0.791 0.76 (0.12-4.82) 0.775

Problem low

Ref

Ref

Ref

Ref

Ref

Ref

Solving normal 1.08 (0.46-2.54) 0.854 1.03 (0.60-1.74) 0.926 0.86 (0.33-2.27) 0.757 0.69 (0.33-1.40) 0.302 0.60 (0.19-1.84) 0.372 1.14 (0.53-2.46) 0.731

high 0.75 (0.16-3.59) 0.715 0.64 (0.22-1.82) 0.397 0.41 (0.09-1.68) 0.997 0.27 (0.02-3.19) 0.297 0.67 (0.11-4.13) 0.668 0.77 (0.18-3.26) 0.718

Total

low

Ref

Ref

Ref

Ref

Ref

Ref

normal 0.74 (0.23-2.45) 0.626 0.45 (0.21-0.97) 0.041* 0.61 (0.15-2.46) 0.484 0.47 (0.16-1.37) 0.166 0.57 (0.09-3.54) 0.548 1.11 (0.38-3.26) 0.845

BSMU 1.14 (1.03-1.27) 0.015* 1.14 (1.06-1.22) <0.001*** 1.20 (1.04-1.40) 0.015* 1.21 (1.09-1.34) 0.001** 1.01 (0.87-1.17) 0.881 0.99 (0.91-1.09) 0.907

Abbreviations: SM Accts = social media accounts, Tm on SM = time on social media, BSMU = body image focused social media usage, RQ = Resilience Quotient; Data were adjusted for sex and age; * =

p-value < 0.05, ** =p-value < 0.01, *** = p-value < 0.001

adolescents having body image dissatisfaction.55 Cross- regional differences in the ideal female figure and body dissatisfaction have been reported, with Americans exhibiting greater body dissatisfaction.56 One study found that the ideal body weight is slimmer in Westernized countries as opposed to less socioeconomically developed or traditional societies.57 These finding may explain why this study which did not find an association between SM usage, resilience, attachment to parent, and body-esteem. This study also found that 11.3% of the participants had inappropriate eating attitudes, with a comparable rate between male and female participants (13.3% and 10.1%, respectively). These results are consistent with previous studies reporting that eating disorders affect 9 - 10% of the world population58,59, with no gender differences in frequency of disordered weight control and overall prevalence of eating disorders study in Singapore. Further studies are required to understand effect of culture and gender specific factors on increase prevalence of male eating-related problems in Asia.60

The study found that participant in the overweight group spent the most time on SM, which is consistent with previous studies linking greater time spent on SM with higher body weight.61 However, overweight participants in this study conducted less body image focused social media activities, which is supported by an Italian study that found women dissatisfied with their body image posted fewer selfies.61 These results may be attributed to overweight stigma and are consistent with previous study linking higher BMI with greater body dissatisfaction.62 In addition, participants spending more time on SM in the current study tended to be at-risk for binging, and those with higher BSMU scores had inappropriate eating attitudes and were at risk for binging, purging, and laxative/drug use. This is consistent with previous research showing that elevated appearance exposure on Facebook was significantly correlated with weight dissatisfaction, drive for thinness, thin ideal internalization, and self-objectification. Body image dissatisfaction has been shown to lead to inappropriate eating behaviors63, so it becomes a viscous cycle.

Higher resilience was associated with a lower risk for problematic eating behaviors in the current study, consistent with a previous research.64 Greater resilience has been shown to help adolescent cope with online risks and is associated with lower incidence of eating problems.65 Lower resilience is associated with a higher likelihood of demonstrating a variety of mental health problems, including eating disorders.66 Higher resilience may have “emotion-regulatory benefits” that mitigate the development of disordered eating behaviors67, and lead to

improved body image and less body image dissatisfaction.20 Our study revealed that higher parental attachment

was associated with lower risk of being in the overweight group. These findings are consistent with previous research that had shown weaker adolescent-parent communication wo be associated with unhealthy weight control behaviors, body dissatisfaction, and low self-esteem.68,69 Moreover, positive relationships with parents have been found to be significant predictors of body image satisfaction.62 Family cohesion has also been shown to be correlated with resilience, which is associated with emotional regulation and can mitigate the development of disordered eating behaviors.70 A healthy family environment and positive communication have been found to be significant protective factors against eating problems.29

The study suggest that parents and caregivers should monitor their children’s social media usage and educate them on how body-related content can affect their body- esteem. It also suggests that content creators should be made aware of the unintended effects of unrealistic body image content on adolescents. Schools should implement training programs to increase resilience in early years so that adolescents have established healthy eating habits and do not rely on social media for guidance. Programs to strengthen the adolescent-parent relationship can help build the child-parent bond, which can assist with both body image issues and potential eating problems.

Strengths and limitations

This is a few study which aimed to investigate the relationship between various social media activities centered on body image, resilience, parental attachment, and eating-related problems. However there are a number of limitations in this study. Firstly, this study was cross-sectional descriptive research, therefore a causal relationship could not be concluded. Secondly, due to the COVID-19 situation, many of randomized schools were unwilling to participate in this study, so purposive sampling was used to choose three schools to be included in this study. In addition, classrooms and students were selected based on teacher convenience, which may have introduced potential bias. Thirdly, this study relied on respondent self-report which can result in report bias. Fourthly, the low Cronbach’s alpha score of BSMU questionnaire indicates that the reliability of the scale may be limited. However, the BSMU questionnaire was developed to measure a complex construct such as body image-related social media use, which may have multiple dimensions. In addition, due to normal behaviors of SM usage which one might do each SM activity with different frequency (such as one might be more likely to click

“like” on pictures or comments, but rarely posting or vice versa). Therefore, these could result in poor Cronbach’s alpha values of the questionnaire. Further testing of the BSMU questionnaire in future studies with larger sample sizes to evaluate the psychometric properties of the questionnaire are recommended. Finally, this study was comprised of only students in the educational system in Bangkok, which could not be a good representation of the general population. Finally, the pandemic might have also affected various mental health problems among adolescents,71 which in turn might have influenced the results of eating-related problems in our study.

CONCLUSION

This study investigates the association between body-image focused social media usage and eating- related problems, as well as the relationships between resilience, attachment, and these problems among high school students. The study highlights the negative impact of social media on body image and eating behaviors and suggests that resilience and adolescent-parent relationship may serve as protective factors against these negative effects.

Declarations Ethical approval

This study received full approval from the institutional ethical review board of the Faculty of Medicine Ramathibodi Hospital, Mahidol University under the code MURA2020/366. The authors confirm that all the methods were carried out in accordance with relevant guidelines and regulations.

Informed consent

Written informed consent was obtained from all the subjects before answering the questionnaires.

Consent for publication

All participants and authors have approved the publication.

Availability of data and material

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

Conflict of interest statement

The authors have no conflict of interest relevant to this article.

Authors’ contribution

CN, KK, HS and PC conceived and designed the study and acquired the data. CN and KK analyzed and interpreted the data. CN and KK drafted the manuscript. The manuscript was critically revised by KK, HS and PC. CN, KK, HS and PC read and approved the final version of the manuscript.

ACKNOWLEDGMENTS

We thank the school directors and school teachers for their kind assistance in the data collection and the participants for cooperating in this study.

Funding

The authors received no funding for this study.

Financial disclosure

Authors have no Financial Disclosure to declare.

Abbreviations

SM = social media

SM Accts = social media accounts Tm on SM = time on social media

BSMU = body image focused social media usage RQ = Resilience Quotient

Emo Stab = emotional stability Prob Sol = problem solving Comms = communication Alien = alienation

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Stability of Extemporaneously Prepared Amitriptyline Hydrochloride Topical Preparations for the Treatment of Neuropathic Pain

Piyanuch Rojsanga, Ph.D.*, Anchalee Jintapattanakit, Ph.D.**, Doungdaw Chantasart, Ph.D.**

*Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Mahidol University, Bangkok 10400, Thailand, **Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok 10400, Thailand.

ABSTRACT

Objective: The aim of this study was to investigate the physicochemical and microbiological stability of extemporaneous amitriptyline hydrochloride (AMH) topical preparations for the treatment of neuropathic pain.

Materials and Methods: AMH tablets were triturated to produce fine powders with a mortar and pestle. These powders were levigated and separately incorporated into four compounding bases: hydrophilic petrolatum USP, anionic cream, cold cream USP, and pluronic lecithin organogel (PLO) having the concentration of 2%w/w AMH. Results: In the in vitro release study, the most significant amount of AMH was released from the PLO, followed by cold cream, anionic cream and hydrophilic petrolatum, respectively; therefore, the compounded AMH in cold cream and AMH in PLO were selected for the evaluation of the in vitro permeation and product stability. The permeation of AMH from PLO across human epidermal membrane was significantly greater than that from the cold cream. Product stability was characterized as having no remarkable change in color or texture and AMH remaining in the range of 90–110% of the initial concentration quantified by high-performance liquid chromatography. Compounded AMH in cold cream was stable at 2–8 °C and 30 °C for 60 days, and 40 °C for 30 days, whereas compounded AMH in PLO was stable at 30 °C and 40 °C for 14 days. There was no visible microbial growth in any of the samples.

Conclusion: Taken together with the in vitro permeation and product stability studies, the present study suggests that AMH in cold cream could be prepared and used as extemporaneous topical preparations with a beyond-use date of 60 days when kept at 2–8 °C and 30 °C.

Keywords: Amitriptyline hydrochloride; neuropathic pain; cold cream; pluronic lecithin organogel; extemporaneous topical preparations (Siriraj Med J 2023; 75: 427-435)

INTRODUCTION

Chronic pain is usually caused by an initial trauma, such as a back sprain or muscle strain.1 It is believed that chronic pain develops after nerves become impaired. Chronic pain is associated with a diminished quality of life, increased health expenditure, and high economic costs. It persists for months or years and can interfere with daily life activities, such as working, having a social life, and taking care of oneself and others. It has been

estimated that chronic pain affects 10 percent of the world’s population.2 However, the phrase “neuropathic pain” which reflects both peripheral and central sensitization mechanisms, came into common use only in the last decade. Important pathophysiologic mechanisms of neuropathic pain are sodium-and calcium-channel upregulation, spinal hyperexcitability, descending facilitation, and aberrant sympathetic-somatic nervous system interactions.3 Current recommended first-line

Corresponding author: Doungdaw Chantasart E-mail: doungdaw.cha@mahidol.ac.th

Received 3 March 2023 Revised 21 April 2023 Accepted 1 May 2023 ORCID ID:http://orcid.org/0009-0008-2231-0575 https://doi.org/10.33192/smj.v75i6.261621

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

treatments include antidepressants (tricyclic agents and serotonin-norepinephrine reuptake inhibitors) and anticonvulsants (gabapentin and pregabalin).3

Amitriptyline is a dibenzocycloheptene-derivative tricyclic antidepressant agent that acts upon many sites. It can act within the central nervous system by inhibiting neuronal reuptake of norepinephrine and serotonin. Moreover, amitriptyline can act within the periphery by blocking Na+, K+, and Ca2+ voltage-gated ion channels and various receptors (muscarinic, cholinergic, nicotinic, histaminergic, α2-adrenergic, adenosine, and N-methyl-D-aspartate receptors).4-6 Amitriptyline, administered orally, is currently one of the treatment options available for managing neuropathic pain. However, the following adverse effects have been reported for oral administration of amitriptyline: drowsiness, dizziness, dry mouth, constipation and sweating.7 Nowadays, topical treatments for managing peripheral neuropathic pain are gaining popularity due to the excellent safety profiles and preferences. Due to its physicochemical properties (MW 277.4 g/mole and log P 4.92),8 amitriptyline is a promising candidate for delivery as a topical analgesic. In a recent review, topically applied amitriptyline at concentrations between 2% and 10% were successfully used for clinical neuropathic pain treatment.9-12 Thompson and Brooks13 found that patients who received higher concentration of amitriptyline experienced greater pain relief, but there were also more reports of adverse effects, including systemic absorption and skin irritation at the site of application. To avoid these adverse effects, a topical preparation of 2% amitriptyline hydrochloride (AMH) was chosen. However, the information regarding the types of compounding bases and the formulations is limited. In addition, there are no marketed topical amitriptyline products currently available. In this study, AMH compounded with four compounding bases (i.e., hydrophilic petrolatum USP, anionic cream, cold cream USP, and pluronic lecithin organogel (PLO)) were prepared. The in vitro drug release was carried out in order to identify the formulations with suitable drug release profiles. Furthermore, in vitro skin permeation and stability studies were conducted to evaluate their potential for use as extemporaneous topical preparations for the treatment of neuropathic pain.

