SMJ

E-ISSN 2228-8082

Volume 75, Number 11, November 2023

Siriraj Medical Journal

The world-leading biomedical science of Thailand

Indexed by

THAILAND SECTION 1954

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

E-mail: sijournal92@gmail.com

By Ignasia Andhini Retnowulan, et al.

MONTHLY

ORIGINAL ARTICLE LETTER TO THE EDITOR

ORIGINAL ARTICLE‌

763 Incidence of Infection-related Complications and Optimal Saline Irrigation Volume for Preoperative

SMJ

Siriraj Medical Journal

The world-leading biomedical science of Thailand

Volume 75 Number 11

November 2023

Bowel Preparation to Reduce Postoperative Infections in Hirschsprung’s Disease with Premature Uterine Contractions Ravit Ruangtrakool, Sasabong Tiyaamornwong

770 Cancer Detection Rate of MRI Ultrasound Fusion Prostate Biopsy in 1,039 Patients and Number Needed to Biopsy in Rargeted Lesion

Sivakorn Choomark, Pubordee Aussavavirojekul, Varat Woranisarakul, Sittiporn Srinualnad

778 Factors Associated with Age at Diagnosis of Autism Spectrum Disorder in Pediatric Patients at Sawanpracharak Hospital, Thailand

Sineenat Teekavanich, Prakasit Wannapaschaiyong

784 Self-evaluation of Sexual History Taking Skills Among Medical Students in Southern Thailand

Thareerat Ananchaisarp, Jirayu Likitkamchorn, Jirapat Jitsaard, Natthanit Srisuriya, Natvara Panichkittikul,

Porramat Chuthong, Pongsakorn Khanphakdee, Peraya Tekasakul, Rossawan Sahuankeaw, Sarawut Piyarattanayothin, Panya Chamroonkiadtikun, Chonnakarn Jatchavala

794 Efficacy of Atropine Eye Drops for Suppressing Myopia Progression in Thai Children

Thammanoon Surachatkumtonekul, Pinpilai Jutasompakorn, Sirawadee Wiriyaudomchart, Kiatthida Hokierti, Jureeporn Sri-in

800 Smartphone Addiction, Daytime Sleepiness and Depression among Undergraduate Medical Students: A Cross-sectional Study in a Medical College of Kolkata, India

Nirmalya Manna, Shibasish Banerjee, Ankush Banerjee, Arup Chakraborty, Debasis Das

809 Clinical Efficacy of Andrographis paniculata Extracted Scrub Compared With 4% Chlorhexidine Scrub in Burn Wounds: A Prospective Randomized Controlled Trial

Pattraporn Vangchanachai, Suttipong Tianwattanatada, Nantaporn Namviriyachote, Vich Thampanya,

Natthida Owattanapanich, Kusuma Chinaroonchai, Suchada Kittidacha, Anchan Ketmek, Pornprom Muangman

817 Hepatocellular Carcinoma's Characteristics in an Endemic Country: A Closer Examination of Tumor Grade and Microvascular Invasion

Ignasia Andhini Retnowulan, Marini Stephanie, Nur Rahadiani, Ridho Ardhi Syaiful, Ening Krisnuhoni

827 The Impact of Retro-apical Urethral Dissection Approach Technique on Positive Surgical Margins in Robotic-assisted Laparoscopic Radical Prostatectomy: A Study in Thailand

LETTER TO THE EDITOR

835

Efficacy and Safety of Combination 308-nm Excimer Laser and Intralesional Corticosteroid versus Intralesional Corticosteroid Monotherapy in the Treatment of Frontal Fibrosing Alopecia: A Pilot Study

Rattapon Thuangtong, Supisara Wongdama, Nuttagarn Jantanapornchai, Chadakan Yan, Kanchalit Thanomkitti,

Daranporn Triwongwaranat

Katunyou Mahamongkol, Malik Hajidae, Pubordee Aussavavirojekul, Thitipat Hansomwong, Sittiporn Srinualnad

SMJ

SIRIRAJ MEDICAL JOURNAL

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

Executive Editor: Apichat Asavamongkolkul Editorial Director: Aasis Unnanuntana

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

Associate Editors

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

Morris Solomon Odell, Monash University, Australia

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

Medical Illustrator: Nuchpraweepawn Saleeon, Mahidol University, Thailand

Proofreaders: Noochpraweeporn Saleeon, Mahidol University, Thailand, Amornrat Sangkaew, Mahidol University, Thailand

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

Incidence of Infection-related Complications and Optimal Saline Irrigation Volume for Preoperative Bowel Preparation to Reduce Postoperative Infections in Hirschsprung’s Disease

Ravit Ruangtrakool, M.D., Sasabong Tiyaamornwong, 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 find incidence of infection-related complications and the optimal volume and duration (days) of rectal NSS irrigation that would result in the low post-operative complications following transanal endorectal pull-through (TERPT) in patients with Hirschprung’s disease.

Materials and Methods: We conducted a retrospective chart reviews of 131 patients diagnosed with Hirschsprung’s

disease who underwent TERPT at Siriraj Hospital between January 2006 and December 2020.

Results: Infection-related complications were observed in 23(17.6%) patients, comprising 22(16.8%) cases of anastomotic strictures, 3(2.3%) cases of anastomotic leakages, and 2(1.5%) cases of intraabdominal collections. The median (Q1, Q3) volume of NSS irrigation (ml/kg/day) for those without complications (38.1 (33.9,50)) and those with complications (39.5 (35,45)) was statistically identical (p = 0.945). Similary, the median duration of for both groups was the same (p = 0.854). The mean (SD) volume of irrigated NSS in those with leakage (55.6 (32.7)) and those without leakage (44.3 (17.9)) showed no statistically significant difference (p = 0.291). Patients with post-operative stricture received the same amount of irrigated NSS (40.7 (11.9)) as those without stricture (45.4 (19.2)) (p = 0.138). Similarly, those with hyponatremia received the same amount of irrigated NSS as those without hyponatrema (p = 0.475).

Conclusion: The volume of rectally irrigated NSS did not correlate with infection-related complications such as

anastomotic leakage, stricture and intraabdominal collection. However, this study observed a low complication rate, thus, future research should cover a larger population.

Keywords: Hirschsprung; endorectal pullthrough; complications; irrigation; bowel preparation (Siriraj Med J 2023; 75: 763-769)

INTRODUCTION

Hirschsprung’s disease (HD) is caused by the absence of ganglion cells in the myenteric and submucosal plexus of the colon, inhibiting the propagation of peristaltic waves. It has an estimated incidence of roughly 1 in 5,000 live births.1 The most effective surgical treatment involves resection of the aganglionic bowel segment and

the identification of normally ganglionated proximal bowel for a level coloanal anastomosis. In 19882-4, L De la Torre and J A Ortega transformed the Soave- Boley endorectal pull-through procedure into a purely transanal approach known as the “transanal endorectal pull-through” (TERPT). If the transanal approach cannot be performed flawlessly, a combined method of abdominal

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

Received 20 July 2023 Revised 19 September 2023 Accepted 22 September 2023 ORCID ID:http://orcid.org/0000-0001-8162-2941 https://doi.org/10.33192/smj.v75i11.264260

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 transanal approaches, dubbed “abdominal assisted transanal endorectal pull-through” (abdo + TERPT), is used.

The reduction of fecal loading is crucial to minimizing complications related to infection such as wound infection, intraabdominal collection, coloanal anastomosis leakage, wound dehiscence, anastomosis retraction and anastomosis stricture. This can be achieved through adequate bowel preparation.

Various bowel preparation regimens, which include rectal normal saline solution (NSS) irrigation before a definitive pull-through operation, have been followed. The Royal Children’s Hospital, Melbourne5 as well as the Children’s Hospital, Pittsburgh6 recommend NSS irrigation of 20 ml/Kg. However, no studies have compared the efficacy of these regimens. The Division of Pediatric Surgery, Faculty of Medicine Siriraj Hospital uses a preoperative bowel preparation regimen with rectal NSS irrigation of 20-50 ml/Kg/session, administered twice a day. The effectiveness of this quantity of NSS is neither proven nor known to be sufficient to do rectal NSS irrigation. Additionally, pre-operative reduction of stool production by altering the diet was implemented. At Siriraj Hospital, a low residual diet was introduced three days prior to the operation. A liquid diet was prescribed on the day prior to the operation, and only a clear liquid diet was allowed on the day of the operation. The required duration for this dietary change regimen remains uncertain, and excessive rectal NSS irrigation might result in hyponatremia.

Neither the optimal volume nor duration of NSS

irrigation have been established with scientific evidence. Thus, this study was conducted to determine the most suitable volume and duration of rectal NSS irrigation to minimize infection-related complications following pull-through operations.

MATERIALS AND METHODS

After obtaining approval from the Siriraj Institutional Review Board (COA. no Si 757/2020), a retrospective study was carried out in children diagnosed with Hirschsprung’s disease who underwent either a transanal endorectal pull-through or abdominal assisted transanal endorectal pull-through at Siriraj Hospital between January 2006 to December 2020. Children diagnosed with kidney disease causing hyponatremia, those who were immunocompromised, those who had previously underwent colostomy, and those with incomplete medical information were excluded from the study.

Infection-related complications were defined as complications occuring within three months postoperatively

including wound infection, intraabdominal collection, coloanal anastomosis leakage, wound dehiscence, anastomosis retraction and anastomosis stricture.

Patients’ demographic data, transitional zone level, preoperative bowel preparation (volume (cc/kg/day) and duration (days)), types of operation, and complications following either transanal endorectal pull-through or abdominal assisted transanal endorectal pull-through were collected. Complications, such as surgical site infection, anastomotic leakage, abscess at anastomosis, intraabdominal collection, wound dehiscence, anastomotic stricture, post-operative hyponatremia, were also recorded. The collected data were analyzed using SPSS software version 18 (SPSS Inc. Released 2009. PASW Statistics for Windows, Version 18.0. Chicago: SPSS Inc). Continuous data were expressed as either median (Q1, Q3) or mean (standard deviation) depending on the distribution of the data and categorical data was expressed as numbers and percentages. A Chi-square test was used to compare proportional data and the Mann-Whitney U test was used to compare continuous data. Multiple binary logistic regression analysis was used to adjust confounding factors. A p-value of <0.05 was considered statistically significant.

RESULTS

This study included 131 patients diagnosed with Hirschsprung’s disease, of whom 85 (64.9%) were male and 46 (35.1%) were female. Ninty-nine patients underwent TERPT, while 32 patients recieved the abdominal assisted TERPT. Postoperative infection-related complications were observed in 23 (17.6%) patients, including 22 (16.8%) anastomotic stricture, 3 (2.3%) cases of anastomotic leakages, and 2 (1.5%) instances of intraabdominal collection.

Patients’ characteristics, with surgical complications (n = 23) and without surgical complications (n = 108), are shown in Table 1.

Among the two groups, there were no significant differences in terms of gender, age, weight, and transitional zone level (p = 0.998, 0.224, 0.629 and 0.732 respectively). The need for abdominal-assisted TERPT was found to be identical among patients with and without complications (p = 0.838)

Table 2 demonstrates the comparison between patients with and without surgical complications, considering factors such as pre-operative volume of NSS irrigation, duration of NSS irrigation, re-operation requirement, and length of hospital stay.

In relation to overall complications, the median (Q1, Q3) volume of rectal NSS irrigation (ml/kg/day) for patients

TABLE 1. Patients’ characteristics: A comparison of those without surgical complications and those with surgical complications.

TERPT: Transanal endorectal pull-through

aChi-square test, bMann-Whitney Test Q1: The lower quartile, first quartile Q3: The upper quartile, third quartile

No surgical Surgical

complication (n=108) complication (n=23)

Total

(n=131)

P-value

TABLE 2. Comparison of pre-op volume of NSS irrigation, duration of NSS irrigation, re-operation frequency, and length of hospital stay between those without surgical complications and those with surgical complications.

aChi-square test, bMann-Whitney Test Q1: The lower quartile, first quartile Q3: The upper quartile, third quartile

without post-operative complications (38.1 (33.9,50)) was comparable to that of patients with complications (39.5 (35,45)), showing no significant difference (p = 0.945). Likewise, the median (Q1, Q3) duration of rectal NSS irrigation was identical in both groups (7.0 (5, 10) days vs. 7.0 (4, 10) days) (p = 0.854). The incidence of each infection-related complication and a comparison of total saline irrigation volume (ml/kg/day) between those with each complication and those without each complication are described in Table 3.

Anastomotic leakage did not show a correlation with volume of rectal NSS irrigation. The mean (SD) volume of rectal NSS irrigation (ml/kg/day) for patients with leakage leakage (55.6 (32.7)) and those without leakage (44.3 (17.9)) displayed no significant difference (p = 0.291). However, the incidence of leakage in this series was only 2.3%.

Anastomotic stricture, the most common complication in this study (22 (16.8%)) did not show a difference in rectal NSS irrigation volumes. Patients with anastomotic stricture were irrigated with NSS at a mean volume of 40.7 (11.9) ml/kg/day, which was not significantly different from the mean volume of 45.4 (19.2) ml/kg/day for patients without anastomotic stricture (p = 0.138).

In our study, patients with hyponatremia received the same amount of rectal NSS irrigation as those without hyponatremia (p-value = 0.475).

In our study, the patient with Hirschsprung’s disease without complications who received the minimal volume of rectal NSS irrigation received 16.19 ml/kg/day and irrigation duration for this patient was 5 days.

DISCUSSION

Prior to conducting a transanal endorectal pull- through/ abdominal assisted transanal endorectal pull- through, preoperative bowel preparation is required to minimize the amount of stool retained in the bowel.

There were three methods of bowel preparation before such operations:

1. Laxatives. These drugs induce strong contractions of the colon and rectum, and thereby facilitate stool evacuation. Two commonly used laxatives include Senna (anthraquinone group) and Bisacodyl (a derivative of the diphenylmethane group). The use of these drugs is contraindicated in cases where obstruction of the colon and rectum is present.

2. Drugs with osmotic effects: These include polyethylene glycol (PEG) and its variations such as

   
   

   
   

   TABLE 3. Incidence of infection-related complications and comparison of total saline irrigation volume (ml/kg/ day) between those with each complication and those without each complication.

   
   

   	Number of patients (total n=131)	NSS irrigation volume (mean (SD)) (ml/kg/day)	P-valuea
   Anastomotic leakage Yes No	3 (2.3%) 128 (97.7%)	55.6 (32.7) 44.3 (17.9)	0.291
   Anastomotic stricture Yes No	22 (16.8%) 109 (83.2%)	40.7 (11.9) 45.4 (19.2)	0.138
   Intra-abdominal collection Yes No	2 (1.5%) 129 (98.5%)	66.4 (38.1) 44.2 (17.9)	0.089
   Re-operation Yes	21 (16.0%)	43.4 (16.7)	0.740
   No	110 (84.0%)	44.8 (18.6)
   Hyponatremia Yes	2 (1.5%)	36.5 (14.2)	0.475
   No	129 (98.5%)	46.3 (19.2)

   aIndependent-samples T test SD: Stardard Deviation

   
   

   PEG preparation with electrolytes (PEG-ELS) or PEG- 3350 without electrolytes. These substances should not be used if an obstruction is suspected.

   Regiments utilizing laxatives and drugs with osmotic effects are frequently used for bowel preparation prior to colonoscopy in pediatric patients.7 However, they are not suitable for preoperative bowel preparation in patients with Hirschsprung’s disease.

3. Rectal NSS irrigation. This preoperative bowel preparation method, performed with a catheter, is a safe and suitable approach for preparing for surgery in cases of Hirschsprung’s disease. Other hypotonic solutions, including distilled water, tap water, or other types of water, are believed to potentially include hyponatremia due to water intoxication. This condition occurs when the colon and rectum absorb water.

Proper bowel prepartion prior to surgery is crucial. If the colon is not sufficiently cleaned, either due to inadequate volume of colonic irrigation or insufficient frequency of irrigation, this can lead to fecal stagnation, and heightened risk of post-surgical infection.