MATERIALS AND METHODS

AMH (≥98% purity analyzed by thin layer chromatography) was purchased from Sigma-Aldrich (St. Louis, MO, USA). The commercial AMH tablets (containing 25 mg per tablet) were kindly provided by the Government Pharmaceutical Organization, Thailand.

Tryptic soya agar (TSA) and sabouraud dextrose agar (SDA) were supplied by Becton, Dickinson and Company (Franklin Lakes, New Jersey). High-performance liquid chromatography (HPLC) grade methanol and acetonitrile were supplied by Honeywell Burdick and Jackson (Ulsan, Korea). All the other materials and solvents used were of analytical reagent grade.

Human abdominal skin (HEM) of female patients aged 30 – 60 years was obtained from abdominoplastic surgical operations (Department of Surgery, Yanhee General Hospital, Thailand). HEM, which includes the stratum corneum and viable epidermis, was separated from the dermis by heat separation technique as described by Chantasart et al.14 The use of human tissue was reviewed and approved by the committee on human rights related to human experimentation, Mahidol University, Thailand (COE. No. MU-DT/PY-IRB 2016/014.0208).

Preparation of AMH formulations

Four compounding bases (i.e., hydrophilic petrolatum USP, anionic cream, cold cream USP, and PLO) were prepared in accordance with the art, science, and technology of pharmaceutical compounding.15 These compounding bases were selected because of their frequency of use in many topical formulations. In addition, hydrophilic petrolatum, anionic cream, and cold cream are official USP ointment bases, and it has been reported that PLO promotes the release of hydrophobic drugs.16-19 Therefore, they were selected as the compounding bases in this study. The compositions and preparation of the four compounding bases are provided in the Supplementary Materials.

To prepare 2%w/w AMH in each compounding base, an appropriate amount of AMH tablets were weighed and triturated to produce fine powders with a mortar and pestle. The powders were levigated and incorporated separately into each of the compounding bases. Mineral oil was the levigating agent used with the incorporation of the drug powders into the hydrophilic petrolatum and cold cream, whereas purified water was the levigating agent used with the drug powders in the anionic cream and PLO. The required levigating agent was introduced to the fine powders in order to achieve a smooth paste. Each compounding base was then added to the prepared paste using the geometric dilution method. All AMH preparations were packed into plastic containers, as shown in Fig 1.

HPLC analysis for AMH

Experiments were performed on a Shimadzu LC-10A system (Shimadzu, Kyoto, Japan) equipped with a model

Fig 1. Appearance of the formulations in various compounding bases, which are (A) hydrophilic petrolatum USP, (B) anionic cream, (C) cold cream USP, and (D) PLO. White or yellowish color represents compounding bases (without drug). Pink color creams represent bases that 2% AMH was incorporated.

series LC-10AD pump, CBM-10A system controller, DGU-12 A degasser and an SPD-10A diode array detector with C8 column (5 µm, 150 mm×4.6 mm) (GL Sciences, Netherlands). The mobile phase consisted of a phosphoric acid, pH 2.0, and acetonitrile (60:40, v/v). The column temperature and flow rate were kept at 25 °C and 1 mL/ min, respectively. The diode array detector was set at 240 nm, and the injection volume was 50 µL.

Sample preparation

On the day of the analysis, the samples were placed at room temperature for 1 h, and 200 mg of each formulation (equivalent to 4 mg of AMH) was mixed with 10 mL of methanol in a 15-mL centrifuge tube. The mixture was then heated at 80 °C in a water bath for 10 min with occasional shaking. Each tube was then removed from the bath, sonicated for 10 min, followed by 5 min of vigorously shaking, before being promptly centrifuged. The supernatant was then transferred to a 100-mL volumetric flask. The extraction procedure was repeated twice, using 10 mL of methanol in the centrifuge tube each time. The combined supernatant in the volumetric flask was diluted with methanol to reach the desired volume, mixed thoroughly volume, mixed, and filtered with a polytetrafluoroethylene membrane of 0.45 µm before injection. The % of AMH remaining in each formulation was calculated using the calibration curve.

Method validation

The chromatographic method was validated for specificity, linearity, range, precision, and accuracy according to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guideline.20 Forced degradation studies on AMH in cold cream were carried out to investigate the

specificity of the method. The AMH in the cold cream base was exposed to water, 0.05 N hydrochloric acid,

0.05 N sodium hydroxide, and 0.3%w/v hydrogen peroxide at 80 °C for 2 h. The samples were then extracted as described in the sample preparation. The selectivity of the method was achieved as the peak purity of the AMH peak was more than 0.95. The method’s linearity was tested using AMH concentrations ranging from 10 to 100 μg/ mL, and the linear regression and correlation coefficient

(r) were calculated. Accuracy was measured by standard addition at three different concentrations of AMH (10, 20, and 40 µg/mL) to the AMH in cold cream. Then, the % recovery of AMH was calculated. The intra-day precision or repeatability of the method was estimated by calculating the relative standard deviation (%RSD) of a sample spiked with three concentrations of standard AMH from the recovery study (n = 9) on two different days and analysis of intermediated precision (n = 18).

For the in vitro skin permeation study, specificity was assessed by comparing the chromatograms of AMH in the receptor medium alone and each sample solution from receiving chamber of the cold cream and PLO. The linearity of the method was in the range of 0.63-10 µg/ mL. Accuracy was evaluated by standard addition at three different concentrations of AMH (1.25, 2.5, 5 µg/mL) to each sample solution obtained from the cold cream and PLO’s donor chamber. Precision was evaluated by analyzing the sample solutions at 8 µg/mL (n = 6) on the same day for repeatability and on two different days as well as analysis for intermediated precision (n = 12). Finally, the %RSD was calculated.

In vitro drug release study

The in vitro release of AMH from four formulations was studied using Franz diffusion cells with an effective area of ~2.40 cm2. Each formulation was spread onto a

regenerated cellulose membrane (Spectra/Por®4 MWCO 12,000–14,000, Spectrum Laboratories, Inc., Rancho Dominguez, California) that had been treated with citrate buffer pH 5.5. The receiver chamber was filled with a precise amount of degassed citrate buffer pH 5.5 (~10 mL) and continuously stirred with a magnetic stir bar. The temperature of receiver solution was maintained at 32 ± 1°C. An aliquot of 300 µL receiver fluid was collected at specified time intervals (i.e., 0.25, 0.5, 1, 2,

4, 6, 8, 12, and 24 h) and immediately replaced in the chamber with the same volume of citrate buffer pH 5.5 to maintain a constant volume. The AMH content in the collected sample was analyzed by HPLC. Data are expressed as the cumulative amount of AMH release per surface area (µg/cm2).

In vitro skin permeation study

The in vitro drug permeation of AMH from AMH in cold cream and PLO across HEM was studied using Franz diffusion cells. HEM (~4x4 cm2) was mounted on the diffusion cells with an effective area of ~2.40 cm2. A regenerated cellulose membrane was placed between the viable epidermis side of the HEM sample and the receiver chamber.14,21 Each formulation was spread onto the epidermis side of the HEM. The receiver chamber was filled with a precise amount of degassed citrate buffer pH

5.5 (~10 mL) and continuously stirred with a magnetic stir bar. The temperature of receiver was maintained at 32 ± 1 °C. An aliquot of 300 µL solutions were collected from the receiver chambers at specific time intervals (4, 6, 8, 10, 12, and 24 h), and then replaced with the same volume of fresh receptor media. The AMH content in the collected sample was analyzed by HPLC. Data are expressed as the cumulative amount of AMH permeation per surface area (µg/cm2).

Stability study

In order to study the stability of the AMH formulations, AMH in cold cream was studied under three conditions, including in refrigerator (2–8 °C), room temperature (30 °C), and an accelerated condition (40 °C). Poloxamer 407, a thermosensitive gel forming agent, changes to a fluid state at 2–8 °C; therefore, the stability of AMH in PLO was studied under two conditions, including 30 °C and 40 °C.

Physical stability testing

The physical characteristics of AMH in cold cream and in PLO were investigated. The physical appearance, color, homogeneity, phase separation, and texture were monitored at each sampling time point. The formulation

viscosity was measured using a rheometer (HAAKE RotoVisco 1 Rotational Rheometer, Therma Fisher Scientific, Germany) with a cone and plate (35/2° Ti) model at 5.00 s-1 shear rate at 30 °C for 5 min. The sample tests were conducted on days 0, 14, 30 and 60.

Chemical stability testing

Chemical stability testing was conducted with a quantitative analysis of AMH using HPLC. The sample tests were conducted on days 0, 14, 30, and 60.

Microbiological stability testing

The AMH in cold cream and in PLO kept under room temperature were tested for their microbiological specifications following the United States Pharmacopeia 41 (USP41) Chapter <61> Microbiological Examination of Nonsterile Products: Microbial Enumeration Test.22 The total aerobic microbial count (TAMC) was conducted using the pour plate method with TSA incubated at 30 °C to 35 °C for three days. In addition, the total combined yeasts and molds count (TYMC) was conducted using the pour plate method with SDA incubated at 20 °C to 25 °C for five days.

Data analysis

Data are expressed as mean ± SD, and statistical significance was determined using repeated measures and the Two-way ANOVA multiple comparisons test. All statistical tests were performed using GraphPad Prism version 7.00 for Windows (GraphPad Software, California). A p-value of less than 0.05 was considered significant.

Stability was defined as no dramatic changes in appearance, color or viscosity. Moreover, the initial AMH concentration (day 0) analyzed by HPLC was defined as 100%, and the subsequent concentrations of each time point were calculated as percentages of the initial concentration. According to the USP, the acceptable limit for most compounded pharmaceutical preparations is typically ± 10%, or within the range of 90.0% to 110.0

% of the active pharmaceutical ingredient.23,24

RESULTS AND DISCUSSION

HPLC method validation

The analysis of the cold cream base and forced degradation samples prepared in the same manner as the samples under the proposed chromatographic conditions showed no interference with the AMH peak, indicating the specificity of the method. Forced degradation is the degradation of AMH in cold cream in conditions that are more severe than accelerated conditions, which is

necessary to demonstrate the specificity of the methods to determine stability. Fig 2 shows the chromatograms of AMH compounded in cold cream. The various stability behaviors of AMH were observed when subjected to neutral (Fig 2B), acidic (Fig 2C), basic (Fig 2D), and oxidizing (Fig 2E) conditions. Although AMH in cold cream remained chemically stable when heated at 80 °C for 2 h (neutral hydrolysis), it degraded under the acidic, basic, and oxidizing conditions at a rate of 22.2%, 27.8% and 47.5%, respectively. The fact that the degradation peaks and AMH were separated under our chromatographic conditions with a peak purity of more than 0.95 indicated the reliability of the assay for stability evaluation.

For the HPLC analysis in the skin permeation study, the chromatograms of AMH in the receptor medium and the samples from the receiving chamber of either the cold cream base or PLO base showed no interference with regard to the AMH peak, revealing the specificity of the method. As shown in Table 1, HPLC method was found to be linear, accurate and precise for the assay of AMH in the formulations and skin permeation study.

Fig 2. Chromatograms of AMH compounded in cold cream under various conditions

(A)control, (B) heat condition, (C) acidic condition, (D) basic condition, and (E) oxidizing condition

Preparation of extemporaneous AMH topical formulations Four separate AMH topical formulations were prepared (Fig 1). Each formulation had a pink color and good spreadability. However, the AMH in hydrophilic petrolatum and the AMH in cold cream had a greasy texture and were difficult to wash out with water, whereas the AMH in anionic cream and AMH in PLO had a light non-greasy texture and were easy to wash out with

water.

In vitro drug release study

Because the drugs need to be released from the topical base before permeating through the skin, in vitro drug release tests from drug preparations across cellulose membranes are often performed before skin permeation studies.25 It is possible to determine how the physicochemical properties of the topical bases and the ingredients affect each formulation’s drug release profiles. The release profiles of AMH from the various topical bases over 24 h are shown in Fig 3. It is clearly illustrated that AMH exhibits the highest drug release performances from the PLO (5,025 ± 682 μg/cm2), followed by cold cream (1,609 ± 299 μg/cm2), anionic cream (484 ± 256 μg/cm2) and hydrophilic petrolatum (134 ± 33 μg/cm2), respectively. The results obtained could be explained by AMH’s physicochemical properties and the formulations of the topical vehicles.

Based on the fact that electrolytes dissociate in ion forms when dissolved in water, in the topical base containing water, AMH, the salt form of the weak base would dissociate into amitriptyline and hydrochloride. Consequently, amitriptyline is dissolved in an oil phase. Several studies have reported that the PLO promotes the release of hydrophobic drugs.16-19 Together with the weak affinity between the poloxamer and amitriptyline, the coexistence of organic and aqueous phases through the structurally well-defined micellar network of phospholipids of PLO, in which low water-soluble amitriptyline can be entrapped within the gel matrix,26 may facilitate the release of amitriptyline (expressed as AMH) from PLO.19 The presence of surfactants in the system can impact

the solubility of the hydrophobic drug and improve the drug release rate. The hydrophobic nature of the external environment of a w/o emulsion facilitates the release of the hydrophobic drug from the external oil phase.27 Therefore, the release of amitriptyline from cold cream would be faster than that from anionic cream (o/w emulsion). In the case of hydrophobic petrolatum, an absorption base, that contains the water-absorbing material of white wax, the ointment matrix was completely immiscible with water and the AMH was dispersed in the base.

TABLE 1. HPLC method validation data of AMH.

Fig 3. In vitro release profiles of AMH from 2%w/w AMH in various compounding bases. Data represent the mean ± SD (n=4-5).

Moreover, the drug molecules had limited mobility due to the viscosity of the ointment base. Consequently, the dissolution and dissociation of AMH likely occurred at or near the physical boundary.28 Together with the low water solubility of amitriptyline, the result was that the release of amitriptyline from the hydrophilic petrolatum was the lowest.

In vitro skin permeation study

Based on the in vitro release studies, it was found that cold cream and PLO are suitable for further skin permeation studies to examine the possibility of using AMH extemporaneous preparations as topical analgesics.

Fig 4 shows the cumulative amount of amitriptyline expressed as AMH in μg/cm2 transferred from PLO and cold cream to the receptor compartment of citrate buffer pH 5.5. Throughout the experimental period of 24 h, the PLO showed significantly higher levels of amitriptyline skin permeability (37.4 ± 6.9 μg/cm2) than the cold cream (20.3 ± 5.2 μg/cm2). These results seem to confirm the conclusions reached by several studies that the PLO provides enhancement of drug transport into or across the skin and is thus widely used in pharmaceutical compounding to enhance the skin permeability of many therapeutic drugs.26 The permeation enhancement effect of PLO is from its structural matrix. The PLO is a colloidal system

Fig 4. In vitro drug permeation profiles of AMH from 2%w/w AMH in PLO and 2%w/w AMH in cold cream. Data represent the mean ± SD (n=5).

that cylindrical inverted micelles of lecithin entrapped in the three-dimensional network of the external aqueous phase.29 The micelles of the surfactant disorganize the stratum corneum, promoting lipid fluidity, decreasing the barrier function and enhancing drug permeation through the skin.30

Stability study

Physical stability testing

The organoleptic properties of AMH compounded in cold cream and PLO remained relatively consistent in all storage conditions. However, AMH compounded in cold cream was slightly more viscous but still spreadable after 60 days stored at 2–8 °C. The same consistency was observed when the cold cream formulations were kept at 30 °C and 40 °C after 14 days. However, regarding the viscosity of the formulations kept at room temperature, AMH in cold cream had a lower viscosity (5,900 cps to 10,900 cps) than the AMH prepared in PLO (124,000 cps to 136,000 cps), as shown in Fig S1A and S1B, respectively. The viscosity of AMH in cold cream was significantly increased when kept at higher temperatures, namely 30 °C for 60 days and 40 °C for 30 days (5,900 cps to 10,900 cps) (p<0.05). For the AMH in PLO, the viscosity presented a slight change after being kept at 30°C (124,000 cps to 136,000 cps), and significant increasing after being kept at 40 °C (132,000 cps to 220,000 cps) for 60 days (p<0.05).

Chemical stability testing

The percentage of the initial concentration of AMH in the formulations at each time point and storage condition

are summarized in Table 2. AMH in cold cream base stored at 2–8 °C and 30 °C, had a significant decrease in the percentage of drug remaining after day 14 compared to day 0 (p < 0.05). However, after 60 days, the percentage of drug remaining was still within the acceptable range of 90–110 % of the initial AMH concentration. When AMH in cold cream preparations were stored at 40°C, there was a significant decrease in the percentage of drug remaining after day 14 and 30 (p < 0.05). Since the phase separation was detected in AMH in the cold cream after being stored at 40 °C for 60 days, i.e. some oil spreading on the surface of the preparation (Fig S2), the percentage of drug remaining was not reported. However, AMH compounded in PLO showed a significant increase in drug concentration after being stored at both 30 °C and 40 °C compared to day 0 (p < 0.05). After 30 days, the percentage of drug remaining of AMH at both 30 °C and 40 °C exceeded the acceptable range of drug remaining. This may be due to water loss from non-airtight plastic containers used in the study, resulting in increased potency of AMH.

Microbiological stability

The microbial content of the formulations of AMH in cold cream and AMH in PLO were determined. According to USP41, Chapter <1111> Microbial Examination of Nonsterile Product Acceptance Criteria for Pharmaceutical Preparations and Substances for Pharmaceutical Use, the total aerobic microbial count must have ≤200 cfu/g after the plate is incubated at 30 °C to 35 °C for 3 days. The total combined yeasts and molds count (must have

≤ 200 cfu/g after the plate is incubated at 20 °C to 25 °C

TABLE 2. Percentage of AMH (% drug remaining) in cold cream and PLO under various storage conditions.

Data represent mean ± SD (n = 4).

*NA = not available

for 5 days. Both formulations complied with the USP41 standard. After 60 days of the study period, both formulations in all conditions above were examined. Microbial growth was absent in all samples tested.

We were able to prepare 2%w/w AMH in hydrophilic petrolatum USP, anionic cream, cold cream USP and PLO. Significant drug release from the cold cream and PLO was found. Compounded preparations of AMH in cold cream and PLO were further studied for in vitro permeation and stability. The compounded preparations of AMH in cold cream were stable at 2–8 °C and 30 °C for 60 days and at 40°C for 30 days, whereas AMH in PLO were stored and found to be stable at 30 °C and 40 °C for 14 days. The organoleptic properties of AMH compounded in cold cream and PLO remained relatively consistent, and the AMH remaining concentration was within the range of 90–110% in all storage conditions. There was no visible microbial growth in any of the sample. Shakshuki et al.31 investigated in vitro amitriptyline permeation across simulated skin from 1%,5% and 10% formulations in each of 3 bases (Lipoderm base, Emollient cream, and Mediflo 30 PLO). They found that amitriptyline 5% or 10% compounded in Lipoderm base or Emollient cream has the highest drug permeation. Kung et al.32 determined skin drug delivery across porcine skin from a 4% amitriptyline formulation comprising isopropyl alcohol combined with propylene glycol or isopropyl myristate. They found that the high concentration of isopropyl alcohol in isopropyl myristate/isopropyl alcohol binary formulations greatly contributes to an increased skin permeation of amitriptyline. Based on the data generated through permeation experiments from previous and our studies, the higher drug permeation could potentially result in greater therapeutic efficacy.

Available evidence supports the effectiveness of topical amitriptyline alone and in combination with other agents (i.e, ketamine and lidocaine) in the treatment of neuropathic pain.12,33 Therefore, it is expected that the AMH topical formulations developed in this study could be used in clinical practice.

CONCLUSION

Based on the results of in vitro permeation and product stability studies in the present study, it is suggested that AMH in cold cream could be prepared and used as extemporaneous topical preparations with a beyond-use date of 60 days when kept at 2–8 °C and 30 °C. AMH in PLO can also be prepared and used as extemporaneous topical preparations with a beyond-use date of 14 days when kept at 30 °C, which is a shorter stability period than that of AMH in cold cream. Changing the plastic containers to glass containers or airtight containers may increase the beyond-use date, leading to significant cost savings for patients as these products tend to be expensive.

Declaration of conflicts of interest

The authors declare that they have no conflicts of interest with the manufacturers or suppliers of any of the products or materials in this study.

ACKNOWLEDGEMENTS

This research project is supported by Mahidol University (Basic Research Fund: fiscal year 2022) (Grant No. BRF1-030/2565). The authors would like to express our deep appreciation to Associate Professor Dr. Chuthamanee Suthisisang for her suggestion of the idea for this research project.

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Long-term Efficacy of Genicular Nerve Ablation for Chronic Osteoarthritic Knee Pain: A Prospective Observational Longitudinal Study

Thanawut Jitsinthunun, M.D.*, Pramote Euasobhon, M.D.*, Amornrat Suttijanuwat, M.D.*,**, Suratsawadee Wangnamthip, M.D.*, Pranee Rushatamukayanunt, M.D.*, Sukunya Jirachaipitak, M.D.*, Nantthasorn Zinboonyahgoon, M.D.*, Mohd Suhaimi Tajudin, M.D.*,***, Rapeepat Narkbunnum, M.D.****, Werasak Sutipornpalangkul, M.D.****

*Department of Anesthesiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand, **Department of Anesthesia, Chaophrayayommarat

Hospital, Suphanburi Province, Thailand, ***Anesthesiology and Critical care Department, Selayang Hospital, Selangor, Malaysia, ****Department of Orthopedic Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.

ABSTRACT

Objective: When patients with chronic osteoarthritis (OA) knee pain do not respond to conservative treatment and are not suitable for knee arthroplasty, radiofrequency ablation (RFA) of the genicular nerve is probably an alternative treatment. This study aimed to evaluate the efficacy and safety of genicular nerve ablation in severe osteoarthritic knee pain patients.

Materials and Methods: Patients with severe chronic OA knee pain were recruited and performed a genicular nerve block (GNB). The patients’ demographic data, numerical rating scale (NRS) at rest and on movement, Thai Oxford knee score (Thai OKS), Thai knee injury and osteoarthritis outcome score physical function short form (Thai KOOS-PS), timed up and go test, brief pain inventory, fall evaluation, and EuroQol 5D-5L were recorded. For the positive block patients (≥50% pain relief for 24 hours), genicular nerve RFA was performed under fluoroscopic or ultrasound guidance. All patients were followed up at the 1st, 3rd, 6th, 9th and 12th months.

Results: 21 patients were included in the study, but only 17 were completely followed up for 12 months. At the 12th month, genicular nerve RFA reduced the mean NRS on movement from 7.9±1.6 to 4.0±2.6 (p=.005), improved knee function (Thai OKS from 18.8±5.3 to 28.5±10.1; p=.006), but did not significantly improve quality of life (EuroQol-5D-5L from 0.43±0.20 to 0.69±0.33; p=.130). No adverse events were observed.

Conclusion: Genicular nerve radiofrequency ablation in severe chronic OA knee patients demonstrated significant pain relief and functional improvement for up to 12 months without serious adverse events.

Keywords: Knee pain; joints; osteoarthritis; radiofrequency ablation; genicular nerve; conservative treatment (Siriraj Med J 2023; 75: 436-444)

INTRODUCTION

Chronic knee osteoarthritis is a disease causing a worldwide health problem because patients suffer from pain, restricted movement, and functional disability1, leading to increased risks of morbidity and mortality.2 In

Thailand, the prevalence of knee osteoarthritis is almost 60% in the elderly.3,4

Regarding osteoarthritis of the knee, the clinical manifestations are pain, stiffness, and a limited range of motion, with the osteoarthritic change visible on X-rays. The

Corresponding author: Pramote Euasobhon E-mail: pramoteo@hotmail.com

Received 9 March 2023 Revised 31 March 2023 Accepted 7 April 2023 ORCID ID:http://orcid.org/0000-0001-5268-5476 https://doi.org/10.33192/smj.v75i6.261692

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

first step of management usually starts with conservative treatment, such as weight reduction5, quadriceps exercise6, lifestyle modification, medications for pain control7, acupuncture8, intra-articular steroid injection9, hyaluronic acid (HA) injection10,11, and platelet-rich plasma (PRP) injection.12 However, if the patients do not respond to conservative strategies, surgical management, especially knee arthroplasty, is the indicated treatment that can provide good pain relief and increase quality of life.13,14 Unfortunately, some patients are unsuitable for surgery because of age or medical comorbidities, and for these radiofrequency ablation (RFA) of the genicular nerve may be considered as an alternative treatment.15,16

Radiofrequency ablation (RFA) of the genicular nerve can be performed under fluoroscopic or ultrasound guidance to identify the structures around the knee and to denervate the sensory nerve supply to the painful structure, which helps to relieve pain and improve knee function.15

Although current several evidence showed the good short-term (3- to 6-month) efficacy of genicular nerve ablation for knee osteoarthritis17-19, data on the long-term one-year follow-up efficacy are still scarce. In the clinical practice guideline for knee osteoarthritis, denervation therapy is mentioned but with a limited strength of recommendation, so genicular nerve RFA may not be considered as a treatment option for knee osteoarthritis, especially in Thailand.20 Therefore, this study aimed to evaluate the efficacy and safety of genicular nerve RFA in severe osteoarthritic knee pain patients.