Clinical guidelines for rectal NSS irrigation vary. The Royal Children’s Hospital, Melbourne recommends pre- operative bowel preparation with NSS rectal irrigation up to a maximum of 20 ml/Kg per session, not exceeding a total volume of 250 ml.5 The Children’s Hospital, Pittsburgh recommends a maximum NSS irrigation of 20 ml/Kg per session, but does not specify a total maximum volume of NSS.6 The Great Ormond Steeet Hospital, London, United Kingdom, recommends that rectal irrigation should continue with NSS until the stool appears watery and free of fecal retention.8 In patient with enterocolitis, treatment includes broad spectrum antibiotics and rectal irrigation. Immediate rectal washout with saline (10-20 ml/Kg) using a large bore soft tube should be initiated immediately and repeated from 2-4 times per day until appropriate decompression is achieved, as determined by clinical examination.9,10

The optimal duration of preoperative bowel preparation

with daily NSS irrigation remains a topic of discussion. Songkhlanakarin University hospital in Thailand reported that rectal irrigation for three days prior to surgery failed to adequately cleanse the bowels.11 However has also been reported that rectal NSS irrigation can be used effectively on the day before surgery, alone, with the first irrigation in the evening before the operation and a second irrigation on the morning of the operation. However, this method requires a large volume of NSS (500-2000 ml (mean 1000 ml)) per colonic irrigation session.12

At the Division of Pediatric Surgery, Department of

Surgery, Faculty of Medicine Siriraj Hospital, preoperative bowel preparation with normal NSS irrigation has been standard practice for over 40 years. For children under one month of age, the protocol involves NSS irrigation of no more more than 20 ml/Kg per session, twice a day, not exceeding 40 ml/Kg per day. For children older than one month, the quantity of NSS used in colonic irrigation does not exceed 50 ml/Kg per session, with colonic irrigation performed twice daily. Thus, the total daily volume of NSS irrigation does not surpass 100 ml/ Kg/day. Nevertheless, questions remain regarding the ideal quantity of NSS irrigation and the optimal number of days required for bowel preparation before surgery. These were key questions of this study.

The demographic data in this study (age, weight, transitional zone, type of operation) showed no significant differences between patients who developed complications and those who did not. This allowed for a focused examination of potential effects of NSS irrigation, without these factors acting as confounding factors.

The findings from our study indicate no statistically significant correlation between volume of rectal NSS irrigation and overall postoperative complications. Patients who did not develop postoperative complications received a mean (Q1, Q3) volume of NSS similar to that of those who developed complications (38.1 (33.9, 50)

ml/kg/day vs. 39.5 (35, 45) ml/kg/day) (p-value = 0.945). Moreover, the mean duration of irrigation between these two groups showed no significant difference (p = 0.854). The minimum NSS volume of rectal NSS irrigation in a patient who did not experience any complications in this study was just 16.19 ml/kg/day and the duration of irrigation for this patient was five days.

The incidence of anastomotic leakage showed no correlation with volume of rectal NSS irrigation. The mean (SD) volume of rectal NSS irrigation in patients with leakage was not statistically different from those without leakage (55.6 (32.7) ml/kg/day, vs. (44.3 (17.9) ml/kg/day) (p-value = 0.291). A possible reason for the lack of correlation between the amount of rectal NSS and anastomotic leakage could be the low incidence of leakage in our series. In our patient’s cohort, anastomotic leakage occurred in only 2.3% of cases whereas other studies reported incidences of 5% to 10%.13-15 A low incidence of leakage requires a larger sample sample size to statistically identify any differences in the volume of NSS irrigation.

Anastomic stricture following the pull-through procedure was the most common complication in our series, (n = 22 (16.8%)). Known risk factors for anastomotic stricture include anastomotic ischemia, cuff ischemia,

anastomotic leak, and small circular anastomosis.16,17 Concealable leaks can subsequently lead to stricture of the colonanal anastomosis. In this study, the mean (SD) volume of NSS irrigation for patients who developed postoperative stricture (40.7 (11.9)) was not significantly different from those without stricture (45.4 (19.2)) (ml/ Kg/day) (P = 0.138). Given that the risk of anastomotic leakage in our study was only 2.3%, the higher incidence of anastomotic stricture could be the result of an overly tight coloanal anastomoses, which may result in minor degree of anastomotic ischemia and stricture. However, our findings suggest that stricture of coloanal anastomosis was not associated with volume of rectal NSS irrigation.

In our study, we found that the volume and duration of NSS irrigation were similar for patients with infection- related surgical complications, such as anastomotic leakage, anastomotic stricture, intraabdominal collection and others, and those without complications. These results were corresponsed with our previous preliminary study.18 The absence of correlation between the volume of rectally irrigated NSS and severe infecton-related complications might be due to low incidences of those complications in our series.

Theoretically, increasing NSS volume could elevate the risk of hyponatremia. However, in our study, those with hyponatremia received the same volume of rectal NSS irrigation as those without hyponatremia (p-value

= 0.475).

Our study did have some limitations.

First, the study was designed retrospectively, which means there may be missing information. We were only able to include 131 patients who had complete medical records.

Second, the number of patients with infection-related complications was relatively small. This made it challenging to compare the group with post-operative complications and the group without complications, particularly in relation to different volumes and duration of rectal NSS irrigation. Due to the relatively low complication rate, further research is needed on a larger population.

Third, the generalizability of our findings is limited. The study was conducted in a single university hospital, and as such, the method and technique of rectal NSS irrigation may differ from those used in other institutions. Morover, the operative technique of transanal endorectal pull-through or abdominal assisted transanal endorectal pull-through may differ as well. Therefore, the incidence rates of post-operative complications we observed might not be applicable elsewhere.

CONCLUSION

Our study found that the volume of rectally irrigated NSS was not correlated with post-operative infection such as anastomotic leakage, anastomotic stricture and intraabdominal collection. The minimum volume of rectal NSS irrigation for patient with Hirschsprung’s disease without complications in this study was 16.19 ml/kg/day over a duration of 5 days.

ACKNOWLEDGEMENTS

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

3. 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.

4. 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(3): 372-80.

5. The Royal Children’s Hospital Melbourne. Bowel washout rectal: clinical guidelines (nursing) [Internet]. Melbourne VIC, Australia [updated 2023 Feb 1; cited 2023 Sep 9]. Available from: https://www.rch.org.au/rchcpg/hospital_clinical_guideline_index/ Bowel_washout_rectal/.

6. UPMC Children’s Hospital of Pittsburgh. Colonic irrigations with metronidazole (Flagyl®) [Internet]. 2023 [cited 2023 Sep 9]. Available from: https://www.chp.edu/our-services/surgery-pediatric/ pediatric-surgery-services-we-offer/colorectal-center-for-children/ patient-family-resources/colonic-irrigation#:~:text=Colonic%20 Irrigations%20with%20Metronidazole%20(Flagyl%C2%AE).

7. Hunter A, Mamula P. Bowel preparation for pediatric colonoscopy procedure. J Pediar Gastroenterol. 2010:51(3):254-61.

8. Great Ormond Street Hospital. Bowel washouts using an antegrade colonic enema (ACE) [Internet]. 2019 [cited 2023 Sep 9]. Available from: https://www.gosh.nhs.uk/conditions- and-treatments/procedures-and-treatments/bowel-washouts- using-antegrade-colonic-enema-ace/.

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

10. Demehri FR, Halaweish IF, Coran AG, Teitelbaum DH.

    
    

    Hirschsprung-associated enterocolitis: pathogenesis, treatment and prevention. Pediatr Surg Int. 2013;29(9):873-81.

11. Parithan P, Chiengkriwate P, Chowchuvech V, Patrapinyokul S, Sangkhathat S. Bowel preparation for pull-through operation in Hirschsprung’s disease. Songkla Med J. 2007;25(5):401-6.

12. Amsh EA, Lukong CS, Mshelbwata PM, Anumah MA, Gomna

    A. One-day bowel preparation in children with colostomy using normal saline. Afri J Paed Surg. 2011;8(3):291-3.

13. 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.

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

15. 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.

16. 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.

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

18. Ruangtrakool R, Krajangjit P. Early surgical complications following transanal endorectal pull-through for Hirschsprung’s Disease. Siriraj Med J. 2023;75(6):445-53.

Cancer Detection Rate of MRI Ultrasound Fusion Prostate Biopsy in 1,039 Patients and Number Needed to Biopsy in Targeted Lesion

Sivakorn Choomark, M.D., Pubordee Aussavavirojekul, M.D., Varat Woranisarakul, M.D., Sittiporn Srinualnad, M.D.

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

ABSTRACT

Objective: To determine the cancer detection rate (CDR) of magnetic resonance imaging ultrasound fusion prostate biopsy (MRI/US fusion prostate biopsy) in Thailand. The secondary aim was to estimate the number needed to biopsy (NNB) for each prostate lesion in a targeted biopsy, classified by Prostate Imaging-Reporting and Data System (PI-RADS).

Materials and Methods: The data of 1,039 consecutive patients who underwent a MRI/US fusion prostate biopsy

at Siriraj Hospital between September 2017 and February 2021 was included and retrospectively reviewed. Those included had previous negative biopsies and were biopsy naïve. The data was analyzed to find the detection rate and NNB.

Results: The overall detection rate of MRI/US fusion prostate biopsy was 58.71%, whereas that of systematic biopsy

was 45.72%. Clinically significant prostate cancer (csPCa) (Gleason score ≥ 3+4) detection rate of MRI/US fusion prostate biopsy was 51.01%. When categorized by PI-RADS category 3, 4, and 5 were 12.16%, 44.98%, 85.71% respectively. NNB in targeted biopsy of PI-RADS 3, 4, and 5 were 8, 7, and 3 times sequentially. Positive predictive factors for prostate cancer (PCa) detection were age, prostate-specific antigen density (PSAD) and PI-RADS, whereas prostate volume was a negative predictive factor.

Conclusion: This study supports the role of MRI/US fusion prostate biopsy in PCa detection and should not avoid

systematic biopsies. The higher the PI-RADS was, the greater the csPCa detection rate. NNB is helpful in guiding the least amount of biopsied cores for each lesion.

Keywords: Cancer detection rate, Magnetic resonance imaging ultrasound fusion prostate biopsy, Number needed to biopsy, PI-RADS score, Gleason score (Siriraj Med J 2023; 75: 770-777)

INTRODUCTION

Prostate cancer (PCa) is the third most common malignancy diagnosed1, and is the eighth cause of cancer death in the world.2 Thai guidelines for PCa screening recommend a prostate specific antigen (PSA) and digital rectal examination (DRE) screening in men aged 50-75, with at least 10 years of estimated life expectancy, and at the age of 45 and older in men with a family history of

PCa. A prostate biopsy is indicated when any of the two investigation above are flagged as abnormal. Currently, prostate biopsies are widely performed following the transrectal ultrasound guided biopsy technique (TRUS biopsy) and 12-cores systematic biopsy strategy. Afterwards, obtained tissues are stained and examined by pathologists. Although it is a frequently used method, the cancer detection rate (CDR) of this method is about 44.4%.3

Corresponding author: Sittiporn Srinualnad E-mail: sitsrinualnad@gmail.com

Received 15 September 2023 Revised 9 October 2023 Accepted 10 October 2023 ORCID ID:http://orcid.org/0000-0002-5118-7675 https://doi.org/10.33192/smj.v75i11.265361

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

The hypothesis of this study is that magnetic resonance imaging ultrasound fusion prostate biopsy (MRI/US fusion prostate biopsy) may be the key to improving the prostate detection rate. Currently, multiparametric magnetic resonance imaging (mpMRI) is the most interesting method utilized for identifying the presence of any suspicious lesions within the prostate. Suspicious lesions were classified into five categories, according to the Prostate Imaging-Reporting and Data System (PI- RADS), and ranged from 1 (no suspicious lesions visible) to 5 (aggressive lesion appearance which is resemble cancer).

As modern imaging technologies allow region of interest (ROI) for cancer become identifiable, numerous biopsy methods are proposed such as cognitive-target biopsy and in-bore MRI guided biopsy. Later, the MRI/US fusion prostate biopsy method was created to overcome inaccuracy problems as it provided real-time lesion tracking and required less effort and hassle.4 Since 2017, MRI/ US fusion prostate biopsies have become the preferred method of urologists at Siriraj Hospital.

Many studies5-7 classified PCa into two categories; clinically insignificant prostate cancer (ciPCa) and clinically significant prostate cancer (csPCa). ciPCa is usually an organ-confined disease while csPCa often manifests as a non-organ-confined disease.8 This study intended to report the CDR of MRI/US fusion prostate biopsies for overall and csPCa at our institute. It also proposed the estimated numbers required for a biopsy for each visible lesion targeted, as classified by the PI-RADS.

MATERIALS AND METHODS

Patients who underwent a MRI/US fusion prostate biopsy between September 2017 and February 2021 were included. All cases had at least one PI-RADS 3 lesion in the multiparametric magnetic resonance imaging (mpMRI) and underwent a MRI/US fusion prostate biopsy, targeted and systematic. Patients under active surveillance protocol, previous diagnosis of PCa, or those who had a radical prostatectomy or incomplete data were excluded. A total of 1,039 patients were eligible for this study. Patients’ demographic data, urological history, DRE, PSA, MRI reports, operative notes, pathological reports, and post-operative complications were collected and analyzed.

Imaging

The mpMRI of the prostate in this study was performed with a 1.5 or 3 Tesla, without endorectal coil. The imaging protocol consisted of T2-weighted imaging, diffusion-weighted imaging (DWI) and apparent

diffusion coefficient (ADC) value. Radiologists reported lesions within the prostate according to the PI-RADS.

Intervention

Most patients in this study were admitted one day prior to the operation. Only a few operations were performed as a one-day surgery. The trans-perineal biopsy approach was the preferred option of most surgeons, and thus, general anesthesia was almost always used to ensure adequate pain control. After a patient was under anesthesia, he was placed in the standard lithotomy position. Catheter placement wasn’t mandatory and the decision was left to the surgeon. A MRI/US fusion prostate biopsy device, known as KOELIS Trinity® system (Koelis, France), was brought in to map current ultrasonographic images with MRI. After each lesion was identified, a targeted biopsy was performed, lesion by lesion, according to the guidance by systematic biopsy in a free-hand manner. Following the operation, patients were observed in the recovery room for two hours before transfer to the ward or discharge. In most cases, patients were discharged within one day of the operation unless they experienced complications.

Systematic biopsy was random biopsy that obtained

tissue from both sides of prostate including the prostatic base, mid gland and apex.7 Targeted biopsy was biopsy at the positive lesions on MRI (PI-RADS 3, 4, 5) with the use of MRI/US fusion prostate biopsy device to obtain tissue from regions of interest. Combination was MRI/ US fusion prostate biopsy including both systematic and targeted biopsy.

Histology

Histopathological tissues were interpreted and reported by assigned pathologists within Siriraj Hospital using the International Society of Urological Pathology (ISUP) consensus definition of Gleason score (GS) and Grade groups (GG). A csPCa was defined as GS ≥ 3+4 or GG ≥ 2, and ciPCa was GS 3+3 or GG 1.7,9,10

Number needed to biopsy

The number needed to biopsy (NNB) was calculated by dividing the total number of biopsies of a particular prostate lesion by the number of positive prostate cancer biopsies. We modified the NNB from the NNB ratio to diagnose s melanoma (Marchetti et al).11 We excluded patients with a benign pathology report and patients with multiple lesions within the prostate in this analysis. A single PI-RADS lesions represented specific patients and lesions and could be properly interpreted. The cumulative line plot of NNB was used to demonstrate cancer detection

yield for each additional biopsy core in each PI-RADS category.

Statistical analysis

The statistical analysis of this study was performed using Python (Python Software Foundation, Wilmington, DE, USA). Univariate and multivariate analyses were performed using linear regression and multiple linear regressions via the package statsmodels version 0.12.0. A p-value less than 0.05 was considered statistically significant difference.