MATERIALS AND METHODS

This prospective observational study was conducted at the Pain Clinic, Faculty of Medicine Siriraj Hospital, Mahidol University, Thailand. After approval by the Institutional Review Board (COA no. Si 292/2019), informed consent was obtained from all participants.

Participants

Chronic osteoarthritic knee patients were recruited if they were 50 years old or over with moderate to severe pain (scoring ≥4 on the numeric rating scale), grades 3–4 according to the Kellgren–Lawrence classification, had refused knee arthroplasty within 1 year, and did not obtain pain relief with conservative treatments, including oral analgesics and physiotherapy, more than 2 months prior to the study.

The exclusion criteria included coagulopathy or bleeding disorders, systemic infection, infection around the knees, previous treatment with visco-supplements within three months, connective tissue diseases that

involved the knees, being on a pacemaker, unknown history of previous treatments, history of schizophrenia, major depressive disorder, and uncontrolled generalized anxiety disorders.

The participants were not allowed to receive other interventional treatments such as intra-articular steroid or visco-supplement injection during the study period. However, the participants could continually receive analgesics or physical therapy as they previously used.

Intervention

Baseline data were recorded as follows: demographic data, numerical rating scale (NRS) at rest and on movement, range of motion (ROM), Thai Oxford knee score (Thai OKS)21,22 Thai knee injury and osteoarthritis outcome score physical function short form (Thai KOOS-PS)23,24 timed up and go (TUG) test25, the Thai version of the brief pain inventory (BPI-T)26, fall evaluation questionnaire (12 questions, score ranging from 0–12, where 0 means the highest to 12 means the lowest risk of falling), and EuroQol 5D-5L.27

Diagnostic genicular nerve block procedure

Diagnostic genicular nerve block (GNB) under fluoroscopic or ultrasound guidance was performed with 0.5% bupivacaine 1 ml for each genicular nerve (superior medial, superior lateral, and inferior medial genicular nerves). Pain scores (i.e., NRS) were recorded before and after the nerve block for 24 hours. If the diagnostic block was positive (≥50% pain relief from baseline NRS for 24 hours), patients were then appointed for genicular nerve ablation.

Genicular nerve radiofrequency ablation procedure

Genicular nerve ablation was performed in the operating room under standard monitoring, with an aseptic technique and under sedation with fentanyl 1–2 mcg/kg. A 16G radiofrequency (RF) cannula, 10 cm long with a 10 mm active tip, was inserted to the target point (superior medial (SM), superior lateral (SL), and inferior medial (IM) genicular nerves) under fluoroscopic or ultrasound guidance depending on the interventionist’s preference (Figs 1 & 2). An RF probe was inserted into the RF cannula and connected to an RF generator (NT1100, NeuroTherm™, USA). Sensory and motor stimulation were tested, less than 0.5 volts and up to 2 volts, respectively, to identify the proper position of the RF cannula. Subsequently, 2% lidocaine 1 ml was injected for reducing pain before applying conventional radiofrequency ablation at 80 degrees Celsius, for 3 minutes for 2 cycles per target nerve.

Fig 1. Fluoroscopic guidance imaging of (1a) antero-posterior and (1b) lateral views of the knee joint demonstrated the position of the radiofrequency cannula at superior lateral and inferior medial genicular nerves.

Fig 2. Ultrasound guidance imaging of (2a) inferior medial (longitudinal view), (2b) superior medial (transverse view) and (2c) superior lateral (transverse view) genicular nerves accompanying vascular flow above the bony cortex.

Data collection and outcome measures

All of the patients were followed up at the 1st, 3rd, 6th, 9th, and 12th month after the procedure for clinical assessment and data collection. The primary outcome was the reduction of the mean NRS on knee movement at the 1st, 3rd, 6th, 9th, and 12th month after the procedure. The patients’ improvement in physical function and quality of life were evaluated by questionnaires (Thai OKS, Thai KOOS-PS, BPI-T, and EuroQol 5D-5L) for the secondary outcomes. The risk of a fall was also assessed for the secondary outcome using the fall evaluation questionnaire and TUG test. Adverse outcomes including infection, bleeding, bruising, skin burns and local numbness were also recorded. Patients who were unable to present at the Pain clinic were contacted by telephone and interviewed using those questionnaires except the TUG test.

Sample size calculation

The sample size calculation was based on a previous

study by Hunter28, considering the mean pain score of knee osteoarthritis of 6.6±2.5. We estimated that genicular RFA could reduce the pain score by approximately 30% at the 12th month. The sample size was calculated by the nQuery program (two dependent means) with an alpha error of 0.05 and study power of 80%. The calculated sample size was 13. We estimated a loss to follow-up of about 20%, and hence factored for 16 patients.

Statistical analysis

The collected data were analyzed using the Statistical Package for the Social Sciences (SPSS) software version

18.0 (SPSS Inc., Chicago, Illinois, United States). Data were described in terms of the frequency (number and percent of cases), mean±SD, and median (IQR) where appropriate. A repeated-measures 1-way analysis of variance and Friedman’s 2-way ANOVA were used to determine the continuous data with normal distribution variables and nonparametric variables, respectively, over

the 6 timepoints; that is, at baseline and 1, 3, 6, 9, and 12 months after the intervention. McNemar’s test was used for categorical variables compared with the baseline.

RESULTS

Study sample description

Thirty-one patients were recruited initially for a genicular nerve block. However, five patients were excluded due to a negative genicular nerve block, five

TABLE 1. Patients’ baseline characteristics.

Parameter Total (n = 21)

Age (years) 74.29±10.57

Sex (Female) 17 (81%)

Body mass index (kg/m2) 26.68±5.62

21, 5 patients were incompletely followed-up, as shown in Fig 3. However, one patient, who did not visit at the 9th month, returned to follow up at the last visit. Therefore, 17 patients were completely followed up at the 12th month.

The patients’ baseline characteristics are shown in Table 1. About half of the patients were Grade 4 osteoarthritis from radiographic findings. The mean pain duration before intervention was approximately 5 years. Fluoroscopic-guided genicular nerve RFA was performed in 7 out of the 21 included patients. No

Fig 3. Participants’ flow diagram

Kellgren–Lawrence grading scale

Grade 3 9 (42.9%)

Grade 4 12 (57.1%)

Data are presented as the mean±SD, median (min, max), or number (%).

participant had proceeded for knee arthroplasty surgery during the 12-month follow-up. However, one patient underwent total knee arthroplasty 28 months after the RFA treatment. Moreover, there was one patient receiving additional treatment of Thai traditional massage and acupuncture.

Effects of genicular nerve RFA on pain reduction

As for the primary outcome, the NRS on movement significantly decreased from 7.9±1.6 at baseline to 2.8±2.7, 3.8±2.3, 4.4±1.9, 3.6±1.9, 4.0±2.6 at the 1st, 3rd, 6th, 9th,

and 12th months, respectively, after genicular nerve RFA (p = .005), as shown in Fig 4.

Effects of genicular nerve RFA on physical function and quality of life

Regarding the secondary outcomes of knee function evaluation, the Thai OKS continued to increase over time from 18.8±5.3 at baseline to 28.5±10.1 at the 12th month, with a significant change from baseline since the 1st month (Table 2). The number of patients who were categorized in the moderate to severe OKS classification also decreased from baseline after the procedure (Table 2). The Thai KOOS-PS significantly decreased from baseline at the 1st, 3rd, and 6th months after intervention (Table 3). BPI-T and EuroQol 5D-5L utility were significantly improved in most of the follow-up months after the procedure, as shown in Table 3. However, the fall evaluation score did not show a significant difference from the baseline (Table 3). The median (IQR) time in the TUG test did not demonstrate a significant change over time from baseline, but the number of patients who had a TUG of more than 12 seconds (risk of falling) seemed to decrease over time, but not with statistical significance (Table 4). No adverse events were detected.

DISCUSSION

In this prospective observational study, we found that radiofrequency ablation (RFA) of the genicular nerve could effectively reduce the mean NRS on movement, and improve knee function and the quality of life of severe osteoarthritic knee patients who did not respond to conservative treatment.

Pain is a major problem for knee osteoarthritis patients. Pain sensation in the knee is conducted by genicular nerves, specifically the articular branches around the knee joint from the femoral, obturator, common peroneal, and tibial nerves.29,30 Blocking sensations from these sensory nerves should result in pain relief. Currently, RFA is one of the popular techniques to ablate the nerves originating from the treatment of low

back pain. Consequently, genicular nerve neurotomy by RFA has emerged, as first proposed by Choi et al.15, targeting the superomedial (SM), superolateral (SL), and inferomedial (IM) genicular nerves. According to the diagnostic nerve block, if the result is positive, patients should respond to genicular nerve ablation and could have a reduced NRS after the intervention.

As RFA denervates the genicular nerves, painful sensations should decrease for a longer period. The duration of the reduced painful sensations may depend on the magnitude of nerve ablation and the rate of regeneration of the nerve after RFA.31 One study in nerve regeneration after RFA found evidence of complete regeneration at 90 days after RFA.32 However, many clinical studies about knee osteoarthritis pain relief after genicular RFA showed that the effect of RFA may last for up to 6 to 12 months33-36, similar to our study. Moreover, some studies have demonstrated that pain relief after genicular RFA can even last for 24 months.28 Recently, Fonkoue and colleagues proposed that targeting two additional genicular nerves (the recurrent fibular nerve and infrapatellar branch of the saphenous nerve) could improve the pain relief outcome.37,38 However, this is still questionable and long-term study is still lacking on this topic. Regarding the RFA technique, a meta- analysis covering conventional, pulsed, and cooled RFA found no difference in analgesic outcome among these RFA techniques.39 Variations in the efficacy of genicular RFA among patients could result from variations in the patients’ genicular nerve anatomy, the knee position of the patient affecting the path of the nerve, or the interventional technique applied in targeting the nerves. Among the non-surgical management options for knee osteoarthritis, genicular nerve RFA is perhaps the most attractive treatment option. Pain relief from RFA genicular nerve seems to be more effective and lasts longer than intra-articular steroid injection, which is typically effective for 4–6 weeks.36,40 This results trend was also found when comparing genicular nerve RFA with intra- articular hyaluronic acid (HA) injection as well.35,51,42 Although intra-articular platelet-rich plasma (PRP) injection might manifest a favorable outcome at 6–12 months43, there has been no head-to-head comparison study performed between genicular RFA and intra- articular PRP injection. Nevertheless, Shen et al. found that the pain score was more significantly reduced when combining genicular nerve RFA with intra-articular HA

and PRP than both without RFA.44

Furthermore, beyond the pain improvement, genicular nerve RFA also improved knee function and quality of life as a consequence of reducing pain, such as

Fig 4. Numerical rating scale (NRS) of pain intensity at baseline and after genicular nerve ablation up to 12 months.

Data are presented as mean±SD.

P<.05 indicates statistical significance, compared to the baseline.

TABLE 2. Thai Oxford knee score (OKS) at baseline and after genicular nerve ablation up to 12 months.

Data are presented as the mean±SD or number (%).

*P<.05 indicates statistical significance, comparing to baseline.

TABLE 3. Thai KOOS-PS, BPI-T, EuroQol 5D-5L and fall evaluation at baseline and after genicular nerve ablation up to 12 months.

Data are presented as the mean±SD or median (IQR).

*P<.05 indicates statistical significance, comparing to baseline.

EQ-5D-5L, EuroQol Group questionnaire with 5 dimensions and 5 levels of severity; Thai KOOS-PS, Thai knee injury and osteoarthritis outcome score physical function short form; BPI-T, brief pain inventory.

TABLE 4. TUG test at baseline and after genicular nerve ablation up to 12 months.

Data are presented as the median (IQR) or number (%). TUG test, timed up and go test.

increasing the range of knee motion, more knee stability, better sleep, and being able to do more activities of daily living using the knee by themselves, including working, shopping, doing hobbies, and using public transport, as shown by the improved Thai OKS, Thai KOOS-PS, BPI-T, and EuroQol 5D-5L evaluations. The previous studies showed similar functional and quality of life improvement outcomes with the same and different questionnaires, including Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Global Perceived Effect (GPE).15,28,36 Although we found a non-homogenous result from each questionnaire at each time point, the trend for the score seemed to be ameliorated.

In our study, we found no different improvement in the risk of a fall from the fall evaluation questionnaire, which might have been because of the already low risk of a fall in the baseline characteristics of the patients (median score of 10 out of 12). The median time for the TUG test and the number of patients who had a TUG test time over 12 seconds (risk of falling) seemed to be lower after genicular nerve RFA, although without statistical difference. Therefore, the improvement in the falling risk was not clear. However, we might interpret the findings as suggesting that genicular nerve RFA did not increase the risk of falling or the walking ability. However, the pain relief would encourage the patients to participate in an intensive rehabilitation and physiotherapy program, which could indirectly reduce the falling risk.

Genicular nerve RFA is quite a low-risk procedure. We did not detect any significant adverse events after the procedure. Most previous studies about genicular nerve RFA did not report any major adverse events45, while some studies found only mild localized side effects.17

Nevertheless, there were some case reports about some serious side effects of genicular nerve RFA, including knee hematoma or hemarthrosis, septic arthritis, severe skin burn, tendon injury, and complex regional pain syndrome (CRPS).46-50

There are some limitations of our study to note, including the small sample size. This was in part due to the COVID rules at the time of the pandemic, where many elective cases in the hospital were postponed. A larger sample size should be considered in further study to ensure the efficacy and safety of genicular nerve ablation. Also, a sham-controlled study, the prevention of fall-associated morbidity and mortality, and the impact of pain-free rehabilitation and muscle strengthening should be considered in further studies.

CONCLUSION

Genicular nerve RFA demonstrated efficacy in pain relief and functional improvement of severe osteoarthritis of the knee for up to 12 months after the procedure without any serious adverse events. This intervention might be considered as an alternative treatment option, especially in patients who could not undergo knee arthroplasty.

ACKNOWLEDGMENTS

The authors are grateful for statistical advice from Miss Julaporn Pooliam and all the administrative support from Miss Nattaya Bunwatsana. Thanks also to Prof. Andrew Rice for his constructive comments on the preparation of this manuscript and International College for Sustainability Studies of Srinakharinwirot University for professional English proofreading and editing.

Conflict of interest

All authors declare no personal or professional conflicts of interest.

Funding

This research project was supported by the Faculty of Medicine Siriraj Hospital, Mahidol University, Grant Number (IO) R016335011.

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    Early Surgical Complications Following Transanal Endorectal Pull-through for Hirschsprung’s Disease

    
    

    Ravit Ruangtrakool, M.D., Piyaporn Krajangjit, M.D.

    Division of Pediatric Surgery, Department of Surgery, Faculty of Medicine Siriraj Hospital, Bangkok 10700, Thailand.

    
    

    
    

    ABSTRACT

    Objective: The purpose of this study was to examine factors affecting early complications following transanal endorectal pull-through (TERPT) in patients with Hirschprung’s disease.

    Materials and Methods: Retrospective chart reviews of patients with Hirschsprung’s disease who underwent TERPT/ abdominal assisted TERPT at Siriraj Hospital between January 2009 and December 2019 was carried out. Results: The overall complication rate was 26% (43/163). The complications were as follows: 14 cases of anastomotic strictures (32.6%), five cases of abscess at anastomosis (11.6%), and three cases of anastomotic leakages (7.0%). In regards to preoperative bowel preparation, when comparing those with and those without post-operative complications, the amount of NSS for rectal irrigation (ml/Kg), duration required (days), and duration of changed diet (days) were the same. Colostomy prior to a pull-through operation could not prevent post-operative complications following endorectal pull-through (p = 1.000). The incidences of early complications following TERPT and abdominal assisted TERPT was the same (p = 0.344). Abdominal assisted TERPT had a higher incidence (4%) of anastomotic leakages whereas TERPT had a higher rate of anastomosis strictures (12%) compared to o abdominal assisted TERPT (5%). The higher the transitional zone, the higher the complication rate. Anastomotic leakages, the most serious complication, rarely occurred following TERPT in the low transitional zone.

    Conclusion: There was no significant risk factor associated with early surgical complications following TERPT. Abdominal assisted TERPT should be selected properly according to the level of transitional zone. The complications correlate with whether a perfect pull-through operation could be performed or not.

    
    

    Keywords: Hirschsprung; endorectal pullthrough; complications; anastomosis; bowel preparation (Siriraj Med J 2023; 75: 445-453)

    
    

    INTRODUCTION

    Hirschsprung’s disease (HD) is caused by the absence of ganglion cells in the myenteric and submucosal plexus of the colon, resulting in a lack of propagation of the peristaltic wave of the colon. The incidence of HD is approximately 1 in 5,000 live births.1 Effective surgical treatment includes resection of the aganglionic portion of the bowel and identification of normally ganglionated proximal bowel with a leveled coloanal anastomosis. Many operative approaches to correct HD are derived from original concepts by Swenson, Duhamel, and Soave-Boley.2-4 The standard Soave-Boley endorectal

    
    

    pull-through procedure uses both the abdominal and transanal approach3,4 and was popularized after the introduction of the laparoscopic pull-through.

    The Soave-Boley endorectal pull-through procedure was transformed into a solely transanal approach named “transanal endorectal pull-through (TERPT)” by L De la Torre and J A Ortega in 1988.5-7 If the transanal approach cannot be performed perfectly, a combination of abdominal and transanal approaches, named “abdominal assisted transanal endorectal pull-through,” (abdo + TERPT) is used.

    
    

    
    

    Corresponding author: Ravit Ruangtrakool E-mail: sisuped@mahidol.ac.th

    Received 10 March 2023 Revised 18 April 2023 Accepted 2 May 2023 ORCID ID:http://orcid.org/0000-0001-8162-2941 https://doi.org/10.33192/smj.v75i6.261710

    
    

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

    During the transanal endorectal pull through procedure, a submucosal dissection of the rectum after a circumferential incision of the rectal mucosa is performed. Following a submucosal dissection, a seromuscular layer of the rectum is incised circumferentially. A mucosectomy of the rectum, leaving a muscular cuff is also performed. The ganglionated colon is pulled through the aganglionic rectal cuff, and a coloanal anastomosis is performed.5-7 When the transition zone is proximal to the mid- sigmoid colon, abdominal assisted transanal endorectal pull-through is considered.6 A pedicled colon flap must be developed to provide adequate length for colon pull- through. In this situation, it might be necessary to ligate and divide either the inferior mesenteric artery just distal to its origin from the aorta or the left colic artery just after it rises from the inferior mesenteric artery. By ligating these vessels at these sites, the arterial supply through

    the marginal artery should not be compromised.6

    The primary pull-through method for HD has been in use since 1980.7,8 A single-stage procedure avoids the complications associated with a colostomy and the need for another operation to close the colostomy. A primary single-stage pull-through is appropriate for most infants and children diagnosed with HD. Contraindications to primary pull-through include severe enterocolitis7-9, massive proximal dilatation7-9, an inability to determine the transition zone7,8, life-threatening comorbidities7,8 and colonic perforation9

    Early postoperative complications include anastomotic leaks and cuff abscess, bowel obstruction, perineal excoriation, stoma complications, and wound infection. On the other hand, late complications include bowel obstruction, constipation, enterocolitis, incontinence, and stricture. In this study, complications that happened in less than or equal to 30 days post-operatively were included.

    Major complications mostly occur at coloanal anastomosis. Anastomotic leaks have been reported in 5% to 10% of cases, while cuff abscess is seen in about 5% of cases.10-12 Factors increasing the risk of these complications include tension on the anastomosis or ischemia of the pull-through segment.10-12

    
    

    Factors affecting anastomotic leakage include:

    1. Levels of transitional zone. When the transition zone is located too high, abdominal assisted transanal endorectal pull-through is considered. The levels of transitional zone required for an abdominal assisted transanal endorectal pull-through instead of an isolated transanal endorectal pull-through is still controversial.

    2. Preoperative bowel preparation. The Division of Pediatric Surgery, Faculty of Medicine, Siriraj Hospital

       uses a preoperative bowel preparation regimen with rectal NSS irrigation of 30-50 ml/Kg/, twice a day. This amount of NSS is not proven to be efficient nor is known to be enough to do rectal NSS irrigation. A reduction of stool production by changing the diet was also done pre-operatively. At Siriraj Hospital, a low residual diet was introduced on the third day before operation. On the second day before operation, a liquid diet was prescribed, and on the day before operation, patients were given only a clear liquid diet. The question of how many days is required to change the diet regimen remains.

    3. Malnutrition. Whether malnutrition caused more complications was questioned.

    4. Colostomy. Whether colostomy proximal to coloanal anastomosis would prevent anastomotic complications remains debatable.

An anastomotic stricture after the pull-through procedure is another important postoperative complication. The risk factors include anastomotic ischemia, cuff ischemia, anastomotic leak, and small circular anastomosis.13

If all factors affecting early anastomosis complications are clarified, there would be a reduction of early complications following transanal endorectal pull-through.

MATERIALS AND METHODS

Following approval by the Siriraj Institutional Review Board, (COA no. Si 276/2020), a retrospective study was carried out in children with Hirschsprung’s disease who underwent either a transanal endorectal pull-through or abdominal assisted transanal endorectal pull-through at Siriraj Hospital between January 2009 and December 2019. Children with another diagnosis (rectal stenosis, meconium plug syndrome), those who underwent other pull-through operations, and incomplete medical information, were excluded from the study.

Patients’ demographic data, nutritional status, transitional zone level, colostomy, bowel preparation before surgery, types of operation, complications following either transanal endorectal pull-through or abdominal assisted transanal endorectal pull-through was collected. Complications, including anastomotic leakage, abscess at anastomosis, intraabdominal collection, anastomotic stricture, rectal cuff stricture, were also recorded. The collected data was analyzed using SPSS software version 18 (SPSS Inc. Released 2009. PASW Statistics for Windows, Version 18.0. Chicago: SPSS Inc). Continuous data was expressed as median and IQR and categorical data was expressed as numbers and percentages. A Chi square test or Fisher’s exact test was used to compare the without post- operative complications and post-operative complication groups. A p-value of <0.05 indicated statistical significance.

RESULTS

Of the 222 patients whose medical records were reviewed, 59 were excluded (41 had other pull-through operations, and 18 had incomplete medical information). One hundred and sixty-three patients were included in this study. Complications were found in 43 patients or 26% (43/163). Post-operative complications are demonstrated in Table 1. Anastomotic strictures were the most common complication (32.6%). Other complications included five cases (11.6%) of abscess at anastomosis, and three cases (7.0%) of anastomotic leakages.

Demographic data and location of the transitional zone in the non-complication (n=120) and complication group (n = 43) is shown in Table 2. The median age of the non-complication group was 3.8 months, and the median age of the complication group was 5.4 months. However, the difference in age and weight of patients in both groups during the operation was not statistically significant.

The most common location of the transitional zone in this study was the rectosigmoid colon (46.3%). Comparing levels of the transitional zone in patients in the non-complication and complication group revealed no statistical significance (p = 0.403).

Whether nutritional status affected post-operative complications was also studied. Nutritional parameters, such

as percentile of body weight according to the WHO Growth Chart, total lymphocyte count, Hct, albumin and globulin were collected and compared between those without complications and those with complications. The effect of nutritional status on post-operative complications is demonstrated in Table 3. Nutritional status seemed to have no impact on the complication rate following endorectal pull-through.

TABLE 1. Post-operative complications.

TABLE 2. Demographic data and location of transitional zone compared between the non-complication group (n =120) and complication group (n = 43)

TABLE 3. Effects of nutritional status on post-operative complications.