RESULTS

Demographic data from 1,039 patients in this study revealed a median age of 69 (64.5-75), median PSA of

8.79 ng/mL (6.29-13.7), median prostate volume of

44.06 mL (29.9-63.6), median PSAD of 0.21 ng/mL2 (0.14-0.34), and median maximal lesion diameter of 13 mm (9-19) (Table 1). Among the biopsied patients, there were 264 instances of previous negative biopsies and 775 biopsy-naïve cases. Most patients in both groups were PI-RADS 4 patients. The presence of PI-RADS 3 patients in each group was less common. A total of 659 patients (63.43%) had one visible lesion in the mpMRI. Another 301 patients (28.97%) had two ROI. There was also one person who had a total of six lesions within the prostate, representing the highest number of lesions in a single patient in this study (Table 2). This study revealed overall and csPCa detection rates of MRI/US fusion prostate biopsy of 58.71% and 51.01%, respectively.

Fig 1 presents the proportion of different cell types found in suspicious lesions, categorized by the MRI findings. The patients with PI-RADS 5, which exhibited the most aggressive features in mpMRI, had highest detection rate for significant cancer at 85.71%. The CDR for csPCa in PI-RADS 4 and 3 were 44.98%, and 12.16% respectively. In PI-RADS 5, the most frequent highest GS was 4+5, or 27.47%, followed by 4+3 and 3+4 or 19.78% each, respectively. On the other hand, PI-RADS 3 and 4 mainly consisted of ciPCa or benign outcomes (GS 6 or lower) at 87.84% and 55.02%, respectively. The most frequent csPCa in PI-RADS 3 and 4 was a GS of 3+4 (4.05%, 23.62%) sequentially (Table 2). In this study, common complications in the first 14 days after biopsy were acute urinary retention (AUR) at 4.33%, and gross hematuria (GH) at 2.98%, however, sepsis was zero.

Regarding the Venn diagram in Fig 2, PCa was mostly found in both targeted core tissues and systematic core tissues, or in 409 patients (39.37%). Another 135 patients (12.99%) with a positive result in targeted biopsy tissue represented the edge of the MRI/US fusion technique over the systematic biopsy strategy. In contrast, 66 patients (6.35%) had infiltrative tumors, which were invisible on mpMRI and were only found by a systematic biopsy. About half of this group, or 34 patients, were diagnosed with csPCa. The rest, or 429 patients (41.29%), tested negative for PCa.

Univariate and multivariate analyses in Table 3 identified significant predictors, which were similar in outcomes. Age, PSAD, prostate volume, and PI-RADS

TABLE 1. Characteristics of 1,039 patients who underwent MRI/US fusion prostate biopsy.

a Data are presented as median (interquartile range)

b Data are presented as n (%)

TABLE 2. MRI lesion and MRI/US fusion prostate biopsy outcomes of 1,039 patients.

Detection rates

100%

90%

12.16%

80%

70%

60%

9.46%

51.01%

44.98%

85.71%

50%

9.55%

7.70%

40%

78.38%

csPCa ciPCa

Benign

30%

20%

10%

0%

41.29%

45.47%

2.57%

11.72%

Total PI-RADS 5 PI-RADS 4 PI-RADS 3

(N = 1039) (n = 273) (n = 618) (n = 148)

Fig 1. Cancer detection rate of MRI/US fusion prostate biopsy of 1,039 patients.

Clinical insignificant prostate cancer (ciPCa): GS 3+3 or GG 1,

Clinically significant prostate cancer (csPCa): GS ≥ 3+4 or GG ≥ 2

Choomark et al.

TABLE 3. Univariate and multivariate analysis in csPCa and overall cancer.

Abbreviations: MPI-RADS: multiple lesion PI-RADS, SPI-RADS: single lesion PI-RADS

NNB = 3

NNB = 7

NNB = 8

Fig 3. Number needed to biopsy (NNB) in each PI-RADS at the 95th Percentile

Fig 2. Venn diagram of MRI/US fusion prostate biopsy of 1,039 patients.

category were significant independent predictors regarding multivariate analyses, whereas prostate volume was the only negative predictor. PSA and average targeted core biopsy per lesion remained significant in univariate analyses, but multivariate analyses suggested otherwise due to their dependency on other factors. Surgeon experience proved to be insignificant regarding CDR when performed by second, third, and fourth postgraduate year residents and also board-certified urologists.

Of a total of 1,039 patients, 292 were eligible for the calculation of NNB, as they had a single lesion in MRI results and were diagnosed with PCa after a biopsy. According to Fig 3, the cumulative plot illustrates an increasing yield of cancer detection in each additional core in targeted biopsies regarding calculated NNBs. For PI-RADS 4 and 5 lesions, 7 and 3 were recommended as the minimum cores, as the curves reached the plateau approximately at 95% yield of cancer detection. In contrast, the number of eligible patients in PI-RADS 3 group was relatively too low to assure 95% yield at the minimum of 8 cores.

DISCUSSION

According to NCCN Guidelines Version 1.2023, mpMRI is recommended in patients with a high PSA and/or very suspicious DRE results, if accessible. Since it is utilized with MRI/US fusion biopsy devices, mpMRI improves the CDR of csPCa significantly, and reduces CDR of lower-risk cancers.7,12-14 On the contrary, Thai guidelines still recommend 12-cores systematic TRUS biopsy as the gold standard in detection of PCa because of limited access to MRIs, scarcity of specialized radiologists, and a lack of other resources. However, this leads to a higher rate of false negatives and lower csPCa detection. When considering obvious beneficial evidence, Thai tertiary medical centers are starting to shift their focus towards targeted biopsies.

This study revealed an overall CDR of MRI/US fusion prostate biopsy was 12.99% higher compared to systematic biopsies, which had a detection rate of 45.72%. Our overall CDR was not different from other studies (47%-62.9%)4-7,12,15-17, but in our study, csPCa was higher than in studies of Kasivisvanathan et al.7,

Ahdoot et al.12, Benelli et al.5, and Hansen et al.6 Thus, this potentially illustrates how the MRI/US fusion prostate biopsy system at our institute is not inferior to other studies. Our identified predictors are similar to another study5 where PI-RADS is a strong predictor on the list in both overall PCa and csPCa, which advocates the use of an MRI before prostate biopsy, if possible. Moreover, this study confirmed that the higher PI-RADS, the greater the detection rate. After we studied the results of the univariate and multivariate analysis, we found that positive predictive factors for PCa detection were age, PSAD, and PI-RADS, whereas prostate volume was a negative predictive factor. Likewise the conclusion of Walton et al.17, CDR decreased with increasing prostate volume. Al-Khalil et al.18 suggested a larger prostate volume would lead to a lower positive CDR. It supposed that benign prostatic hyperplasia (BPH) caused transition zone (TZ) hyperplasia and led to atrophy and apoptosis of cell in peripheral zone (PZ), and this is the zone where most PCa develops. This decreases the likelihood of PCa in the remaining glands.

This study still recommends both systematic and targeted biopsies in MRI/US fusion prostate biopsy procedures because 34 (3.37%) out of 1,039 patients with csPCa would be missed, if targeted biopsy alone was done. Similar to the MRI-FIRST trial14, which studied naïve biopsy, their results showed that 5.2% of csPCa would be missed if systematic biopsies were skipped. As we experienced several cases that involved an unnecessary biopsy, which is a waste of both time and resources of our pathologists, we use the NNB method to estimate how many core tissues were needed to gain enough yield to detect cancer. Moreover, we hoped this method would further decrease the workload of pathologists. Several previous studies5,14 of biopsied targeted lesions revealed at least 3 cores per lesion, but they did not provide certain evidences for their recommendation. With our reporting system, which didn’t specify or detail histopathological information for each and every biopsied lesion for research purpose, the calculated NNB for multiple ROI would become too susceptible to bias to draw any trustworthy conclusion. Our study selected patients with single ROI and calculated NNB of targeted lesion in PI-RADS 3, 4, and 5. Since, these NNB was derived from patients with single ROI, interference on multiple ROI was limited. We hope this study inspires clinicians to develop a method to study NNB of multiple ROIs in the future.

This study had a few limitations. First, this study

was a retrospective study at a single institution. Second, a version difference (v2.0 and v2.1) of PI-RADS existed in our cohort, so there may be some inconsistency in

distinguishing PI-RADS category 2 and 3, but PI-RADS 4 and 5 lesions are not affected. Third, the NNB we calculated was only usable for a single lesion.

CONCLUSION

This study supports the role of MRI/US fusion prostate biopsy in PCa detection. The combination of both targeted biopsy and systematic biopsy enhances CDR of PCa in comparison with systematic biopsy alone. The higher the PI-RADS on mpMRI was, the greater the csPCa detection rate. PI-RADS 3 mainly consisted of benign outcomes and ciPCa. Positive predictive factors for PCa detection were age, PSAD and PI-RADS, whereas prostate volume was a negative predictive factor. NNB is helpful in guiding the least amount of biopsied cores in single targeted lesion on MRI.

ACKNOWLEDGEMENTS

The authors would like to express gratitude to Katunyou Mahamongkol, M.D., Miss Jitsiri Chaiyatho and the coordinators at Siriraj Hospital for their valuable contributions to this study.

Conflicts of interest

The authors declare they have no conflict of interest.

REFERENCES

1. Srinualnad S, Hansomwong T, Aussavavirojekul P, Saksirisampant

   P. Paradigm Shift from Open Surgery to Minimally Invasive Surgery in Three Approaches for Radical Prostatectomy: Comparing Outcomes and Learning Curves. Siriraj Med J. 2022;74(10): 618-26.

2. Giona S. The Epidemiology of Prostate Cancer. In: Bott SRJ, Ng KL, editors. Prostate Cancer. Brisbane (AU): Exon Publications Copyright: The Authors.; 2021.

3. Presti JC, Jr., O’Dowd GJ, Miller MC, Mattu R, Veltri RW. Extended peripheral zone biopsy schemes increase cancer detection rates and minimize variance in prostate specific antigen and age related cancer rates: results of a community multi-practice study. J Urol. 2003;169(1):125-9.

4. Boonseana S, Srinualnad S, Leewansangtong S, Tantranont N, Woranisarakul V. Prostate cancer detection rate using MRI/ ultrasound fusion-guided prostate biopsy in Siriraj Hospital. Insight Urology. 2022;43(2):128-33.

5. Benelli A, Vaccaro C, Guzzo S, Nedbal C, Varca V, Gregori A. The role of MRI/TRUS fusion biopsy in the diagnosis of clinically significantprostatecancer.TherAdvUrol.2020;12:1756287220916613.

6. Hansen NL, Kesch C, Barrett T, Koo B, Radtke JP, Bonekamp D, et al. Multicentre evaluation of targeted and systematic biopsies using magnetic resonance and ultrasound image-fusion guided transperineal prostate biopsy in patients with a previous negative biopsy. BJU Int. 2017;120(5):631-8.

7. Kasivisvanathan V, Rannikko AS, Borghi M, Panebianco V, Mynderse LA, Vaarala MH, et al. MRI-Targeted or Standard Biopsy for Prostate-Cancer Diagnosis. N Engl J Med. 2018;

   378(19):1767-77.

8. Sitthinamsuwan P, Ratanarapee S, Leewansangthong S, Senawong

   S. Correlation between Gleason Scores of Prostatic Biopsies and Radical Prostatectomy Specimens. Siriraj Med J. 2009;61(1): 13-5.

9. Wegelin O, Exterkate L, van der Leest M, Kummer JA, Vreuls W, de Bruin PC, et al. The FUTURE Trial: A Multicenter Randomised Controlled Trial on Target Biopsy Techniques Based on Magnetic Resonance Imaging in the Diagnosis of Prostate Cancer in Patients with Prior Negative Biopsies. Eur Urol. 2019;75(4):582-90.

10. van der Leest M, Cornel E, Israel B, Hendriks R, Padhani AR, Hoogenboom M, et al. Head-to-head Comparison of Transrectal Ultrasound-guided Prostate Biopsy Versus Multiparametric Prostate Resonance Imaging with Subsequent Magnetic Resonance- guided Biopsy in Biopsy-naive Men with Elevated Prostate- specific Antigen: A Large Prospective Multicenter Clinical Study. Eur Urol. 2019;75(4):570-8.

11. Marchetti MA, Yu A, Nanda J, Tschandl P, Kittler H, Marghoob AA, et al. Number needed to biopsy ratio and diagnostic accuracy for melanoma detection. J Am Acad Dermatol. 2020;83(3): 780-7.

12. Ahdoot M, Wilbur AR, Reese SE, Lebastchi AH, Mehralivand S, Gomella PT, et al. MRI-Targeted, Systematic, and Combined Biopsy for Prostate Cancer Diagnosis. N Engl J Med. 2020; 382(10):917-28.

13. Siddiqui MM, Rais-Bahrami S, Turkbey B, George AK, Rothwax J, Shakir N, et al. Comparison of MR/ultrasound fusion-guided biopsy with ultrasound-guided biopsy for the diagnosis of prostate cancer. JAMA. 2015;313(4):390-7.

14. Rouvière O, Puech P, Renard-Penna R, Claudon M, Roy C, Mège-Lechevallier F, et al. Use of prostate systematic and targeted biopsy on the basis of multiparametric MRI in biopsy- naive patients (MRI-FIRST): a prospective, multicentre, paired diagnostic study. Lancet Oncol. 2019;20(1):100-9.

15. Rastinehad AR, Turkbey B, Salami SS, Yaskiv O, George AK, Fakhoury M, et al. Improving detection of clinically significant prostate cancer: magnetic resonance imaging/transrectal ultrasound fusion guided prostate biopsy. J Urol. 2014;191(6): 1749-54.

16. Borkowetz A, Platzek I, Toma M, Laniado M, Baretton G, Froehner M, et al. Comparison of systematic transrectal biopsy to transperineal magnetic resonance imaging/ultrasound-fusion biopsy for the diagnosis of prostate cancer. BJU Int. 2015;116(6): 873-9.

17. Walton Diaz A, Hoang AN, Turkbey B, Hong CW, Truong H, Sterling T, et al. Can magnetic resonance-ultrasound fusion biopsy improve cancer detection in enlarged prostates? J Urol. 2013;190(6):2020-5.

18. Al-Khalil S, Ibilibor C, Cammack JT, de Riese W. Association of prostate volume with incidence and aggressiveness of prostate cancer. Res Rep Urol. 2016;8:201-5.

Factors Associated with Age at Diagnosis of Autism Spectrum Disorder in Pediatric Patients at Sawanpracharak Hospital, Thailand

Sineenat Teekavanich, M.D.*, Prakasit Wannapaschaiyong, M.D.**

*Department of Pediatrics, Sawanpracharak Hospital, Nakhon Sawan 60000, Thailand, **Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.

ABSTRACT

Objective: This study aimed to determine the average age at diagnosis and the characteristics associated with the age of children at the diagnosis of autism spectrum disorder (ASD) at Sawanpracharak Hospital.

Materials and Methods: A retrospective cross-sectional study was conducted from May 2023 to July 2023. Data were collected from the medical patient files of all children diagnosed with ASD between 2020 to 2022. Descriptive analysis was used to examine the characteristics of the children and their caregivers, and the children’s age at diagnosis. Factors associated with the age at diagnosis were assessed by chi-square test analysis.

Results: In total, 100 patient records with complete information were collected. The average age at the diagnosis

of ASD was 4.57± 1.61 years old, with 60% of the patients diagnosed after four years of age. Social communication deficit symptoms, including non-response to name and lack of pointing out objects of interest, were significantly associated with an early ASD diagnosis (p-value = 0.023 and 0.002, respectively). Being a firstborn child and the presence of delayed development were found to delay the diagnosis of ASD meaning it occurred at a later age (p-value = 0.002 and 0.019, respectively). However, sex, the caregiver’s education, and socioeconomic status were not related to the age at diagnosis.

Conclusion: Most children with ASD who received treatment at Sawanpracharak Hospital were diagnosed late. Being

a firstborn child, poor response to name being called, lack of pointing out objects of interest, and delayed development were related to the age of the children at ASD diagnosis. Differences in diagnostic age based on sociodemographic and clinical characteristics indicate the need for coordinated measures for the early detection of ASD.

Keywords: Autism Spectrum Disorder; age of diagnosis; associated factors; delayed development; social communication deficit (Siriraj Med J 2023; 75: 778-783)

INTRODUCTION

Autismspectrumdisorder(ASD)isaneurodevelopmental disorder that affects children’s development, learning ability, and daily life activities. In addition, families caring for children with ASD face increased stress from the difficulty of caring for these children and the burden of the treatment costs, which can affect family relationships. The diagnostic criteria for ASD are based

on the Diagnostic Standards and Statistical Manual for Psychological Disorders, fifth edition (DSM-5), consisting of two core symptoms: social communication deficits and restrictive, repetitive behavior or interest.1 Currently, the reported prevalence rate of ASD is as high as 1 in 36 children2, and the prevalence rate in boys is 2–3 times that of girls.3 The cause of ASD is a combination of two factors: genetic and environmental factors.4,5 The environmental

Corresponding author: Prakasit Wannapaschaiyong E-mail: pra_ka_sit@hotmail.com

Received 30 August 2023 Revised 26 September 2023 Accepted 27 September 2023 ORCID ID:http://orcid.org/0000-0001-7099-0183 https://doi.org/10.33192/smj.v75i11.265066

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

factors that correlate with this disease include maternal exposure to certain drugs or chemicals, intrauterine infections, perinatal or postnatal complications, and advanced parental age.5

At present, there are many treatment modalities for children with ASD. However, the existing modalities are not a cure for this disease, but rather, current treatment methods areaimedatminimizingdisabilitiesandminimizing children’s dependence on others in society.6 A study by Rogers and Vismara (2008) found that children with autism who received early treatment before age 3 had a better prognosis than those who received treatment after age 3.7 The results of their study may be explained by the fact that children’s brains develop rapidly and are highly adaptable before the age of 3. Early detection is crucial for early intervention in children with ASD. Therefore, the American Academy of Pediatrics (AAP) has issued recommendations for ASD screening in all children aged between 18 and 24 months old who attend health check-ups at a well-child clinic.6

In Thailand, there is no explicit recommendation for ASD screening. Previous studies have found that the average age at ASD diagnosis is between 3.9 and 5.7 years old8, considered a delayed diagnosis. The factors related to a delayed diagnosis include living in rural areas, impoverished families, and lower parental education.9,10 In contrast, severely impaired language development and abnormal noticeable repetitive movement contribute to the early diagnosis of ASD.11 However, in Thailand, no study has yet analyzed the average age at ASD diagnosis and the factors related to the age at ASD diagnosis. Thus, this study aimed to narrow this knowledge gap and use the obtained information to develop future ASD screening guidelines for Nakhon Sawan, Thailand.

MATERIALS AND METHODS

Study design and population

This was a hospital-based, descriptive retrospective cross-sectional study that was conducted from May 2023 to July 2023. All children who were diagnosed with ASD at Sawanpracharak Hospital between 2020 and 2022, according to DSM-5 criteria, were included in this study. In 2020, a developmental and behavioral pediatrician started work at Sawanpracharak Hospital and set up a complete patient record system; this was thus defined as the starting period for the data collection. A total of 100 ASD patient files with complete patient records were collected. The data collected included sex, birth order, age at diagnosis, comorbidity, family history of ASD, number of primary physicians whom the patients consulted before diagnosis, residence, symptoms that

caregivers notice before consulting physicians, and the primary caregiver’s characteristics. Although Rogers and Vismara’s study suggested that diagnosis after three years of age is late,7 in our study, almost all the children were diagnosed with ASD after 3 years of age, so we decided to use the age of 4-years old to distinguish early diagnosis from late diagnosis.

The Institutional Review Board (IRB) of Sawanpracharak Hospital (COA. 38/2565) approved the study protocol.

Data analysis

The coding in the case record forms was verified and entered into the computer system using Microsoft Excel. SPSS Statistics Program Version 26 (IBM Corp., Armonk, NY) was used for data processing and statistical analysis. The frequency, percentage of categorical data, and mean ± standard deviation were used for the descriptive analysis. In order to investigate the factors related to the age at diagnosis, the chi-squared test or Fisher’s exact test was used.

RESULTS

In this study, a total of 100 complete patient records of pediatric patients diagnosed with ASD at Sawanpracharak Hospital between 2020 and 2022 were collected and analyzed. The average age of the children at ASD diagnosis was 4.57 ± 1.61 years old. Most of the patients (88%) were boys and 61% were firstborn children. The most common comorbid conditions of these children were global developmental delay (60%) and ADHD (51%). At the same time, 9% had a positive family history of ASD. In addition, the majority of these children (84%) were diagnosed after consulting 1–2 primary physicians. Most of these children (73%) live outside the urban areas of Nakhon Sawan Province. When considering only the symptoms that caregivers observed before seeking medical consultation, the most common were hyperactivity (60%), lack of pointing out an object of interest (46%), and delayed development (39%) (Table 1).

Table 2 shows that almost all the primary caregivers

(93%) were female, and almost half (44%) were between 30 and 39 years old. Most caregivers (81%) had an education level below a bachelor’s degree. In addition, most of these children’s families (82%) earned less than USD 886 a month.

Among all the children, 40 were diagnosed with ASD before the age of four, and were classified as an early diagnosis. In contrast, the other 60, who were diagnosed after age four, were classified as a late diagnosis. The frequency distribution of the age at diagnosis based on

TABLE 1. Demographic characteristics of children with ASD who received treatment and comparison of the patients’ demographic characteristics between the “early age at diagnosis group” and “later age at diagnosis group.

Abbreviations: ASD = autism spectrum disorder, GDD = global developmental delay, ADHD = attention deficit/hyperactivity disorder. Data presented as number (percentage)

The comparison of differences was analyzed by chi-square test. aThe associations were assessed using Fisher’s exact test. *Statistically significant at p-value < 0.05.

TABLE 2. Demographic characteristics of primary caregivers’ children with ASD and comparison of the primary caregivers’ demographic characteristics between the “early age at diagnosis group” and “later age at diagnosis group.

Data presented as number (percentage).

The comparison of differences was analyzed by chi-square test. aThe associations were assessed using Fisher’s exact test. *Statistically significant at p-value < 0.05.

+1 US dollar = 33.90 bahts

various variables is illustrated in Table 1&2 using chi-square or Fisher’s exact test analysis. The symptoms observed by caregivers before the children received a medical consultation had a statistically significant association with the age at diagnosis. There was a substantial correlation between the earlier-diagnosed and the later-diagnosed age groups in having several symptoms, such as no response to name (p-value = 0.023) and lack of pointing out objects of interest (p-value = 0.002), with the earlier-diagnosed age group having a broader distribution (Table 1). On the other hand, delayed development was more common in the later-diagnosed age group (p-value = 0.019). In addition, being a firstborn child was associated with a late diagnosis of ASD (p-value = 0.002) (Table 1).

DISCUSSION

Our result reveals that the mean age at diagnosis of ASD in pediatric patients consulted at Sawanpracharak Hospital was 4.57± 1.61 years old. ASD typically shows its first signs at around 12 months of age. However,

diagnosis is only possible from the age of 18 months.12 According to previous studies, the range for the average age of diagnosis is 2.7 to 7.2 years old.12,13 Looking at the overall situation, the age at diagnosis in our population is no different from previous studies. However, recent studies have shown a trend toward early diagnosis before 3 years of age.14,15 Therefore, this result is important information to remind our hospital to actively adjust its policies to facilitate the early detection of this condition. Considering the factors that may be associated with the age at diagnosis, our study found that firstborn children were more likely to be diagnosed with ASD later than non-firstborn children. Our findings are inconsistent with previous studies that did not find an association between birth order and age at diagnosis.16,17 This disparity may be explained by the nature of our population, whose caregivers have a low education level and are unaware of the child’s expected age-appropriate development.18 However, once these caregivers had experience of raising children, they began to notice the

development difference between the first child and the non-first child. Therefore, non-firstborn children would have autism-specific symptoms noticed earlier.

In our study, the main symptoms observed by caregivers before seeking medical consultation were related to an early diagnosis of ASD, including unresponsiveness to name and lack of pointing out objects of interest. These results are consistent with Loubersak’s study (2023), which found that delayed social communication skills are associated with a younger ASD diagnosis.12 Social communication skills, including nonverbal communication, are often the symptoms that concern parents and that they notice first. Children with these symptoms are often not interested in interacting with their parents properly or using age-appropriate communication. Furthermore, early communication skills, including pointing out objects of interest and responding to names, can be found before a child is 12 months old, and observed even before children have linguistic ability. Thus, children with these symptoms are often diagnosed early.

In contrast, previous studies have shown that children

with developmental delays are diagnosed with ASD earlier than those without delayed development.12,16 That our findings are inconsistent with those studies may be explained by the fact that developmental retardation can mask the specific symptoms of autism.19 Moreover, before 2020, pediatric patients who came for consultation at Sawanpracharak Hospital were examined by general pediatricians who may not have been skilled in diagnosing ASD. Thus, this reason may have led to a delay in diagnosing this group of children.

In addition, our study did not find differences in sex, caregiver’s education, socioeconomic status, and distance to access treatment between the early- and late-diagnosed ASD groups. This finding is similar to Loubersak’s study (2023).12 These data indicate that the educational level or economic status of the caregiver is not a factor related to gaining the knowledge to observe the symptoms and characteristics of ASD. Therefore, educating caregivers to observe ASD symptoms is crucial for early diagnosis. In addition, nowadays, transportation is more convenient, so even children in remote areas far from the hospital should not have problems accessing treatment.

Our study is the first research study in Thailand to explore the factors associated with the age at diagnosis of ASD. A key benefit of finding the related factors is that they can inform the development of an intervention that can minimize the problem of the delayed diagnosis of ASD in Nakhon Sawan Province. Moreover, the average age at diagnosis data in this study may also support

developing a proactive ASD screening policy for Thailand. The American Academy of Pediatrics (AAP) has issued recommendations since 2020 for standardized ASD screening in all children aged 18 to 24 months old who come to be vaccinated in well-child visits.6 However, in Thailand, this important recommendation has not yet been implemented.

There are some limitations of this study to be noted, including this study involved a retrospective design, which means it omitted some data that may have affected the recruitment population in our study. The generalizability of our study results is also limited since our population was collected from a single-center site and involved relatively small numbers of patients. A multicenter prospective study design with a larger popopulation should be considered in a future study.

CONCLUSION

At Sawanpracharak Hospital, more than half of the children with ASD had a delayed diagnosis. Children with delayed social communication skills, including non-response to name and lack of pointing out objects of interest, were more likely to be diagnosed early. In contrast, firstborn children and children with delayed development tended to be diagnosed later.

Conflict of interest

All authors declare no conflict of interest.

REFERENCES

1. American Psychiatric Association D-TF. Diagnostic and statistical manual of mental disorders: DSM-5. 5th ed. Washington, DC: American Psychiatric Publishing, 2013.

2. Maenner MJ, Warren Z, Williams AR, Amoakohene E, Bakian AV, Bilder DA, et al. Prevalence and Characteristics of Autism Spectrum Disorder Among Children Aged 8 Years - Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2020. MMWR Surveill Summ. 2023;72(2):1-14.

3. Begeer S, Mandell D, Wijnker-Holmes B, Venderbosch S, Rem D, Stekelenburg F, et al. Sex differences in the timing of identification among children and adults with autism spectrum disorders. J Autism Dev Disord. 2013;43(5):1151-6.

4. Ronemus M, Iossifov I, Levy D, Wigler M. The role of de novo mutations in the genetics of autism spectrum disorders. Nat Rev Genet. 2014;15(2):133-41.

5. Sandin S, Hultman CM, Kolevzon A, Gross R, MacCabe JH, Reichenberg A. Advancing maternal age is associated with increasing risk for autism: a review and meta-analysis. J Am Acad Child Adolesc Psychiatry. 2012;51(5):477-86.e1.

6. Hyman SL, Levy SE, Myers SM, Council On Children With Disabilities SOD, Behavioral P. Identification, Evaluation, and Management of Children With Autism Spectrum Disorder. Pediatrics. 2020;145(1):73-75.

7. Rogers SJ, Vismara LA. Evidence-based comprehensive treatments for early autism. J Clin Child Adolesc Psychol. 2008;37(1):8-38.

8. Mandell DS, Morales KH, Xie M, Lawer LJ, Stahmer AC, Marcus SC. Age of diagnosis among Medicaid-enrolled children with autism, 2001-2004. Psychiatr Serv. 2010;61(8):822-9.

9. Shattuck PT, Durkin M, Maenner M, Newschaffer C, Mandell DS, Wiggins L, et al. Timing of identification among children with an autism spectrum disorder: findings from a population- based surveillance study. J Am Acad Child Adolesc Psychiatry. 2009;48(5):474-83.

10. Rosenberg RE, Landa R, Law JK, Stuart EA, Law PA. Factors affecting age at initial autism spectrum disorder diagnosis in a national survey. Autism Res Treat. 2011;2011:874619.

11. Mandell DS, Novak MM, Zubritsky CD. Factors associated with age of diagnosis among children with autism spectrum disorders. Pediatrics. 2005;116(6):1480-6.

12. Loubersac J, Michelon C, Ferrando L, Picot MC, Baghdadli A. Predictors of an earlier diagnosis of Autism Spectrum Disorder in children and adolescents: a systematic review (1987-2017). Eur Child Adolesc Psychiatry. 2023;32(3):375-93.

13. van‘t Hof M, Tisseur C, van Berckelear-Onnes I, van Nieuwenhuyzen A, Daniels AM, Deen M, et al. Age at autism spectrum disorder diagnosis: A systematic review and meta-analysis from 2012 to 2019. Autism. 2021;25(4):862-73.

14. Garrido D, Carballo G, Artis J, Garcia-Retamero R. Timing

    of Parents’ Concerns Related to Autism Spectrum Disorder and its Diagnosis: A Mediation Analysis. Span J Psychol. 2018;21:E59.

15. Salomone E, Charman T, McConachie H, Warreyn P, Working Group CAEtSSoEA. Prevalence and correlates of use of complementary and alternative medicine in children with autism spectrum disorder in Europe. Eur J Pediatr. 2015;174(10):1277- 85.

16. Soe SM, Linn K. Factors associated with Age of Diagnosis Among Myanmar Children with Autism Spectrum Disorders. International Journal of Child Development and Mental Health. 2016;4(2): 25-38.

17. Frenette P, Dodds L, MacPherson K, Flowerdew G, Hennen B, Bryson S. Factors affecting the age at diagnosis of autism spectrum disorders in Nova Scotia, Canada. Autism. 2013;17(2):184-95.

18. Wannapaschaiyong P, Penphattarakul A, Rojmahamongkol P, Sutchritpongsa S. The Relationship Between Primary Caregivers’ Psychosocial Factors and Self Esteem in Children and Adolescents with ADHD: An Exploratory Crosssectional Study. Siriraj Med J. 2023;75(8):584-91.

19. Miller LE, Burke JD, Robins DL, Fein DA. Diagnosing Autism Spectrum Disorder in Children with Low Mental Age. J Autism Dev Disord. 2019;49(3):1080-95.

Self-evaluation of Sexual History Taking Skills Among Medical Students in Southern Thailand

Thareerat Ananchaisarp, M.D.*, Jirayu Likitkamchorn,**, Jirapat Jitsaard,**, Natthanit Srisuriya,**, Natvara Panichkittikul,**, Porramat Chuthong,**, Pongsakorn Khanphakdee,**, Peraya Tekasakul,**, Rossawan Sahuankeaw,**, Sarawut Piyarattanayothin,**, Panya Chamroonkiadtikun, M.D.*, Chonnakarn Jatchavala, M.D., MSc.***

*Department of Family and Preventive Medicine, **Fifth-year medical student, Faculty of Medicine, ***Department of Psychiatry, Faculty of Medicine,

Prince of Songkla University, Songkhla 90110, Thailand.

ABSTRACT

Objective: Sexual health is an important issue in a holistic approach in general clinical practice. Inappropriate sexual history taking could lead to improper clinical management. This study aimed to examine perceptions of practice, attitudes toward sexual history taking and their associated factors among final year medical students in southern Thailand.