Pre-operative risk factors for post-operative complications include pre-operative bowel preparation, previous history of Hirschsprung’s associated enterocolitis, and colostomy prior to pull-through operation. All pre- operative risk factors for post-operative complications were compared between those without complications and those with complications and are demonstrated in Table 4.

Bowel preparation for a pull-through operation at the Division of Pediatric Surgery, Faculty of Medicine, Siriraj Hospital used rectal NSS irrigation of 30-50 ml/ Kg/ twice a day. Comparing those without and those with post-operative complications, the amount of NSS for rectal irrigation (ml/Kg), duration required for rectal NSS irrigation (days), and duration of changing diet (days) were the same (p = 0.961, p = 0.553 and p = 0.296, respectively), The minimum NSS volume for rectal irrigation without any complications in this study was just 10 ml/kg. A previous history of Hirschsprung’s associated enterocolitis may increase post-operative complications (p = 0.072).

Colostomy prior to a pull-through operation could not prevent post-operative complications following endorectal pull-through (p = 1.000).

The intra-operative risk factors for post-operative complications were compared between those without

complications and those with complications and are shown in Table 5.

When the transition zone was proximal to the mid-sigmoid colon, an abdominal assisted transanal endorectal pull-through (abdo + TERPT) was considered. Early complications following endorectal pull through, whether transanal endorectal pull through or abdominal assisted transanal endorectal pull-through, were the same (p = 0.344). In abdominal assisted transanal endorectal pull-through, division of the inferior mesenteric artery (IMA) to create a pedicled colon flap with adequate length for endorectal pull-through was considered. By ligating the inferior mesenteric artery, there was concern of the compromised arterial supply. In this study, inferior mesenteric artery ligation did not affect complications following abdominal assisted transanal endorectal pull- through (p = 1.000).

Two types of coloanal anastomosis for endorectal pull-through were described. The standard technique was two-layer anastomosis. The first layer sutured the seromuscular layer of the pull-through colon to the rectal cuff, and then the second layer sutured full thickness of the pull-through colon to the rectal mucosa and lower rectal cuff at 0.5 cm above the dentate line. There were only a few patients who received one layer of coloanal anastomosis by suturing full thickness of the pull-through

TABLE 4. Pre-operative risk factors for post-operative complications compared between those without complications and those with complications.

TABLE 5. The intra-operative risk factors of post-operative complications compared between those without complication and those with complications.

colon to the rectal mucosa and lower rectal cuff 0.5 cm above the dentate line. In our study, both types of coloanal anastomosis had no difference in complication rates (p = 0.713).

The incidence of post-operative complications when comparing levels of transitional zone are demonstrated in Table 6. The results show a higher transitional zone meant more complications. The complication rates following pull-through for Hirschsprung’s disease with transitional

zone proximal to sigmoid colon (except total colonic aganglionosis (TCA)) was about 30.0%-33.3% whereas complications in patients with a transitional zone at the rectum and rectosigmoid colon was about 21%-25.6%. The complications after a pull-through operation for classical Hirschsprung’s disease were minor. The incidence of anastomotic strictures in patients who had a transitional zone at the rectum and rectosigmoid colon was 16% and 5% respectively. Anastomotic leakage, which was the

TABLE 6. Incidences of post-operative complications comparing levels of transitional zone.

most serious complication, was found in Hirschsprung patients with a transitional zone at the descending colon and transverse colon. This leakage seldom occurs in classical Hirschsprung’s disease.

When the transition zone was proximal to the mid- sigmoid colon, abdominal assisted transanal endorectal pull-through (abdo + TERPT) was considered. A comparison of the incidences and types of complications between the

transanal endorectal pull-through and abdominal assisted transanal endorectal pull-through is demonstrated in Table 7.

Abdominal assisted endorectal pull-through had a higher incidence (4%) of anastomotic leakage whereas there were no anastomotic leakages in transanal enorectal pull through. Transanal endorectal pull-through had a higher rate of anastomotic strictures (12%) compared to

TABLE 7. Incidences and types of complications comparing transanal endorectal pull-through (TERPT) and abdominal assisted transanal endorectal pull-through (Abdo + TERPT).

abdominal assisted endorectal pull-through (5%). Those who had a transitional zone located at the descending colon or transverse colon, complications of abdominal assisted endorectal pull-through was around 6%. Although complications following these two techniques of pull- through are comparable, abdominal assisted endorectal pull-through had a higher incidence of leakages. The complications correlate with whether a pull-through operation could be done safely. Moreover, retained aganglionosis colon was observed in 3% of abdominal assisted pull-through, even if exploratory laparotomy was done.

DISCUSSION

The aim of this study was to identify possible risk factors of postoperative complications within 30 days of transanal endorectal pull-through (TERPT) and/or abdominal assisted transanal endorectal pull-through (abdo + TERPT). The overall complication rate in this study was 26% (43/163), which is comparable to 22% seen in a study by Hoff N, et al.14

Major complications mostly occurred in coloanal anastomosis. Besides the high incidence of anastomotic strictures in our study, complications at coloanal anastomosis were comparative to other studies. In our study, anastomotic leaks were seen in 7% of cases whereas other studies reported 5% to 10%.10-12 In our series, anastomotic abscess was present in 11.6% of all cases whereas others reported 5%.10-12 The risk of leakages and cuff abscess was caused by tension on the anastomosis or ischemia of the pull-through segment.10-12 In our series, this complication mostly occurred in abdominal assisted transanal endorectal pull-through in a higher transitional zone. This might be the result of ischemia of the pull-through segment.

The most common location of the transitional zone in this study was the rectosigmoid colon (46.3%). In this study, the levels of the transitional zone had no impact on the complication rate following the pull-through operation (p = 0.403). This might be the result of a high percentage of abdominal assisted transanal endorectal pull though performed in our series.

Although, nutritional status in our study seemed to have had no impact on complication rates following endorectal pull-through, complete nutritional status could not be evaluated in many cases. Albumin and globulin levels were not measured in many patients before the operation.

Various bowel preparation regimens using rectal NSS irrigation before a definite pull-through operation were followed. The Royal Children’s Hospital, Melbourne15 as

well as the Children’s Hospital, Pittsburgh16 recommend using NSS irrigation of 20 ml/Kg. However, there is no study comparing the efficiency of these regimens. The Division of Pediatric Surgery, Faculty of Medicine, Siriraj Hospital used a bowel preparation regimen using a rectal NSS irrigation amount of 30-50 ml/Kg twice a day. Comparing those without and with post-operative complications, the amount of NSS for rectal irrigation (ml/Kg), duration required to do this rectal NSS irrigation (days) and duration of changing diet (days) were the same (p = 0.961, p = 0.553 and p = 0.296, respectively). Colostomy before operations were performed in cases where contraindications to primary pull-through were found, and included: severe enterocolitis, massive proximal dilatation, inability to determine the transition zone and life-threatening comorbidities.17,18 In this multi- step surgical treatment for Hirschsprung’s disease, a colostomy helped with bowel preparation before the operation was performed.. In our study, a colostomy prior to a pull-through operation could not prevent post-operative complications following endorectal pull-

through (p = 1.000).

When the transition zone was proximal to the mid- sigmoid colon, abdominal assisted transanal endorectal pull-through (abdo+ TERPT) was considered. Early complications following endorectal pull through, whether transanal endorectal pull through or abdominal assisted transanal endorectal pull-through, were the same (p = 0.344). Therefore, the level of transitional zone could not have a direct impact on complications which were linked to whether pull-through operations could be performed safely.

Abdominal assisted endorectal pull-through had an incidence of 4% for anastomotic leakage, while no anastomotic leakages were found in transanal enorectal pull-through. However, transanal endorectal pull-through had higher rate of anastomosis strictures (12%) compared to abdominal assisted endorectal pull-through (5%). In our study, a high incidence of anastomotic stricture could be the result of tight coloanal anastomosis in patients without laparotomy. A minor degree of anastomotic ischemia and stricture was also encountered.

In abdominal assisted transanal endorectal pull- through, a pedicled colon flap must be developed for endorectal pull-through. In this situation, the pull-through colon derives its vascular supply from the marginal artery. Therefore, to mobilize the descending colon and splenic flexure, it might be necessary to ligate and divide either the inferior mesenteric artery just distal to its origin from the aorta or the left colic artery just after it rises from the inferior mesenteric artery. By

ligating these vessels at these sites, the arterial supply through the marginal artery should be preserved.6 The appropriate length of the pedicle can be determined by pulling the intended site of anastomosis down into the pelvis and allowing a few extra centimeters for a tension-free coloanal anastomosis. However, in our study, patients with abdominal assisted transanal endorectal pull-through with inferior mesenteric artery ligation were not affected by complications following the operation (p = 1.000).

Surprisingly, in our study, anastomotic stricture was the most common complication (32.6%). Anastomosis stricture was found frequently in those with a low transitional zone. Sixteen percent of patients with transitional zones located in the rectum had anastomotic stricture. In our series, transanal endorectal pull-through had higher risk (12%) of anastomotic strictures than abdominal-assisted transanal endorectal pull-through (5%). Other studies13,19 have reported that anastomotic strictures are the result of anastomotic ischemia, cuff ischemia, anastomotic leaks, and small circular anastomosis. In our study, the reason why abdominal assisted transanal endorectal pull-through had a lower rate of anastomotic stricture might be due to less tight coloanal anastomosis and/ orlower levels of rectal cuff resection during laparotomy. Some reports6,20 suggest that the posterior wall of the cuff should be split to the intended point of anastomosis. The rectal cuff should also be inspected to ensure it is straight and does not fold down into the anorectal canal. A short rectal muscular cuff might also decrease the incidence of enterocolitis by reducing obstructions caused by the spastic cuff.20 Most strictures can be managed by daily home dilatation. Occasionally, a repeat pull-through is needed to ameliorate the problem.

The higher the transitional zone, the higher the complication rate. Excluding total colonic aganglionosis (TCA), complications following pull-through for Hirschsprung’s disease with transitional zone proximal to sigmoid colon was about 30%-33%, whereas complications following those with a transitional zone at the rectum and rectosigmoid colon was about 21.0%-25.6%. There were only minor complications of classical Hirschsprung disease. Anastomotic strictures in patients with a transitional zone at the rectum and rectosigmoid colon occurred in 16% and 5%, respectively. Anastomotic leakage, which was the most serious complication, was found in Hirschsprung patients with a transitional zone at the descending colon and transverse colon. These leakages seldom occur in classical Hirschsprung’s disease.

Transanal endorectal pull-through might not show the level of the transitional zone as clearly as abdominal

assisted transanal endorectal pull-through. During transanal endorectal pull-through, pulling the colon during anorectal surgery might make it more difficult to identify the transitional zone, leading to a retained aganglionosis segment. However, retained aganglionosis was still found in 3% of abdominal assisted pull-through cases, even if laparotomy was done.

Our study did have some limitations.

First, it had a retrospective design which meant some information may be missing. Fifty-nine patients were excluded (41 had other pull through operations, and 18 had incomplete medical information), which meant only 163 patients were included in the study.

Second, the type of operation, whether transanal endorectal pull-through, abdominal assisted transanal endorectal pull-through, or whether pre-operative colostomy should be done, depended on each surgeon’s preference. Third, the generalizability of the results is restricted.

The study was conducted in one university hospital, and thus, there may be complications following operation that are not evident elsewhere. This study was conducted in Siriraj Hospital, in which only the traditional surgical techniques were applied. The youngest pediatric surgical staff in here had at least ten-year experience in surgical treatment for Hirschsprung’s disease.

CONCLUSION

No significant risk factors were associated with early surgical complications following TERPT. The incidence of early complications following TERPT and abdominal assisted TERPT was the same (p = 0.344). Abdominal assisted TERPT had a higher incidence (4%) of anastomotic leakages whereas TERPT had higher rate of anastomosis strictures (12%) compared to abdominal assisted TERPT (5%). The higher the transitional zone, the higher the complication rate was. Abdominal assisted TERPT should be selected properly for higher level of the transitional zone. The complications correlated with whether a perfect pull-through operation could be performed or not.

ACKNOWLEDGEMENTS

The researcher would like to thank Dr. Sasima Tongsai from the Division of Clinical Epidemiology, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University for her continuous help with data processing and statistical analysis.

Conflicts of interest: The authors have no conflicts of interest to declare.