Materials and Methods: This cross-sectional survey was conducted between September and October 2022, using

a self-reported questionnaire via Google forms. The self-reported questionnaire consisted of questions related to the practice and attitude toward sexual history taking (α = 0.90 and 0.71, respectively), as well as perceptions of the undergraduate medical training on taking a sexual history (α = 0.91). Descriptive data analysis and multiple logistic regression was conducted by using Program R.

Results: Of 91 participants, most were male and Buddhist (54.9% and 87.9%). In general, most medical students

rated their proficiency in sexual history taking skills as fair-to-good across all aspects. The majority showed a positive attitude toward sexual history taking (68.1%) and reported that contraception was the main reason that they usually have such discussions with female patients (36.3%), while the prevention of sexual transmitted diseases (STDs) was the most common issue during annual examinations, and when with patients with suspected STDs (27.5% and 49.5%). Male medical students and those who perceived good-to-very good knowledge and well-to very well-trained skills of sexual history taking were significantly associated with more regular sexual history taking. [adjusted OR (95%CI) = 4.51(1.19-17.11) and 5.3 (1.51-18.65), respectively] Moreover, students with a good attitude toward sexual history taking were significantly associated with a perceived good-to-very-good training in both history taking and communication skills.

Conclusion: Most medical students exhibited a positive attitude toward sexual history taking, and they stated that

birth control and STDs symptoms were typically the primary subjects they discussed with patients in general. There was a significant association between being male, a perception of good knowledge and well-trained skills, and a more consistent practice of sexual history taking. Additionally, medical students who displayed a good attitude towards taking sexual history significantly showed a perception that they had received sufficient training in both the areas of history taking and communication skills.

Keywords: Clinical practice; medical history taking; sexual health; undergraduate medical education (Siriraj Med J 2023; 75: 784-793)

Corresponding author: Chonnakarn Jatchavala E-mail: jchonnak@medicine.psu.ac.th

Received 29 August 2023 Revised 27 September 2023 Accepted 30 September 2023 ORCID ID:http://orcid.org/0000-0001-9765-2184 https://doi.org/10.33192/smj.v75i11.264811

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

INTRODUCTION

Sexual problems and their consequences, such as, sexually transmitted diseases (STDs), teenage pregnancy, and sexual dysfunction are important global issues. Thus, sexual history taking by health care providers can be very beneficial for both early detection and proper management, not only for mentioned sexual health issues but also holistic care, such as family relationships, which can be helpful in many aspects of medical treatment.1-3 Although sexual history taking was known of being needed and expected by most patients, a study in the US found that only 58.0% of general practitioners (GPs) had asked their patients about their sexual activities.4 Whereas 12.0-34.0% of them regularly took a complete sexual history, 76.0% of American GPs would take sexual history when their patient chiefly complained of sexual related issues.5

These incomplete clinical practices may lead to

attitude toward sexual history taking, which are the primary processes of sexual health care in clinical practice. Moreover, medical students’ perceptions on undergraduate training could feed-back to the institute for developing medical education, which focuses on real-life educational content.

MATERIALS AND METHODS

Design and participants

This study used a cross-sectional design and was approved by the Human Research Ethics Committee of the Faculty of Medicine, Prince of Songkla University (REC 65-296-9-1). The participants were final-year medical students at the Prince of Songkla University (PSU).

Study sample and sampling

𝑁𝑁𝑁𝑁(1 − 𝑁𝑁)𝑧𝑧2 ∝

misdiagnosis of sexual-related diseases, especially STDs, teenage pregnancy, and erectile dysfunction, which are global public health concerns nowadays. The common

𝑛𝑛 =

1−2

𝑑𝑑2(𝑁𝑁 − 1) + 𝑁𝑁(1 − 𝑁𝑁)𝑧𝑧2 ∝

1−2

reasons why most physicians have not taken a sexual history, were their lack of confidence and inexperience. A study discovered that the reason may be insufficient training and practice during their time at medical school.6,7 56.0% of American GPs reported that they were inadequately trained for sexual history taking according to their undergraduate medical curriculum. Another study in regard to Malaysian medical students found that about half of them felt uncomfortable discussing sexual issues with their patients.6

However, no current studies on sexual history taking in undergraduate medical education were conducted in Thailand, and there is a small amount of reported research in regard to low-and middle-income countries. Most relevant studies were from other countries where medical curriculum, cultures and contexts were different from Thailand, and especially southern Thailand.6,7 Some parts of this region have been dubbed by the media as South border provinces (SBP) because of their complicated political and religious conditions which leads to ongoing violence and insurgency since 2004.8 Hence, background and perspectives found from many previous studies on medical doctors, who studied or worked within these areas may be different from other regions of country.9 For these reasons, this study aimed to examine clinical practices and attitudes toward sexual history taking among medical students in southern Thailand, as well as their associated factors. The researchers explored the Thai undergraduate medical curriculum in sexual health, especially Thai medical students’ practice and

The sample size was calculated based on the primary objective using the finite population proportion as: Due to the limited information reported on attitudes, practice, and perception on training toward sexual history taking among medical students; the researchers used prevalence

= 0.5 for maximized sample size and alpha (α) = 0.05 for the margin of error (d).

The calculated sample size was 91 medical students. We invited all the 118 medical students who studied at PSU medical school. 92 students enrolled to the survey, but one of them withdraw her/himself before the survey was completed.

Data collection

The survey was circulated among the final year medical students, via google form, during September and October 2022. The form of the questionnaire was designed for participants to be anonymous and distributed by the unit of student affairs, faculty of Medicine, Prince of Songkla university, Thailand.

Measurements

Literature regrading undergraduate medical education, and the medical curriculum on sexual health was reviewed by all authors as per the core concept of the primary aims, before the rest of the co-authors reviewed studies on practices, attitude toward sexual history taking and medical students’ perceptions or perspectives on their undergraduate training, regarding the issue of sexual health for the main objectives of this study.

The self-reported questionnaire consists of 4 parts as below:

1. Participants’ characteristics; gender, sexual orientation, age, ethnicity, religion, grade point average (GPA), and romantic relationship status

2. Attitude toward sexual history taking consisted of 5 questions (five-point scales: 1 = strongly disagree, 2 = disagree, 3 = neither agree nor disagree, 4 = agree, 5 = strongly agree):

   1. Importance of sexual history taking in general practice

   2. Impact of sexual history taking on clinical management

   3. Preference of patients to discuss on their sexual history from physician’s question

   4. Importance of confidentiality of patients ‘sexual history

   5. Preference of medical students on duration of time taking sexual history

      The Likert scale was the grouped attitude toward sexual history taking into three groups by using Best’s criterion: good (high level, score = 19-25), fair (moderate level, score = 12-18) and poor (low level, score = 5-11) attitude.

3. Practice on sexual history taking consisted of 15 questions (five-frequency scale: always [100%], usually [75-99%], often [50-75%], rarely [<50%] and never [0%])

4. Perceptions about the undergraduate medical training on taking a sexual history consisted of 9 questions about their knowledge, skills in sexual history taking and confidence on their communication skill. (There were five-rating scales: very high, high, moderate, low, and very low). The first draft of the questionnaire was tested for content validity by three experts in sexual health. The Item Objective Congruence Index (IOC) was calculated for each question and re-adjusted until the IOC value >

0.5. Then, the questionnaire was re-tested for its reliability by 30 final-year medical students in other medical schools in southern Thailand. The Cronbach’s alpha coefficient were 0.71 for the second part, 0.90 for the third part, and 0.91 for the last part of questionnaire.

Statistical analysis

All data were analyzed by the R program. Descriptive analysis was used to analyzed baseline characteristics, practice on sexual history taking and perception on undergraduate medical training of sexual history taking. The mentioned parts were presented as frequency and percentages, while multiple logistic regression was used to analyze factors associate with practice, attitude toward sexual history taking and perceptions on undergraduate medical training. A p-value =< 0.05 is considered statistically significant.

RESULTS

Demographic data

Of 91 medical students who participated in the study, most of participants were male (54.9%), with a median age of 23.0 years old (23.0, 24.0). Most of them were Thai, Buddhist and identified that their sexual orientation is heterosexual (96.7%, 87.9% and 78.0%). 72.5% of the students stated their grade point average (GPA) as between 3.01 and 4.00. More than half of the participants were single, without a current romantic relationship (63.7%) (Table 1).

Attitudes towards sexual history taking among Thai medical students

Approximately two-thirds of our participants had a high level of attitude toward sexual history taking (68.1%) and no one had a low level of attitude. Most of the participants had a strong-to-very strong agreement that sexual history taking is important for general practice (83.4%) and it significantly affected medical care (64.9%). In addition, confidentiality about the patient’s sexual history was the most critical issue (94.5%). However, 74.7% of them moderately-to-highly agreed that it took time for them to take sexual history in general, in an unpredictable manner. (Fig 1)

Practice on sexual history taking among medical students

To survey on the clinical practice, the questionnaire asked how many percent of patient consultations incorporated the taking of sexual history. Contraceptive methods were the most frequently incorporated questions asked of patients with any chief complaints (36.3% in female patients and 17.6% in male patients). During visits for annual checkups and patients with suspected sexually transmitted diseases (STDs), the most frequently asked question was about preventive methods for sexually transmitted infections. (27.5% and 49.5% respectively However, approximately half of medical students rarely- to-never asked about their partner’s gender (48.2%) and sexual activity patterns for patients who were suspected STDs (57.2%). Whereas sexual dysfunction symptoms had rarely-to-never been asked by the medical students for general patients who came with other chief complaints (61.6%) (Table 2).

Overall, most medical students assessed their ability

to conduct sexual history taking as moderate-to-good in all areas, including communication skills. Approximately two-thirds of the participants perceived that, they had skills which were well-to-very-well trained and good- to-very good knowledge in discussing and advising on

TABLE 1. Participants’ demographic data.

Characteristic Number (%)

Sex assigned at birth

Male Female

50 (54.9)

41 (45.1)

Age [Median (Q1, Q3)] 23 (23,24)

Sexual orientation

Race

Thai Cambodian/Chinese

88 (96.7)

3 (3.3)

Religion

Marital status

Single 58 (63.7)

In relationship 28 (30.8)

Non specified 5 (5.5)

Fig 1. Attitude toward sexual history taking among Thai medical students.

contraception (64.9% and 67.1% respectively), while sexual dysfunction was the topic most perceived having a moderate-to-poor skill and knowledge as (69.3% and 70.4%) However, 57.2% of them perceived their own communication skill on sexual history which were good- to-very good. (Table 3).

Factors associated practice and attitude toward sexual history taking in an undergraduate medical curriculum This part of questionnaire asked participants directly

for the perception of all skills trained under the curriculum of undergraduate medical education. According to the attitude toward sexual history taking, no significant associated factor was found. However, males and students who perceived good-to-very good knowledge and skills as well-to-very well-trained; were statistically significantly associated with usually-to-always sexual history taking in patients with symptoms leading to the suspicion of STDs {[adjusted OR (95%CI) = 4.51 (1.19-17.11)] and

[adjusted OR (95%CI) =5.3 (1.51-18.65)]}. In addition, a perception of good-to-very good skill and knowledge on sexual history taking and sexual health also was associated with more regular sexual history taking in general patients with any chief complaint [adjusted OR (95%CI) = 4.85 (1.43-16.41)] (Table 4).

Regarding perceived knowledge and skills of sexual history taking among medical students, perception of well-to-very well-trained skills regarding the curriculum, and perceived good-to-very good communication skill were statistically significant associated factors. [adjusted OR (95%CI) = 4.93 (1.5-16.22) and 3.45 (1.22-9.73),

respectively (Table 5).

DISCUSSION

To take sexual history must involve questions of sexual behavior, sexual function, sexual orientation, gender identity, sexual health risks, contraceptive uses and protection of transmitted diseases.1,10 This study covered the questions that should be asked in most general practices and inquired regarding the confidence of medical students about their trained skills and knowledge, in the context of feedback to the Thai curriculum of medical degrees (M.D.). Moreover, this survey is the first study to precisely examine sexual history taking among Thai medical students, particularly those studying in southern Thailand, in the past 10 years.

Compared with a Malaysian study, agreement on the importance of sexual history taking and patients’ confidentiality were found to be similar.6 In addition, they also showed the same opinion of hesitancy due

TABLE 2. Sexual history taking practice among medical students.

to time-consuming process of sexual history taking, which may be a part of normal Asian culture, regarding discussing sensitive issues such as sexual function.6 For these reasons, socio-cultural context should be embedded into not only sexual history taking skill, but other sensitive topics such as taking the history of psychiatric symptoms. In addition, sexual health should be embedded in both preventive care and medical treatment.1,4 However, less than half of medical students regularly took a sexual history during annual check-up visits, whereas most of them regularly asked the patients with suspected sexually transmitted diseases. Approximately half of the medical students did not ask about the history of sexual abuse and related behaviors in these patients.

While contraception is a common topic in doctor-patient discussions, the students tended to discuss it more with female patients than with male patients. These results may give feedback on the undergraduate curriculum of preventive medicine to enhance sexual health into the Thai medical education. Even though no factor associated with attitudes toward sexual history taking was found, male gender and perception on knowledge and skill regarding trained curriculum of Thai M.D. were associated factors of such practices. We can imply that the results showed the significance of appropriate teaching and training on sexual health in Thailand. Most of Thai medical students perceived their knowledge and skill on sexual history taking as fair-to-poor. Thus, further

TABLE 2. Perception of knowledge and skills of sexual history taking regarding medical curriculum.

development on sexual health and associated clinical skills regarding the undergraduate medical curriculum should be more focused on this. Furthermore, 42.8% of medical students perceived their communication skills as fair-to-poor, and this perception was significantly associated to knowledge and skills of sexual history taking.

Communication skills themselves are critical for medical practice because it is essential for building trust and rapport with patients who are often anxious and stressed, especially when they visit health care providers for sensitive issues such as psychological and sexual- related problems.11 Moreover, providing high-quality care needs good-to-very good communication skills for gathering accurate and complete patients’ information. Medical doctors must be able to communicate effectively with patients to obtain their health information, as well as clearly communicate with them for proper self-care.12 Thus, this skill may not influence only the skill of sexual history taking but may influence the general skills of medical practices.

However, these medical students have studied their

clinical practice during the COVID-19 pandemic (the fourth-to sixth years regarding the curriculum). This globally challenging situation has presented a struggle in regard to communication in general. Medical students faced challenges communicating with patients, colleagues, and medical instructors. The uses of tele-medicine and other remote teachings for undergraduate medical education may assist them for more effective communication skill. A previous study on history taking among medical students at the same medical school reported that 91% of them showed confidence on history taking in psychiatric practice in 2017-2018, whilst this study found only 42.8% reported self-assurance on the same topic.11,12 Although they engage in history taking on different issues, both are vulnerable, and their dissimilarities of prevalence could reveal the communication skill struggles during the pandemic.13 For these reasons, medical educators should provide more training and resources, such as remote classroom, case-based learning, and simulation, to help the students to improve their communication skills in the context of the COVID-19 pandemic and beyond.14

TABLE 4. Factor associated with practice and attitude toward sexual history taking among medical students.

Factor

High level of attitude toward

sexual history taking

Usually to always in practice in sexual history taking

Crude OR

(95% CI)

Adjusted OR

(95% CI)

P-value

Visiting for annual examination

Crude OR Adjusted OR

Visiting with suspected STDs

Crude OR Adjusted OR

Visiting for any chief complaint

(95% CI)

(95% CI)

P-value

(95% CI)

Crude OR

P-value

(95% CI) (95% CI)

Adjusted OR

(95% CI)

P-value

Sex assigned at birth

Original Article SMJ

Factor

High level of attitude toward

sexual history taking

Usually to always in practice in sexual history taking

Visiting for annual examination

Crude OR Adjusted OR

Visiting with suspected STDs

Crude OR Adjusted OR

Visiting for any chief complaint

Crude OR

Adjusted OR

Crude OR

Adjusted OR

TABLE 4. Factor associated with practice and attitude toward sexual history taking among medical students. (Continue)

aNon-heterosexual = Homosexual, Bisexual, and Pansexual

bReligion: others = Muslim, Christian, Irreligious, and Non specified

https://he02.tci-thaijo.org/index.php/sirirajmedj/index Volume 75, No.11: 2023 Siriraj Medical Journal 791

TABLE 5. Factor associated with the perception of knowledge and skills of sexual history taking regard to medical curriculum.

aNon-heterosexual = Homosexual, Bisexual, and Pansexual

bReligion: others = Muslim, Christian, Irreli¬gious, and Non specific

Limitations and suggestions

This study has a cross-sectional design. It is useful for gathering information on specific topics such as the sexual history taking on medical students in southern Thailand. Even though more than half of medical students in southern Thailand have studied at the Prince of Songkla university, this study was conducted at a single centre. Thus, this study may not be representative for all Southern- Thai medical students. Another limitation is the temporal sequence of events because all data was collected at a single point in time. So, it was difficult to establishing a cause-and-effect relationship, especially when the survey was done during the COVID-19 pandemic. The first recommendation for further studies should be to conduct multi-center surveys that include all clinics, such as those that offer rehabilitation services.15 In addition, a time-series study may be beneficial in following the outcomes of curriculum development.

CONCLUSION

This study on medical education aimed to examine the perception of practice, attitude toward sexual history taking and their associated factors among the final year medical students in southern Thailand. Most participants were male and Buddhists. Most of them showed a good attitude towards sexual history taking and reported that contraception was the primary topic discussed with patients. The prevention of sexually transmitted diseases (STDs) was the most common issue for both annual examinations and patients with suspected STDs. Male medical students who perceived good-to-very good knowledge and well-to-very well-trained skills in sexual history taking were significantly associated with more regular sexual history taking. Additionally, Thai medical students with a positive attitude towards sexual history taking were significantly associated with good training of their skills in both history taking and communication.

ACKNOWLEDGEMENTS

This research was a part of the project by the second to the tenth co-authors for their Family Medicine and Community Medicine III, IV program as a section of their undergraduate medical curriculum, in the academic year of 2022. All authors would like to thank Mr. Kittisak Choomalee and Ms. Kruewan Jongborwanwiwat for their helpful statistical support. Finally, we also deeply appreciate Mr Athanasios Maniatis from the International Affairs Unit, in the faculty of Medicine at the Prince

of Songkla University for his assistance in manuscript revision.

REFERENCES

1. World Health Organization. Sexual health [Internet]. Geneva: WHO; 2006 [cited 2022 Aug 2]. Available from: https://www. who.int/health-topics/sexual-health

2. Brookmeyer KA, Coor A, Kachur RE, Beltran O, Reno HE, Dittus PJ. Sexual history taking in clinical settings: a narrative review. Sex Transm Dis. 2021;48(6):393-402.

3. Zannoni R, Dobberkau E, Kaduszkiewicz H, Stirn AV. Addressing sexual problems in German primary care: a qualitative study. J Prim Care Community Health. 2021;12:21501327211046437.

4. Verhoeven V, Bovijn K, Helder A, Peremans L, Hermann I, Van Royen P, et al. Discussing STIs: doctors are from Mars, patients from Venus. Fam Pract. 2003;20(1):11-5.

5. Wimberly YH, Hogben M, Moore-Ruffin J, Moore SE, Fry- Johnson Y. Sexual history-taking among primary care physicians. J Natl Med Assoc. 2006;98(12):1924-9.

6. Ariffin F, Chin KL, Ng C, Miskan M, Lee VK, Isa MR. Are medical students confident in taking a sexual history? An assessment on attitude and skills from an upper middle income country. BMC Res Notes. 2015;8:248.

7. Ashton MR, Cook RL, Wiesenfeld HC, Krohn MA, Zamborsky T, Scholle SH, et al. Primary care physician attitudes regarding sexually transmitted diseases. Sex Transm Dis. 2002;29(4): 246-51.

8. Jatchavala C, Vittayanont A. Post-traumatic stress disorder symptoms among patients with substance-related disorders in the restive areas of south Thailand insurgency. Songkla Med

   J. 2017;35(2):121-32.

9. Jatchavala C, Pitanupong J. Resilience in medical doctors within the areas of the Southern Thailand insurgency. Siriraj Med J. 2019;71(3):228-33.

10. Planned Parenthood. Sexual Orientation [Internet]. Washington, DC: Planned Parenthood Federation of America [cited 2022 Oct 9]. Available from: https://www.plannedparenthood.org/ learn/sexual-orientation/sexual-orientation

11. Jatchavala C, Pitanupong J. Self-perceived incompetence in psychiatric practice of practitioners from Southern Thailand: one yearfollowinggraduation. Walailak JSci& Tech. 2021;18(12):10408.

12. Jatchavala C, Sangkool J. A survey concerning the psychiatric practices of medical doctors, who graduated from Prince of Songkla University in 2017. J Ment Health Thai. 2019;27(1): 52-64.

13. Nagendrappa S, de Filippis R, Ramalho R, Ransing R, Orsolini L, Ullah I, et al. Challenges and opportunities of psychiatric training during COVID-19: early career psychiatrists' perspective across the World. Acad Psychiatry. 2021;45(5):656-7.

14. Orsolini L, Jatchavala C, Noor IM, Ransing R, Satake Y, Shoib S, et al. Training and education in digital psychiatry: a perspective from Asia-Pacific region. Asia Pac Psychiatry. 2021;13(4): e12501.

15. Rittirong P, Thirapatarapong W, Thanakiatpinyo T. Patients’ Need for Sexual Counseling in the Cardiac Rehabilitation Service. Siriraj Med J. 2023;75(7):522-8.

Efficacy of Atropine Eye Drops for Suppressing Myopia Progression in Thai Children

Thammanoon Surachatkumtonekul, M.D.*, Pinpilai Jutasompakorn, M.D.**, Sirawadee Wiriyaudomchart, M.D.*, Kiatthida Hokierti, M.D.*, Jureeporn Sri-in**

*Department of Ophthalmology, **Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.

ABSTRACT

Objective: This retrospective cohort study aimed to assess the efficacy and safety of low-dose atropine eye drops in retarding myopic progression among school-age children at Siriraj Hospital.

Materials and Methods: The medical records of 247 myopia-diagnosed patients were reviewed. All patients were received low-dose atropine eye drops and had at least one follow-up visit within 1 year after the treatment initiation. Spherical equivalent (SE) measurements were collected at pre- and post-treatment visits, as well as any reported side effects. Comparing the SE changes observed between the pre- and post-treatment periods, as well as between the two different concentrations of atropine was analyzed.

Results: A total of 493 eyes were analyzed, with 461 eyes receiving 0.01% atropine eye drops and 32 eyes being

administered 0.05%. The demographic data between two groups showed no significant difference. The comparison of SE change one year prior to and one year after treatment in the 0.01% and 0.05% group yielded a p-value of less than 0.001 and 0.003, respectively, (SE change were -0.38 D (-0.75-0.00 D) and -0.25 D (-0.72-(-0.25 D)) in the 0.01% and 0.05% group, respectively). However, the between-group comparison of SE change at 6 months and 1 year showed no significant difference. Regarding side effects, one-third of the eyes (12 eyes) in the 0.05% group (37.5%) experienced adverse effects while only eight eyes (1.7%) in the 0.01% group reported side effects.

Conclusion: This research contributes support to the effectiveness of employing low-dose atropine for the treatment

of myopia in Thai children. However, the use of 0.05% atropine was associated with a higher incidence of side effects.

Keywords: Myopia; Atropine Eye Drops (Siriraj Med J 2023; 75: 794-799)

INTRODUCTION

Myopia, or nearsightedness, is a visual condition resulting in blurred distance vision. Holden and colleagues estimated a prevalence of myopia in 1.4 billion individuals worldwide in 2000 (22.9%), with a predicted increase to

4.8 billion by 2050.1 The prevalence of myopia has been on the rise globally, particularly in Asian populations, and reportedly dramatically increased during the COVID-19 pandemic period.2-6 Multiple factors have been attributed to the development of myopia, including genetic, environmental, and lifestyle factors, such as

increased screen time on electronic devices, decreased outdoor exposure, and prolonged reading and studying.7 Myopia usually occurs and progresses during the school- age period.7 High myopia (-5.0 diopters or more), which can develop during the school-age period, can potentially extend beyond just affecting a person’s daily activities and can lead to subsequent complications, such as retinal detachment, glaucoma, cataract, or macular pathologies.8-10 Therefore, proactive practice to prevent and mitigate its progression should be taken into consideration.

The treatment approaches for myopia encompass

Corresponding author: Thammanoon Surachatkumtonekul E-mail: si95thim@gmail.com

Received 29 July 2023 Revised 11 September 2023 Accepted 19 September 2023 ORCID ID:http://orcid.org/0000-0002-0037-6863 https://doi.org/10.33192/smj.v75i11.264383

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

various strategies, including environmental modifications, optical interventions, and medical treatment. Among the treatment options, atropine, which is a liquid medication that comes in the form of eye drops, has gained significant attention in recent years due to its ability to suppress the elongation of the eyeball and slow the progression of myopia.11 Although the exact mechanism by which atropine slows myopia is not fully understood, it is believed to involve non-selective antimuscarinic, mydriatic, and cycloplegic effects, which block accommodation of the eye.12 Other mechanisms, such as dopamine release, increased choroidal thickness, remodeling of scleral fibroblasts, and the inhibition of glycosaminoglycan in eye growth, are still not well elucidated.12-16 However, the optimal concentration of atropine that strikes a balance between its efficacy and limiting its side effects remains uncertain. Several randomized controlled trials have been conducted to observe the outcomes and side effects of different atropine concentrations, ranging from 0.01% to 1%, in school-age children with myopia.

The ATOM 117 and ATOM 218 studies conducted in

Singapore found that 0.01% atropine was the most effective concentration in suppressing axial length elongation with minimal side effects. Similarly, a retrospective study from Tiana et al.19 and a prospective study in Japan20 reported similar results. However, in a Hong Kong study, 0.05% was reported to be the most effective concentration among the 0.01%, 0.025%, 0.05% tested concentrations, and a placebo, with no serious side effects observed in any of the groups.21,22 These results highlight the variability in the optimal concentration, even among school-age Asian populations.23 Additionally, no study has yet been conducted in a Thai population to determine the appropriate concentration and potential side effects of atropine, despite started using 0.01% atropine since 2016 and 0.05% since 2019 in Siriraj Hospital in concentrations of 0.05% and. 0.01%. Therefore, we conducted this study to provide information specific to a Thai population to aid in clinical practice.

MATERIALS AND METHODS

This study was approved by the the International Review Board of Faculty of Medicine Siriraj Hospital (COA no. Si 650/2022). Following the approval, patients diagnosed with ICD-10 codes referring to myopia (H25.1) were identified. This retrospective comparative cohort study consisted of school-age patients aged 5–18 years old who were diagnosed with myopia with a spherical equivalent (SE) higher than -1.00 diopter (D) for more than 1 year. All the included patients were receiving atropine as the

treatment at Department of Ophthalmology, Faculty of Medicine Siriraj Hospital, between January 2017 and December 2022. The inclusion criteria encompass the following conditions: individuals aged between 5 and 18 years old, myopic children with spherical equivalent (SE) greater than -1.0 D, who have been diagnosed with myopia for over one year and exhibit evidence of progression (indicated by changes in SE) and have not undergone any other forms of treatment aside from wearing eyeglasses prior to the prescription of atropine. Patients with concomitant ocular conditions that could potentially impact visual acuity, such as corneal pathologies, cataracts, and glaucoma, were excluded from the study. Additionally, individuals who were diagnosed with myopia subsequent to ophthalmic surgery or were lost to follow- up within the first year after initiating treatment were also excluded.

The required sample size was calculated with an

alpha of 0.05, mean difference from a previous study of 0.22021, power of 80%, and ratio of 6:1 between the 0.01% and 0.05% concentration atropine treatments. The required sample sizes according to the calculations were 71 and 426 in the 0.05% and 0.01% groups, respectively.

Evaluation method

The patient’s demographic data, clinical features, and ocular examination data were retrospectively reviewed. Age at myopia diagnosis, age at starting atropine eye drops, sex, coexisting ocular diseases, best-corrected visual acuity (BCVA) before treatment, and autorefraction were recorded. At post-treatment visits, the spherical equivalent refractive errors were measured, and the side effects of the atropine eye drops at 6 months and 1 year were recorded.

Descriptive statistics were utilized to summarize the demographic data and clinical characteristics of the patients. Categorical data were presented as frequencies and percentages, while continuous variables were presented as median values and interquartile ranges (IQR) or as the mean and standard deviation (SD). Comparisons between the two groups were evaluated using Fisher exact or Mann– Whitney U test according to the distributive nature. The visual acuity data were transformed logarithmically to the minimum angle of resolution (logMAR) equivalents for statistical analysis. Changes in BCVA, spherical values, and spherical equivalent (SE) after treatment were evaluated using the Wilcoxon signed-rank test. A p-value of less than 0.05 was considered statistically significant. All the analyses were conducted using SPSS Statistics version 28.0 (SPSS, Inc, Chicago, IL, USA).

RESULTS

Overall, 247 cases (493 eyes) were enrolled in the study, among which 461 eyes received 0.01% atropine eye drops, while 32 eyes received 0.05% atropine eye drops. Table 1 presents all the relevant demographic data of the patients. The mean age of the patients in the 0.01% atropine group was 10.70 years old (SD ± 2.85), while in the 0.05% atropine group, the mean age was

10.06 years old (SD ± 3.67). No significant differences were observed in the demographic data between the patients receiving 0.01% atropine and those receiving 0.05% atropine.

Before treatment, myopic progression (spherical equivalent change) over one year in the 0.01% atropine group was -0.87 D (-1.37 to -0.5 D), while in the 0.05% atropine group, was -0.5 D (-1.09 to 0 D) (P-value 0.010). Following the initiation of atropine treatment, at the 6-month mark, myopic progression in the 0.01% atropine group (spherical equivalent) was -0.13 D (-0.38 to 0.13 D), whereas in the 0.05% atropine group was 0 D (-0.22 to 0.22 D) (P-value 0.053). After one year of treatment, myopic progression in the 0.01% atropine group (spherical equivalent) was -0.38 D (-0.75 to 0 D), and in the 0.05% atropine group, was -0.25 D (-0.75 to

TABLE 1. Demographic data and clinical findings.

Abbreviations: IQR = interquartile range, SD = standard deviation, BCVA = Best-corrected visual acuity, logMAR = logarithmic minimum angle of resolution, SE = spherical equivalent.

*p-values were obtained by chi-square test.

†p-values were obtained by independent t test.

#p-values were obtained by Mann Whitney U test.

-0.25 D) (p-value 0.799). When comparing the efficacy within each atropine group before and after one year of treatment, both concentrations demonstrated a significant ability to slow myopic progression (p-value < 0.001 for the 0.01% atropine group and p-value = 0.003 for the 0.05% atropine group). However, when comparing the efficacy between the two groups at the one-year mark, no significant difference was observed (p-value = 0.799) (Fig 1).

In the 0.01% atropine group, four cases (8 eyes) (1.7%) experienced adverse drug reactions, with blurred near vision reported in two cases, headache in one case, and eye irritation in one case. Conversely, in the 0.05% atropine group, six cases (12 eyes) (37.5%) exhibited adverse drug reactions, including two cases of photophobia, one case of pupil dilatation, and three cases of blurred near vision (P-value 0.001).

DISCUSSION

Since 196624, atropine has been utilized as a mean to decelerate the progression of myopia and is widely regarded as the most effective medication available today.11 Topical atropine, available in varying concentrations ranging from 0.01% to 1%, has been employed to effectively delay the progression of myopia18,24-28 Numerous studies have indicated that 0.01% atropine may be the most suitable

concentration for managing myopia progression.17,18,29-33 However, it is important to note that no specific concentration of atropine has yet received approval from the US Food and Drug Administration (FDA) for the treatment of myopia.