REFERENCES

1. Spouge D, Baird PA. Hirschsprung disease in a large birth cohort. Teratology 1985;32:171-7.

2. Swenson O. My early experience with Hirschsprung’s disease. J Pediatric Surg 1989;24:839-45.

3. Soave F. A new surgical technique for the treatment of Hirschsprung’s disease. Surgery 1964;56:1007-14.

4. Boley SJ. New modification of the surgical treatment of Hirschsprung’s disease. Surgery 1964;56:1015-7.

5. De la Torre L, Ortega A. Transanal versus open endorectal pull- through for Hirschsprung’s disease. J Pediatr Surg 2000;35: 1630-2.

6. Morowitz MJ, Georgeson KE. Laparoscopic assisted pull- through for Hirschsprung’s disease. In: Holcomb GW, Georgeson KE, Rothenberg SS, eds. In: Atlas of Pediatric Laparoscopy and Thoracoscopy, Philadelphia, Elsevier, 2008.p.101-85.

7. Teitelbaum DH, Cilley RE, Sherman NJ, Bliss D, Uitvlugt ND, Renaud EJ, et al. A decade of experience with the primary pull-through for Hirschsprung disease in the newborn period: A multicenter analysis of outcomes. Ann Surg 2000; 232:372-80.

8. So HB, Schwartz DL, Becker JM, Daum F, Schneider KM. Endorectal “pull-through” without preliminary colostomy in neonates with Hirschsprung’s disease. J Pediatr Surg 1980;15:470-1.

9. Mungnirandr A. Hirschsprung’s disease: Review article. Siriraj Med J 2017:69(4):223-7.

10. Fortuna RS, Weber TR, Tracy Jr. TF, Silen ML, Cradock TV. Critical analysis of the operative treatment of Hirschsprung’s disease. Arch Surg 1996;131:520-5.

11. Tariq GM, Brereton RJ, Wright VM. Complications of endorectal pull-through for Hirschsprung’s disease. J Pediatr Surg 1991;26: 1202-6.

12. Little DC, Snyder CL. Early and late complications following operative repair of Hirschsprung’s disease. In: Holschneider AM, Puri P, eds. Hirschsprung’s Disease and Allied Disorders, 3rd ed. New York: Springer; 2008.p.375-85.

13. Teitelbaum DH, Coran AG. Long-term results and quality of life after treatment of Hirschsprung’s disease and allied disorders. In: Holschneider AM, Puri P, eds. Hirschsprung’s Disease and Allied Disorders, 3rd ed. New York: Springer; 2008.p.389-97.

14. Hoff N, Wester T, Granström AL. Classification of short-term complications after transanal endorectal pullthrough for Hirschsprung’s disease using the Clavien-Dindo-grading system. Pediatr Surg Int 2019;35(11):1239-43.

15. Clinical Guidelines (Nursing) ( 2019). Bowel washout rectal, retrived September,2019, from https://www.rch.org.au/rchcpg/ hospital_clinical_guideline_index/Bowel_washout_rectal/

16. Colonic irrigation, Children’s Hospital Pittsburgh from http:// www.chp.edu/our-services/surgery-pediatric/pediatric-surgery- services-we-offer

17. Georgeson KE. Hirschsprung’s disease. In: Holcomb III GW, Murphy JA. eds. Ashcraft’s Pediatric Surgery, 5th edition, Philadelphia: Saunders Elsevier; 2010.p.456-67.

18. Langer JC, Fitzgerald PG, Winthrop AL, Srinathan SK, Foglia RP, Skinner MA, et al. One-stage versus two-stage Soave pull- through for Hirschsprung’s disease in the first year of life. J Pediatr Surg 1996;31:33-7.

19. Engum SA, Grosfeld JL. Long-term results of treatment of Hirschsprung’s disease. Semin Pediatr Surg 2004;13:273-85.

20. Nasr A, Langer JC. Evolution of the technique in the transanal pull-through for Hirschsprung’s disease: Effect on outcome. J Pediatr Surg 2007;42:36-40.

The Benefit of Unattended Automated Office Blood Pressure Measurement on the White-coat Effect: A Cross-sectional Study

Chavalit Chotruangnapa, M.D., Piyawan Thongdang, M.D.

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

ABSTRACT

Objective: To compare blood pressure (BP) and heart rate measured by attended and unattended automated office blood pressure measurement (AOBPM) versus home blood pressure measurement (HBPM) and the effect of unattended AOBPM on the classification of BP phenotypes.

Materials and Methods: The cross-sectional study was conducted at the outpatient department in Siriraj Hospital, Thailand. All participants measured their office BP using attended and unattended techniques in random order and recorded home BP twice a day for consecutive 7 days. The agreement between office BP from both AOBPM methods and that from HBPM was analyzed using the Bland-Altman plot. The change in the proportion of each BP phenotype was also analyzed.

Results: We included 114 participants. The mean age was 57.96 ± 15.07 years. The average BP from attended AOBPM, unattended AOBPM, and HBPM were 150.52 ± 16.12/81.77 ± 11.04, 139.68 ± 13.80/78.55 ± 11.71, and 126.91 ±

9.80/76.40 ± 8.37 mmHg, respectively. The BP and heart rate measured by these techniques were significantly different (p-value of <0.001). Bland-Altman analysis showed the biases of attended and unattended SBP versus home SBP were 23.61 and 12.77 mmHg, respectively. Unattended AOBPM significantly decreased the numbers of patients classified as white-coat and sustained hypertension regardless of BP thresholds (p-value of <0.001 for both groups). Conclusion: Unattended AOBPM significantly minimizes the white-coat effect in real-life clinical practice and may help physicians avoid overdiagnosis of hypertension. Nevertheless, it does not replace HBPM.

Keywords: Attended automated blood pressure measurement; unattended automated blood pressure measurement; home blood pressure; white-coat hypertension; masked hypertension (Siriraj Med J 2023; 75: 454-465)

INTRODUCTION

Nowadays hypertension is still a major problem of public health worldwide, and it is one of the etiologies of premature cardiovascular morbidity and mortality.1 The early diagnosis and treatment of hypertension are important to prevent de novo hypertension-mediated organ damage and reduce cardiovascular risk. Blood pressure (BP) measurement is an essential part of hypertension management. According to the growing pieces of evidence

which have indicated the better cardiovascular predictive power of home blood pressure (HBPM) over office blood pressure measurement (OBPM)2,3, the current hypertension guidelines have not only emphasized the standard technique of OBPM but have also recommended using out-of-office BP measurement, especially HBPM.4-7 Because of numerous interfering factors in the process of OBPM, including patients’ effect, observers’ effect, and the hospital’s environment, the office BP may be

Corresponding author: Chavalit Chotruangnapa E-mail: chavalit.cho@mahidol.ac.th

Received 21 March 2023 Revised 22 April 2023 Accepted 23 April 2023 ORCID: https://orcid.org/0000-0002-2761-6310 https://doi.org/10.33192/smj.v75i6.261881

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

inaccurate.8,9 The white-coat effect is an important cause of inaccurate BP from conventional, or attended, OBPM.9 Unattended OBPM is a newly developed technique that can be used to measure patients’ BP by using automated BP devices in a private area without observers. It can be called unattended automated office blood pressure measurement (unattended AOBPM). This technique which was adopted in the systolic blood pressure intervention trial (SPRINT), has been widely debated in regard to BP values.10-13 Some recent evidence has shown that unattended OBPM gets rid of the white-coat effect and results in a lower BP reading than attended OBPM.14-16 However, the application of unattended OBPM in real- world clinical practice remains limited and the BP values resulting from different techniques of BP measurement are controversial due to the heterogeneity of the protocol of BP measurement.14,17 The primary objective of this study was to investigate the difference and agreement of BP parameters and heart rate between attended AOBPM, unattended AOBPM, and HBPM in real-world clinical practice in the outpatient department of a tertiary care hospital. Moreover, this study aimed to investigate the proportion of BP phenotypes that were classified by the different OBPM techniques and BP thresholds.

MATERIALS AND METHODS

Study population

The cross-sectional study was conducted from March 1, 2021 to October 31, 2022, at the hypertension clinic, which is a part of the outpatient department of Siriraj Hospital, Bangkok, Thailand. We included clinically stable patients with an age of at least 18 years who visited the hypertension clinic and were able to completely measure their BP on the arm following this study’s protocol. All eligible participants gave their informed consent. The exclusion criteria were pregnancy, cardiac arrhythmia, and incomplete data from BP records. This study was approved by the Siriraj Institutional Review Board (SIRB) (COA no. Si 085/2021). The Thai Clinical Trials Registry number is TCTR20230122002 (https:// www.thaiclinicaltrials.org/show/TCTR20230122002).

Blood pressure measurement protocol

The techniques of BP measurement consisted of attended OBPM, unattended OBPM, and HBPM. Well- trained nurses informed all participants about avoiding caffeine intake and exercise at least 30 minutes before the BP measurement and emptying the urinary bladder before BP measurement as well as all steps of the BP measurement protocols. All these methods were performed in a sitting position on a chair with back support and

both feet were placed on the floor. An appropriate-sized cuff was placed on the non-dominant arm at the same level as the heart. A period of 5 minutes of resting was required before taking a BP measurement. In both office BP measurement techniques, an automated Omron HEM-907 (Omron Healthcare Co. Ltd.) device was used for three repeated BP measurements with a 1-minute of interval between each one. Attended AOBPM was performed by a nurse, who started the program of the automated BP device and then stayed in the same place as the patients until the measurement was finished. On the other hand, the only patients who performed unattended AOBPM were in a private room. There, the patients activated the automated BP device by themselves for three serial BP measurements one minute apart. There were no nurses or staff in the room until the BP measurement was completed. All records of office BP parameters and heart rates from each method were considered when calculating the average value from each one. The nurses and the investigators were independent. The sequence of attended and unattended AOBPM was randomized by the nurses in a 1:1 ratio.

The HBPM method was begun in a manner to the aforementioned OBPM method on the day after the OPD visit. Validated oscillometric BP devices including Omron HEM-7130 and HEM-7211 (Omron Healthcare Co. Ltd.) were recommended for use in HBPM. The patients were asked to perform two repeated BP measurements each morning and evening for consecutive 7 days. The data of the HBPM records were sent to the investigators at the next follow-up visit. All numbers of BP and heart rate were used to calculate to the average home BP. In addition, the average BP measurements, namely, the average morning and evening BP, were separately calculated.

Definition of BP phenotypes

We identified four BP phenotypes based on the type of BP measurement (office and home BP), with two different thresholds according to the 2017 American and 2018 European hypertension guidelines4,5; these phenotypes were as follows; normotension (both office and home BPs were normal), white-coat hypertension (office BP was abnormally high while home BP was normal), masked hypertension (office BP was normal but home BP was abnormally high), and sustained hypertension (both office and home BPs were abnormally high). Abnormal office and home BPs following the 2017 American hypertension guideline were defined as a systolic BP (SBP) which was at least 130 mmHg and/or a diastolic BP (DBP) which was at least 80 mmHg.4 On the contrary, the 2018 European

hypertension guidelines defined an abnormal office SBP as an office SBP which was at least 140 mmHg and/or an office DBP was at least 90 mmHg.5 An abnormal home BP was defined as a home SBP which was at least 135 mmHg and/or a home DBP which was at least 85 mmHg.5

Data collection

The demographic data were collected from the participants and their electronic medical records at Siriraj Hospital. They consisted of age, gender, body mass index, comorbidities (i.e., diabetes mellitus, dyslipidemia, coronary artery disease, cerebrovascular disease, and chronic kidney disease), current smoking status, use of antihypertensive medications and their types, and laboratory results (i.e., fasting plasma glucose, glycated hemoglobin, serum creatinine, estimated glomerular filtration rate (eGFR), and lipid profiles).

Statistical analysis

Based on a previous study that investigated the association between unattended office BP and home BP17, we planned to enroll at least 55 participants to provide 90% statistical power for the detection of an approximately 10 mmHg difference in BP between unattended AOBPM and HBPM at a two-sided alpha level of 0.05.