At our institution, the hospital pharmacy unit has been preparing 0.01% atropine eye drops for clinical use since 2016, followed by the introduction of 0.05% atropine in 2019. Consequently, the sample size in our study consisted of more eyes in the 0.01% atropine group (461 eyes) than in the 0.05% atropine group (32 eyes), with the latter group number being lower than the expected sample size calculated statistically (71 eyes). Furthermore, in the 0.05% group, the change in spherical equivalent (SE) prior to treatment initiation showed a smaller shift. This observation might be attributed to the smaller sample size and a proclivity to prescribe a higher concentration of atropine, likely driven by the younger age of the participants and a higher incidence of family history of myopia (37.5% and 26.6% in the 0.05% and 0.01% groups, respectively). The results of our study demonstrated statistically significant efficacy in myopia retardation during the one-year follow-up period in both the 0.01% and 0.05% atropine groups, consistent with findings from similar studies conducted worldwide. However, although the 0.05% atropine group

Fig 1. Comparison of SE change between before and after starting treatment and between atropine groups.

• 0.01% atropine group (N = 461): SE change -0.87 D (1-year before treatment), SE change -0.38 D (1-year after treatment) (p value < 0.001)

• 0.05% atropine group (N = 32): SE change -0.50 D (1-year before treatment), SE change -0.25 D (1-year after treatment) (p value = 0.003)

• Green circle = 6 months after treatment (SE change -0.13 D (0.01% atropine) vs 0.00 D (0.05% atropine) p value = 0.053)

• Yellow circle = 1 year after treatment (SE change -0.38 D (0.01% atropine) vs -0.25 D (0.05% atropine) p value = 0.799)

* = Comparison was done by using Wilcoxon signed-rank test. # = Comparison was done by using Mann Whitney-U test.

Abbreviation: SE = spherical equivalent

exhibited a tendency toward a smaller change in spherical equivalent compared to the 0.01% atropine group, this difference did not reach statistical significance. This lack of statistical significance may be attributed to the discrepancy in the sample size between our two groups. There are known to be some possible adverse drug reactions associated with topical atropine, which are dependent on its concentration23, with higher concentrations being associated with an increased likelihood of side effects. In the present study, a small number of patients in the 0.01% atropine group (1.7%) reported experiencing side effects. These side effects included one case of headache, two cases of blurred near vision, and one case of eye irritation. Conversely, approximately one-third of the patients in the 0.05% atropine group experienced side effects. These side effects included two cases of photophobia, one case of pupil dilatation, and three cases of blurred

near vision.

The present study has several limitations that need to be acknowledged. First, the small sample size, particularly within the 0.05% atropine group, restricted the statistical power and may have affected the ability to establish significant differences in clinical outcomes between the two atropine concentrations. Therefore, caution should be exercised when interpreting the results. Additionally, the relatively short one-year follow-up period may not have captured the long-term effects of atropine treatment for myopia management. The efficacy and safety profiles of 0.05% and 0.01% atropine concentrations may evolve over an extended period, highlighting the importance of conducting studies with longer follow-up durations. Furthermore, the present study only explored the comparative effectiveness of two atropine concentrations (0.05% and 0.01%).

To overcome these limitations and provide more robust and conclusive results, future studies should aim to include larger sample sizes to enhance the statistical power and improve the generalizability. Moreover, extending the follow-up period to multiple years would offer insights into the sustainability of the observed outcomes and potential long-term effects. Lastly, investigating additional concentrations of atropine would help elucidate the dose–response relationship and aid optimizing treatment strategies.

CONCLUSION

In conclusion, this preliminary study had shown that both 0.01% and 0.05% atropine concentrations are effective in delaying myopic progression among Thai school-age children. However, the higher incidence of adverse drug reactions in the 0.05% atropine group

suggests the need for careful consideration when choosing the optimal concentration for myopia management in this specific population.

REFERENCES

1. Holden BA, Fricke TR, Wilson DA, Jong M, Naidoo KS, Sankaridurg P, et al. Global Prevalence of Myopia and High Myopia and Temporal Trends from 2000 through 2050. Ophthalmology. 2016;123(5):1036-42.

2. Matsumura S, Ching-Yu C, Saw S-M. Global Epidemiology of Myopia. In: Ang M, Wong TY, editors. Updates on Myopia: A Clinical Perspective. Singapore: Springer Singapore; 2020.

   p. 27-51.

3. Dolgin E. The myopia boom. Nature. 2015;519(7543):276-8.

4. Zhang X, Cheung SSL, Chan HN, Zhang Y, Wang YM, Yip BH, et al. Myopia incidence and lifestyle changes among school children during the COVID-19 pandemic: a population-based prospective study. Br J Ophthalmol. 2022;106(12):1772-8.

5. Xu L, Ma Y, Yuan J, Zhang Y, Wang H, Zhang G, et al. COVID-19 Quarantine Reveals That Behavioral Changes Have an Effect on Myopia Progression. Ophthalmology. 2021;128(11):1652-4.

6. Pan CW, Dirani M, Cheng CY, Wong TY, Saw SM. The age- specific prevalence of myopia in Asia: a meta-analysis. Optom Vis Sci. 2015;92(3):258-66.

7. Theophanous C, Modjtahedi BS, Batech M, Marlin DS, Luong TQ, Fong DS. Myopia prevalence and risk factors in children. Clin Ophthalmol. 2018;12:1581-7.

8. Saw SM, Gazzard G, Shih-Yen EC, Chua WH. Myopia and associated pathological complications. Ophthalmic Physiol Opt. 2005;25(5):381-91.

9. Mitchell P, Hourihan F, Sandbach J, Wang JJ. The relationship between glaucoma and myopia: the Blue Mountains Eye Study. Ophthalmology. 1999;106(10):2010-5.

10. Iwase A, Araie M, Tomidokoro A, Yamamoto T, Shimizu H, Kitazawa Y. Prevalence and causes of low vision and blindness in a Japanese adult population: the Tajimi Study. Ophthalmology. 2006;113(8):1354-62.

11. Huang J, Wen D, Wang Q, McAlinden C, Flitcroft I, Chen H, et al. Efficacy Comparison of 16 Interventions for Myopia Control in Children: A Network Meta-analysis. Ophthalmology. 2016;123(4):697-708.

12. Tran HDM, Tran YH, Tran TD, Jong M, Coroneo M, Sankaridurg P. A Review of Myopia Control with Atropine. J Ocul Pharmacol Ther. 2018;34(5):374-379.

13. Zhang Z, Zhou Y, Xie Z, Chen T, Gu Y, Lu S, Wu Z. The effect of topical atropine on the choroidal thickness of healthy children. Sci Rep. 2016;6:34936.

14. Barathi VA, Beuerman RW. Molecular mechanisms of muscarinic receptors in mouse scleral fibroblasts: Prior to and after induction of experimental myopia with atropine treatment. Mol Vis. 2011;17:680-92.

15. Barathi VA, Weon SR, Beuerman RW. Expression of muscarinic receptors in human and mouse sclera and their role in the regulation of scleral fibroblasts proliferation. Mol Vis. 2009;15: 1277-93.

16. Gallego P, Martinez-Garcia C, Perez-Merino P, Ibares-Frías L, Mayo-Iscar A, Merayo-Lloves J. Scleral changes induced by atropine in chicks as an experimental model of myopia. Ophthalmic Physiol Opt. 2012;32:478–84

17. Chua WH, Balakrishnan V, Chan YH, Tong L, Ling Y, Quah BL, et al. Atropine for the treatment of childhood myopia. Ophthalmology. 2006;113(12):2285-91.

18. Chia A, Chua WH, Cheung YB, Wong WL, Lingham A, Fong A, et al. Atropine for the treatment of childhood myopia: safety and efficacy of 0.5%, 0.1%, and 0.01% doses (Atropine for the Treatment of Myopia 2). Ophthalmology. 2012;119(2): 347-54.

19. Clark TY, Clark RA. Atropine 0.01% Eyedrops Significantly Reduce the Progression of Childhood Myopia. J Ocul Pharmacol Ther. 2015;31(9):541-5.

20. Hieda O, Hiraoka T, Fujikado T, Ishiko S, Hasebe S, Torii H, et al. Efficacy and safety of 0.01% atropine for prevention of childhood myopia in a 2-year randomized placebo-controlled study. Jpn J Ophthalmol. 2021;65(3):315-25.

21. Yam JC, Jiang Y, Tang SM, Law AKP, Chan JJ, Wong E, et al. Low-Concentration Atropine for Myopia Progression (LAMP) Study: A Randomized, Double-Blinded, Placebo-Controlled Trial of 0.05%, 0.025%, and 0.01% Atropine Eye Drops in Myopia Control. Ophthalmology. 2019;126(1):113-24.

22. Yam JC, Li FF, Zhang X, Tang SM, Yip BHK, Kam KW, Ko ST, Young AL, Tham CC, Chen LJ, Pang CP. Two-Year Clinical Trial of the Low-Concentration Atropine for Myopia Progression (LAMP) Study: Phase 2 Report. Ophthalmology. 2020;127(7): 910-9.

23. Gong Q, Janowski M, Luo M, Wei H, Chen B, Yang G, et al. Efficacy and Adverse Effects of Atropine in Childhood Myopia: A Meta-analysis. JAMA Ophthalmol. 2017;135(6):624-30.

24. Bedrossian RH. Treatment of progressive myopia with atropine. Presented at: The XX International Congress of Ophthalmology; 14–19 August 1966; Munich, Germany.

25. Gimbel HV. The control of myopia with atropine. Can J Ophthalmol. 1973;8(4):527-32.

26. Yen MY, Liu JH, Kao SC, Shiao CH. Comparison of the effect of atropine and cyclopentolate on myopia. Ann Ophthalmol. 1989;21(5):180-2, 187.

27. Fan DS, Lam DS, Chan CK, Fan AH, Cheung EY, Rao SK. Topical atropine in retarding myopic progression and axial length growth in children with moderate to severe myopia: a pilot study. Jpn J Ophthalmol. 2007;51(1):27-33.

28. Sri-in J, Sisan W, Kingkhangphloo P, Jutasompakorn P, Chandranipapongse W, Chatsiricharoenkul S, et al. Stability and Sterility of Extemporaneously Prepared 0.01% Atropine Ophthalmic Solution in Artificial Tears and Balanced Salt Solution. Siriraj Med J [Internet]. 2022 Feb. 1 [cited 2023 Sep. 10];74(2):

    91-9.

29. Tong L, Huang XL, Koh AL, Zhang X, Tan DT, Chua WH. Atropine for the treatment of childhood myopia: effect on myopia progression after cessation of atropine. Ophthalmology. 2009;116(3):572-9.

30. Chia A, Chua WH, Wen L, Fong A, Goon YY, Tan D. Atropine for the treatment of childhood myopia: changes after stopping atropine 0.01%, 0.1% and 0.5%. Am J Ophthalmol. 2014;157(2): 451-7.e1.

31. Chia A, Lu QS, Tan D. Five-Year Clinical Trial on Atropine for the Treatment of Myopia 2: Myopia Control with Atropine 0.01% Eyedrops. Ophthalmology. 2016;123(2):391-9.

32. Pineles SL, Kraker RT, VanderVeen DK, Hutchinson AK, Galvin JA, Wilson LB, et al. Atropine for the Prevention of Myopia Progression in Children: A Report by the American Academy of Ophthalmology. Ophthalmology. 2017;124(12):1857- 66.

33. Kaiti R, Shyangbo R, Sharma IP. Role of Atropine in the control of Myopia Progression- A Review. Beyoglu Eye J. 2022;7(3):157- 66.

Smartphone Addiction, Daytime Sleepiness and Depression among Undergraduate Medical Students: A Cross-sectional Study in a Medical College of Kolkata, India

Nirmalya Manna, M.D., Shibasish Banerjee, M.D., Ankush Banerjee, M.D., Arup Chakraborty, M.D., Debasis Das, M.D.

Department of Community Medicine, Medical College, Kolkata, India.

ABSTRACT

Objective: Smartphone addiction has become an emerging problem among the youth, especially among medical students in India. It has the potential to hamper their sleep quality as well act as a precipitating factor for depression. This study thus assessed the magnitude of smartphone addiction, excessive daytime sleepiness and depression among undergraduate medical students in Kolkata and elicited its determinants.

Materials and Methods: This cross-sectional study was conducted among 204 undergraduate medical students

in a selected medical college of Kolkata from March to June 2023. Smartphone addiction, daytime sleepiness and depression were assessed using the SAS-SV, EPSS and PHQ-9 questionnaires. Logistic regression analysis was undertaken to determine the associated factors of smartphone addiction, while Spearman’s correlation coefficient was estimated to find the relationship of smartphone addiction with depression and daytime sleepiness.

Results: Approximately 29.4% participants were addicted to smartphone, 45.5% were suffering from excessive

daytime sleepiness. The depression scores on the PHQ-9 scale showed a mean value of 8.15 (±4.72). Factors significantly associated with smartphone addiction were increasing age (AOR=1.23, 95%CI=1.12-2.21), male gender (AOR=2.12, 95% CI=1.36-3.45) and duration of smart phone usage >6 hours per day (AOR=1.92, 95%CI=1.23- 2.45). Smartphone addiction showed positive correlation with both daytime sleepiness (ρ =0.5, p-value<0.05) and depression (ρ=0.23, p-value=0.001)

Conclusion: Utmost care should be taken for promoting good mental health and wellbeing among medical students.

Motivation and counselling sessions along with peer support groups can help in combating this addictive behaviour and depressive symptoms.

Keywords: Depression; excessive sleepiness; medical students; smartphone addiction (Siriraj Med J 2023; 75: 800-808)

INTRODUCTION

With the advancement of artificial intelligence and technology over the past decade, smartphones have become an indispensable entity in our daily life. A smartphone is characterized not only by its conventional utilities of communication but also consists of sophisticated software, internet, and multimedia functionality. The Telecom Regulatory Authority of India has reported

the wireless telephone density to be 82.57% as on 31st December 2022.1 Recent trends in smartphone market analysis predicts a growth of smartphone market size from 1.45 in the year 2023 to 1.78 in 20282 The rapid escalation in India has been boosted by “Digital India” initiative launched by the government to ensure the availability of government’s services electronically via smartphone and internet to its citizens.3

Corresponding author: Ankush Banerjee E-mail: ankush.banerjee20@gmail.com

Received 12 September 2023 Revised 30 September 2023 Accepted 30 September 2023 ORCID ID:http://orcid.org/0000-0003-2762-123X https://doi.org/10.33192/smj.v75i11.265331

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

Gambling addiction has been classified under “substance-related and addictive disorders.” as per the latest version of Diagnostic and Statistical Manual of Mental Disorders (DSM-5)4,5 Smartphone addiction is often characterized by the presence of the following elements: functional impairment, compulsive behavior, withdrawal, and tolerance. These characteristics bear quite similarities with the DSM-5 criteria of substance use and addictive disorders.6 Thus, psychologists often opine an irrational overuse of smartphones to be denoted as smartphone addiction which has high propensity in becoming one of the most prevalent forms of addictions.7 A major proportion of smartphone users comprises college-going young adults; especially medical students, who utilize their smartphone not only for communication and recreational purposes, but also as an educational tool in their vast medical curriculum. Research work suggests that smartphone has become such a significant part in a student’s life that they do not necessarily realize their level of dependence on it.8 Smartphone addiction can have adverse effects on the health and well-being of an individual as it can precipitate physical ailments (neck and wrist pain and accidents) as well as behavioral problems (depression).9 It can also interfere with academic performances, reduce social interactions, cause negligence in personal life and form an important environmental factor disturbing quality sleep, thus leading to lethargy and excessive sleepiness during daytime working hours. Sleep restoration has shown a strong relationship with better physical, cognitive, and psychological well-being in adults, adolescents, as well as in children. Good quality sleep is thus an essential entity in a student’s life as poor sleep quality increases the risk of physical and mental

disorders.10-12

Unfortunately, medical students are exposed to high levels of stress right from the beginning of their course, and this makes them highly vulnerable to sleep deprivation. Smartphone addiction if present in these students might aggravate this problem and have impact on their sleep quality. Lack of sufficient sleep often leads to undesired consequences like medical errors, job burnout and depression.13 In addition, the emergence of the COVID-19 pandemic has shown an increase in the mode of virtual learning which has the potential to initiate a vicious cycle of smartphone addiction, sleep deprivation and mental distress. Moreover, previous studies in Asia have opined smartphone addiction acting as a defense mechanism to compensate for sadness, boredom and other mental health disorders.14 A previous study among medical students in Thailand have demonstrated 11.1% of participants suffering from depression which highlighted

the relationship between smartphone addiction and depression among medical students.15 There is dearth of literature in this domain among undergraduate medical students in the city of Kolkata, especially after the emergence of the pandemic. With this backdrop, this study envisaged to assess the magnitude of smartphone addiction, excessive daytime sleepiness, and depression among undergraduate medical students of a medical college in Kolkata and elicit its associated determinants.