Continuous variables of demographic data were recorded as mean ± standard deviation and median and interquartile range depending on the data’ distribution. The Kolmogorov-Smirnov equality-of-distributions test was analyzed for identifying the normal distributed continuous variables. Categorical variables were recorded as number and percentage. The analysis of the difference and agreement of BP parameters and heart rates between the three different techniques of BP measurement was performed by using Bland-Altman plots. One-way analysis of variance (ANOVA) with the Bonferroni test was used for the comparison of the BP and heart rate parameters of the three techniques. A Pearson correlation was performed to analyze the relationship between the results of the three BP measurement techniques. The chi-square test or Fisher’s exact test was used for the analysis of comparing the proportions of the BP phenotypes that were classified by using attended and unattended AOBPM at each BP threshold. The statistical significance was designated as a p-value of <0.05. Stata Statistical Software version 17 (StataCorp LLC, College Station, TX) was used for all analyses.

RESULTS

A total of 114 patients were enrolled in this study.

Most of them were female patients (62.3%). Of all patients, 94% were taking at least one antihypertensive medication. Dyslipidemia was the most common comorbidity (81.6%). The mean age was 57.96 ± 15.07 years and the median body mass index was 24.59 kg/m2. The details of the demographic data are shown in Table 1. The results of Kolmogorov-Smirnov equality-of-distributions test of the continuous variables (i.e., age, eGFR, cholesterol, high- density lipoprotein cholesterol, low-density lipoprotein cholesterol, SBP, DBP, and heart rate) indicated the normal distribution (p-value of >0.05).

Comparison of the BP and heart rate of the different BP measurement techniques

Table 2 shows the data of systolic and diastolic BP that were measured; they were calssified by attended OBPM, unattended OBPM, and HBPM. The average morning home BP was 127.19 ± 10.28/77.30 ± 8.39 mmHg and the average evening home BP was 126.63 ± 11.05/75.50 ± 9.27 mmHg. Overall analysis revealed that that SBP, DBP, and heart rate from the different methods of measurement were significantly different. Bonferroni’s post-hoc analysis indicated that attended OBPM provided the significantly highest systolic blood pressure (SBP), with significance, among all BP measurement techniques. The average home SBP was significantly lower than office SBP as well. Only the diastolic blood pressure (DBP) from attended OBPM was significantly higher than the average home DBP. Moreover, the average heart rate from HBPM was significantly lower than the office heart rate that was measured during both attended and unattended OBPM. Even though the DBP and heart rates of both attended and unattended OBPMs were not significantly different, unattended OBPM provided a lower DBP and heart rate than attended OBPM.

Bland-Altman plot analysis is shown in Table 3 and Fig 1 – 3. The results revealed that the biases of attended versus unattended office SBP, DBP, and heart rate were 10.83 mmHg, 3.23 mmHg, and 3.42 beats/ minute, respectively. Both OBPM techniques had higher biases of SBP, DBP, and heart rate than the HBPM technique. The BP and heart rate of all techniques of BP measurement were significantly associated, as shown in Table 4. The correlation between BP and heart rate was particularly high between attended and unattended OBPMs. Notwithstanding, the correlation coefficients of the SBP from both OBPM technique versus HBPM technique were quite low (r = 0.19, p-value of 0.041 for attended office SBP versus average home SBP; r = 0.28, p-value of 0.003 for unattended office SBP versus average home SBP).

TABLE 1. Demographic data.

*median and interquartile range

Abbreviations: HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol

TABLE 2. Blood pressure and heart rate of the different blood pressure measurement techniques.

*p-value for overall comparison of attended office BP versus unattended office BP versus average home BP

**The presented numbers of the HR of home BP measurement were calculated from 111 subjects’ records due to the missing HR data of 3 subjects.

†p-value of <0.001 for comparing attended vs unattended office BP

‡p-value of <0.001 for comparing attended office BP vs average home BP

⁋p-value of <0.005 for comparing unattended office BP vs average home BP

Abbreviations: BP, blood pressure; SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate; SD, standard deviation

TABLE 3. Bland-Altman plot analysis of blood pressure and heart rate from the different blood pressure measurement techniques.

Abbreviations: BP, blood pressure; CI, confidence interval; LoA, limits of agreement; HR, heart rate

Fig 1. Bland-Altman plot for (A) the comparison of attended versus unattended office SBP, (B) the comparison of attended office versus home SBP, and (C) the comparison of unattended office versus home SBP.

Abbreviation: SBP, systolic blood pressure

Fig 2. Bland-Altman plot for (A) the comparison of attended versus unattended office DBP, (B) the comparison of attended office versus home DBP, and (C) the comparison of unattended office versus home DBP.

Abbreviation: DBP, diastolic blood pressure

Fig 3. Bland-Altman plot for (A) the comparison of attended versus unattended office heart rate, (B) the comparison of attended office versus home heart rate, and (C) the comparison of unattended office versus home heart rate.

TABLE 4. The correlations of blood pressure and heart rate between the different blood pressure measurement techniques.

Abbreviations: BP, blood pressure; HR, heart rate

The classification of BP phenotypes by using the different techniques of AOBPM

The proportions of all patients’ BP phenotypes are separately presented according to the different BP thresholds (Table 5). According to the thresholds of normal office and home BPs, which were less than 130/80 mmHg, the proportions of patients with normotension, white-coat hypertension, masked hypertension, and sustained hypertension by attended AOBPM were 5.26%, 50%, 0.88%, and 43.86%, respectively. When unattended

AOBPM was performed, the proportions of normotensive, white-coat, masked, and sustained hypertensive patients were changed to 14.91%, 40.35%, 4.39%, and 40.35%, respectively. These results were found to be different when using the other BP thresholds, which consisted of a normal office BP of less than 140/90 mmHg and a normal home BP of less than 135/85 mmHg. Of all patients, the BP phenotypes which were classified by attended AOBPM consisted of 20.18% normotensive patients, 51.75% white-coat hypertensive ones, 1.75% masked

TABLE 5. Classification of blood pressure phenotypes based on the different techniques of office blood pressure measurements and the different blood pressure thresholds of the 2017 ACC/AHA and 2018 ESC/ESH hypertension guidelines in all 114 patients.

*p-value for comparing attended versus unattended method

Abbreviation: ACC/AHA, American College of Cardiology/American Heart Association; ESC/ESH, European Society of Cardiology/ European Society of Hypertension; BP, blood pressure; HT, hypertension

hypertensive ones, and 26.32% sustained hypertensive ones. The proportion of the normotensive group was significantly increased in proportions (41.23%; p-value of <0.001) while the proportions of the others (i.e., white- coat and sustained hypertensive groups (30.7%; p-value of <0.001 and 24.56%; p-value of <0.001, respectively)) were significantly decreased in proportion by using the technique of attended AOBPM regardless of BP thresholds. The ratio of identified masked hypertension classified by the two methods of AOBPM was only significantly different as regards the BP threshold of the 2017 American hypertension guideline (p-value of 0.044). Furthermore, we separately reveal the results of the classification of BP phenotypes in patients who were and were not taking antihypertensive medications in Supplementary Table 1 & 2.

DISCUSSION

Since the results of SPRINT were published, there has been strong interest in the methods of BP measurement, especially unattended AOBPM, and such methods have been widely debated. Standardized BP measurement is emphasized in both office and home settings. The observer’s effect may confound BP which is measured at the clinic more than that measured at home. The results of this study show a significant difference in office SBP between both techniques of OBPM. SBP measurements from unattended AOBPM were significantly lower than those from attended AOBPM. It indicated that the observer’s effect was an important confounding factor of inaccurate OBPM. Our results were concordant with the findings from the previous study of Keeley EC., et al.18 which showed a significantly higher attended office SBP. Moreover, the study of Fanelli E., et al.19 highlighted the higher attended office SBP, particularly in patients who initially measured their office BP by attended technique. The sequence of AOBPM techniques might not have affected the results in our study because the process for identifying the initial AOBPM technique in each participant was randomly performed. Although the difference in office DBP and heart rate between both AOBPM techniques did not reach statistical significance, attended office DBP and heart rate tended to be higher than unattended ones. A possible underlying mechanism is more activation of the sympathetic nervous system during attended OBPM compared with unattended OBPM.20

The office BP and heart rate from both attended and unattended AOBPMs were statistically higher than home BP and heart rate. This finding supported the presence of the white-coat effect that resulted from patient response to hospital situations, including BP measurement. Office

heart rate is still obviously higher than home heart rate despite the fact that some patients took beta-blockers. It implies that the sympathetic nervous system plays a major role in the pathophysiology of the white-coat effect.21,22 The discrepancies of the biases of office SBP versus home SBP from the Bland-Altman analysis were large in attended AOBPM (23.61 mmHg) and, to a lesser extent, in unattended AOBPM (12.77 mmHg). Our finding indicated unattended AOBPM was not completely devoid of the white-coat effect because office BP, especially SBP, was higher than home BP. This was different from some previous studies.19,23 The systematic review and meta-analysis of Pappaccogli M., et al.23 revealed similar BP levels between unattended AOBPM and HBPM. Nevertheless, there should be some caution taken in interpreting this result because of the high heterogeneity of the included studies for meta-analysis. The study of Fanelli E., et al.19 showed that the BP levels from both AOBPM techniques were lower than home BP. There is a limitation of missing data on the complete home BP of 32 subjects (approximately 22% of the total 118 subjects); therefore, the results may be interfered with by this missing data. In addition, the different baseline characteristics of participants, different methodologies of study, and the environment in each study site may result in different findings. The high correlation of attended and unattended office BP in our study is similar to that found in other studies.17,18,24,25 Our study showed that BP measured by AOBPM and HBPM was significantly correlated. This is consistent with some previous studies. However, the degree of correlation between office SBP and home SBP was low. The exact reason for the weak relationship between office SBP and home SBP is not well known. A previous study25 showed similar results of association to our study. Most of the enrolled patients in the previous study (96.4%)25 and our study (93.86%) were taking at least one antihypertensive medication. We suppose that taking antihypertensive medications25 and several different drug regimens may result in increased variability of office SBP.26,27

Due to the differences in office BP between attended and unattended techniques, we investigated whether the classification of BP phenotypes was affected by them. Our results showed a significant change in the proportion of all BP phenotypes. Unattended AOBPM resulted in decreased numbers of white-coat hypertensive patients because it lowered patients’ white-coat effect. The slightly weak correlation between the unattended office and home BP indicated that unattended AOBPM could not replace HBPM. Therefore, there were increased normotensive and masked hypertensive patients. Nevertheless, we

cannot evaluate the diagnostic performance, especially accuracy, for the identification of BP phenotypes because of the lack of ambulatory BP monitoring (ABPM), which is the gold standard for the diagnosis of hypertension. The strengths of this study consist of using the same standardized protocol of BP measurement for all participants and the randomized order of AOBPM. The measured office BP is not confounded by these factors. The design of our pragmatic study can reflect the real- life outcome in routine clinical practice. There are some limitations in our study. First, most of the participants were taking antihypertensive medications, so their different regimens of such medications including types and numbers may have affected office BP and home BP. Moreover, they may be also affected by the different measured and unmeasured factors of the patients’ baseline characteristics, such as age, gender, comorbidities, physical activity and dietary pattern, etc. This limitation may result in high discrepancies in BP parameters and heart rate between the three measured techniques. Second, home BP was collected from the data recorded on paper because the home BP devices used in this study do not send BP data via an online system. Some patients may have failed to record some high BP measurements in their records. Therefore, home BP may not represent actual BP at home. Third, both attended and unattended AOBPM were measured and averaged in a single visit, whereas HBPM was recorded and averaged over 7 days. Given the daily variation of the measurement, the differences between each technique were significant. Finally, ABPM is not performed in our study so there was no gold standard method used to identify abnormal elevated

BP, as previously mentioned.

CONCLUSION

Unattended AOBPM results in a lesser white-coat effect than attended AOBPM, however, unattended office BP remains higher than home BP in our study. The office BP measurement method affects the classification of BP phenotypes. The technique of unattended AOBPM can be applied to routine clinical practice.

ACKNOWLEDGEMENTS

We are grateful and appreciative to all patients who kindly spent their time participating in our study and to Miss Wilaiporn Hancharoenkul, who is a nurse with expertise in BP measurement and independent of all investigators, for facilitating the smooth process of our study. Ultimately, we greatly acknowledge Associate Professor Weranuj Roubsanthisuk for her kind support of our study.

Declaration of interest statement: All authors declare there is no conflict of interest.

Funding: None.

Author contributions

Chotruangnapa C created the research question, performed the literature review and then designed the research methodology. All authors conducted and collected the data. The data were statistically analyzed and the manuscript was written by Chotruangnapa C. All authors critically reviewed and approved the final manuscript.

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