MATERIALS AND METHODS

This cross-sectional study was conducted from March to June 2023 among undergraduate medical students of Medical College and Hospital, Kolkata. Data were collected from the study participants from April to May 2023. The study was conducted after taking clearance from Institutional Ethics Committee for Human Research of Medical College and Hospital, Kolkata (Approval ID: MC/ KOL/IEC/NON-SPON/1832/04/2023 dated: 05/04/2023).

Participants who did not give written informed consent or were absent during the data collection phase were excluded from the study.

Sampling

A previous study conducted by Nowreen N et al4 among undergraduate medical students of SKIMS Medical College, Srinagar, India showed the prevalence of smartphone addiction to be 34.4% Considering P=0.344 (34.4%),

Z1-α=1.96, Q=1-P and absolute error of precision (L) to be 8% (0.08), the minimum sample size was estimated using the (Z1-α)2PQ/L2, which comes to be 135.16 Since

simple random sampling was not done, a design effect of

1.5 was added and the final sample size came to be 204.

Multistage probabilistic sampling technique was used to select the study participants. Students were distributed into 5 groups according to their academic year of study. (1st year, 2nd year, 3rd year, 4th year and internship period). Data regarding total number of students present in each of the academic years was collected from the college registers and line listing was done. At first, the total number of students required from each academic year was calculated according to proportionate allocation as per the sample size. Then after calculating the requisite number of participants from each year, in the 2nd stage, participants from each year were selected through simple random sampling by computer generated random number tables

Data collection, study tools and parameters used

On the day of data collection, the investigators explained the purpose & procedure of the study elaborately

to the participants and written informed consent was taken from them. They were assured of the confidentiality of the data. The study was conducted via face-to-face interview with the study participants with the help of a pre-designed pre-tested self-administered questionnaire. Pre-testing of the questionnaire was done among 30 students of a different medical college who were not included in the study. Reliability of the questionnaire was checked by estimating Cronbach’s alpha coefficient while face and content validity of the questionnaire were checked by public health experts. The questionnaire consisted of the following domains:

1. Socio-demographic characteristics like age in completed years, gender, per-capita monthly family income, place of residence

2. Smartphone usage characteristics like duration of usage in completed years, average hours used per day, number of apps present in smartphone, purpose of use of smartphones.

3. Presence of smartphone addiction was assessed by the validated Smartphone Addiction Scale-Short Version (SAS-SV) consisting of 10-items. This 10-item self-report instrument addressed the following 5 content areas: Daily-life disturbance, withdrawal, cyberspace-oriented relationship, overuse, and tolerance. For each item, participants expressed their opinion on a 6-point Likert scale ranging from ‘1’ for ‘strongly disagree’ to ‘6’ for ‘strongly agree’. Total scores range from 6 to 60 with increasing scores indicating increasing addiction. Males were considered to be addicted to smartphones if scores were higher than 31 while females were addicted if scores were higher than 33.17,18

4. Presence of excessive daytime sleepiness was assessed using the Epworth Sleepiness Scale (ESS) consisting of 8-items. Participants could give their response in a 4-point Likert scaling pattern ranging from ‘would never nod off’ as ‘0’ to ‘high chance of nodding off’ as 3. Total scores thus range from 0 to 24, higher scores indicating increasing chances of excessive daytime sleepiness. Moreover, if a person scored 11 or more out of 24, he/she was considered as having excessive daytime sleepiness.19,20

5. Presence of depression among the study participants was assessed by the Patient Health Questionnaire-9 (PHQ-9) which consisted of 9-items. Participants gave their responses in a 4-point Likert scaling pattern ranging from ‘0’ for ‘Not at all’ to ‘3’ for ‘Nearly every day’. Total scores thus ranged from 0 to 27 with higher scores indicating increasing depression. The scores were also categorized as follows: 0-4 as minimal

depression, 5-9 as mild depression, 10-14 as moderate, 15-19 as moderately severe and 20-27 as severe depression.21

Data analysis

Data were analyzed using Microsoft Excel (v.2019) and SPSS (version 16.0 IBM Corp. USA). Continuous data were denoted as mean (±standard deviation) or as median with interquartile range, whereas categorical data were expressed as number with percentages. Kolmogorov- Smirnov and Shapiro-Wilk test were performed to test the normal distribution of the data. Multicollinearity among the variables was excluded by estimating variance inflation factor (VIF>10). Factors associated with smartphone addiction were analyzed using univariate and multivariable binary logistic regression models. Only the biologically plausible significant variables in the univariate analysis (p-value<0.05 at 95% confidence interval) were included in the final multivariable model. Pearson’s or Spearman correlation coefficient (whichever applicable) was estimated to find out the relationship between excessive sleepiness and depression with smartphone addiction among the study participants.

RESULTS

Socio-demographic characteristics ofthestudy participants

Among 204 study participants, the median age was 20 years (IQR=19-21 years). Approximately 72% of the participants were males, 141 (69.1%) resided in urban areas while 148 (72.5%) participants lived in hostel premises of the institute. The median per-capita income of the study participants was ₹12500 (IQR= ₹6250-₹22500). A major proportion (65.2%) of participants belonged to Class I socio-economic status as per modified BG Prasad scale 2022.22 Other socio-demographic characteristics have been described in detail in Table 1.

Smartphone usage characteristics of the study participants

Approximately 38% of the participants have used a smartphone for a duration of 3-5 years, 90 (44.1%) participants utilize their smartphones for 4-6 hours duration per day. Approximately 46% of the participants had 11- 20 apps in their smartphones. Other smartphone usage characteristics of the participants have been described in detail in Table 1.

Smartphone addiction, daytime sleepiness, and depression among the study participants

The total scores of the SAS-SV scale had a median value of 27 (IQR=21-34), 60 (29.4%) participants were found to be addicted to their smartphones (Table 2).

TABLE 1. Socio-demographic and smartphone usage characteristics of the study participants (n=204).

*multiple response

The daytime sleepiness scale scores showed a median value of 10 (IQR=7.25-13), 45.6% (n=93) participants were found to have excessive daytime sleepiness. The depression scores on the PHQ-9 scale showed a mean value of 8.15 (±4.72). 53(26%) had moderate levels of depression, 15(7.4%) had moderately severe depression and 5(2.5%) were having severe levels of depression. (Fig 1)

Factors associated with smartphone addiction among the study participants

Multivariable logistic regression analysis showed that increasing age (AOR=1.23, 95%CI=1.12-2.21), male gender (AOR=2.12, 95% CI=1.36-3.45) and duration of smart phone usage >6 hours per day (AOR=1.92, 95%CI=1.23- 2.45) were significantly associated with the presence of smartphone addiction among the study participants. The non-significant Hosmer-Lemeshow test (p-value>0.05) indicated goodness of fit of the multivariable model,

while 26-38% of the variance of the outcome variable could be explained by this multivariable model. (Table 3)

Correlation between smartphone addiction with daytime sleepiness and depression scores

Spearman’s correlation coefficient (ρ) was estimated to find the relationship of smartphone addiction with daytime sleepiness and depression scores. Smartphone addiction and sleepiness scores showed moderate positive correlation between them which was found to be statistically significant (ρ=0.5, p-value <0.001) (Fig 2). However, there was mild significant positive correlation between smartphone addiction and depression scores (ρ=0.23, p-value=0.001) (Fig 3).

DISCUSSION

Medical students are the future backbone of the healthcare infrastructure of any country, thus care of their

TABLE 2. Responses of the study participants on the SAS-SV questionnaire (n=204).

15 (7.4%) 5 (2.5%)

Minimal depression

Mild depression

53 (26%)

53 (26%)

78 (38.2%)

Moderate depression

Moderately severe depression

Severe depression

Fig 1. Pie Diagram showing pattern of depression among the study

participants (n=204).

TABLE 3. Factors associated with presence of smartphone addiction among the study participants: Univariate and multivariable binary logistic regression analysis (n=204).

*continuous variables

OR=Odds Ratio, CI=Confidence interval Hosmer-Lemeshow test of significance = 0.12 Cox and Snell R2=0.26 and Nagelkerke’s R2=0.38

ρ=0.5, p-value<0.001

Fig 2. Scatter plot showing correlation between smartphone addiction and daytime sleepiness among the study participants [n=204].

ρ=0.233, p-value=0.001

Fig 3. Scatter plot showing relationship between smartphone addiction and depression among the study participants [n=204].

mental health and wellbeing is of utmost importance. This study made a unique attempt in the state of West Bengal by determining the levels of smartphone addiction, daytime sleepiness, and depression among undergraduate medical students of a selected medical college in Kolkata. Moreover, a novel aspect was explored by determining the relationship between smartphone addiction with daytime sleepiness and depression among the study participants. Almost one-third of participants were found to have smartphone addiction which is quite alarming and shows the increasing levels of dependency on internet, technology, and artificial intelligence in the current scenario.

A study was conducted in a medical college of Durgapur, West Bengal by Choudhury S et al where 19.4% of males and 11.1% of females were found to be addicted to smartphones.23 Another study among nursing students in Nadia, West Bengal by Ghosh T et al found approximately 50% of their participants having smartphone addiction.24 A study conducted by Senthuraman AR et al among undergraduate students pursuing medical education in Andaman and Nicobar Islands found an alarming proportion of 85.4% of students to be addicted to their smartphones.25 However, in contrast, the current study utilized the validated SAS-SV questionnaire for assessing addiction to smartphones and determined 29.4% of medical students having smartphone addiction.

Age was found to be a significant predictor of smartphone addiction as older participants were found to have high risk of smartphone addiction as compared to their younger counterparts. Age and year of academic year of medical curriculum were found to be multicollinear, hence academic year was excluded from the multivariable regression model to reduce confounding. Students in finals years of the MBBS curriculum generally comprise the older age group of the participants There is increased burden of subjects in the final years which often requires increased amount of studying not only from textbooks but also from the internet. Moreover, students in final years and internship periods often concentrate on preparing for postgraduate entrance examinations which often compels them to spend large hours on their smartphones. This predisposes them to develop dependency on these devices. However, discordant findings were found from a study conducted in Jammu and Kashmir, India by Nowreen N et al where younger participants were found to have increasing smartphone addiction.4

Male gender emerged as an important factor

associated with the presence of smartphone addiction among the study participants. Concordant findings were found in a study conducted by Chatterjee S et al among medical students of a north Indian medical college where approximately 46% males were found to be addicted to their smartphones in comparison to 33% of females.26

Another predictor for the presence of smartphone addiction was also elicited in the current study in the form of hours of smartphone usage per day. The study conducted by Choudhury S et al in West Bengal also demonstrated total hours of smartphone usage to be associated with presence of smartphone dependence among medical students.23

Depression among medical students has gained increasing importance nowadays which often gets precipitated by the burden of the vast medical curriculum. A systematic review and metanalysis by Dutta G et al demonstrated the pooled prevalence of depression among undergraduate medical students in India to be 50%.27 However, the current study detected approximately 74% of the participants suffering from some amount of depression ranging from mild to severe levels. Similar findings were reported in a study conducted by Santander- Hernanadez FM et al in Peru among medical students during the COVID-19 pandemic where 78.4% students were suffering from depression. They also demonstrated addictive smartphone usage to be significantly associated with the presence of depressive symptoms among medical students.28 Concordance was also detected in the current study as smartphone addiction was found to have positive relationship with the presence of depression among the study participants.

Smartphone addiction often compels students to

spend long hours on their devices due to which they often remain awake for long hours during night-time. This hampers their sleep quality which often precipitates lethargy and sleepiness during daytime working hours. The current study also assessed for the presence of excessive daytime sleepiness among the study participants by which 45.6% were found to have excessive daytime sleepiness. A study conducted by Dagnew B et al among medical students in Ethiopia showed slightly less proportion (31%) of excessive daytime sleepiness among the participants as compared to the current study.20 Mild positive correlation between smartphone addiction and daytime sleepiness was found in the current study. The study conducted in Jammu and Kashmir, India by Nowreen N et al showed concordant findings where positive correlation was found between smartphone addiction and sleep quality.4

Limitations

Since this study was cross-sectional in nature, establishment of causality between the different factors and the outcome variable could not be achieved. Moreover, as this was a single institution-based study, the results might not generalizable to the community, thus compromising the external validity of the results. Some of the responses were recall-based, hence bias might be possible.

Conclusion and recommendations

A significant proportion of participants were found to have smartphone addiction which nowadays has become an important public health issue. Sleep quality often gets hampered leading to excessive lethargy and sleepiness during working hours. Nearly half of the participants were found to be suffering from excessive daytime sleepiness which is quite alarming. Thus, medical students need to be motivated and counselled regarding the adverse effects of smartphone over usage. Dissemination of appropriate information through faculty and peer groups will also help in the long run. Peer group support systems can help in reducing the burden of depression and addictive smartphone usage which in turn will help in promoting good mental health and wellbeing among them. Further research through qualitative exploration in multicentric settings is needed on this domain which can help in improve the mental health and well being of the future Indian medical fraternity.

Funding

None

Conflict of interest

The authors declare no conflict of interests

Data availability statement

All the data supporting the results reported in the current study are available upon reasonable request to the corresponding author.

REFERENCES

1. Government of India, Telecom Regulatory Authority of India. Telecom-subscription reports [Internet] Available from: https:// www.trai.gov.in/release-publication/reports/telecom-subscriptions- reports [last accessed on 2023, Mar 28]

2. Mordor Intelligence. Smartphone Market Size & Share Analysis

   • Growth Trends & Forecasts (2023 - 2028) [Internet] Available from: https://www.mordorintelligence.com/industry-reports/ smartphones-market [last accessed on 2023, July 28]

3. Government of India, Digital India. [Internet] Available from: http://digitalindia.gov.in/. [last accessed on 2023, Mar 28]

4. Nowreen N, Ahad F. Effect of smartphone usage on quality of sleep in medical students. National Journal of Physiology, Pharmacy and Pharmacology. 2018;8(9):1366.

5. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington DC: American Psychiatric Association; 2013.

6. Lin YH, Lin YC, Lee YH, Lin PH, Lin SH, Chang LR, et al. Time distortion associated with smartphone addiction: Identifying smartphone addiction via a mobile application(App). J Psychiatr Res. 2015;65:139-45.

7. Walsh SP, White KM. Me, my mobile and I: The role of self and prototypical identity influences in the prediction of mobile phone behavior. J Appl Soc Psychol. 2007;37:2405-34.

   
   

8. Roberts JA, Yaya LH, Manolis C. The invisible addiction: Cell-phone activities and addiction among male and female college students. J Behav Addict. 2014;3:254-65.

9. Haug S, Castro RP, Kwon M, Filler A, Kowatsch T, Schaub MP. Smartphone use and smartphone addiction among young people in Switzerland. J Behav Addictions. 2015;4:299-307.

10. Kuss DJ, Griffiths MD. Online social networking and addiction

    • A review of the psychological literature. Int J Environ Res Publ Health. 2011;8:3528-52.

11. Sahin S, Ozdemir K, Unsal A, Temiz N. Evaluation of mobile phone addiction level and sleep quality in university students. Pak J Med Sci. 2013;29:913-8.

12. Yogesh S, Abha S, Priyanka S. Short communication mobile usage and sleep patterns among medical students. Indian J Physiol Pharmacol. 2014;58:100-3.

13. Chatlaong T, Pitanupong J, Wiwattanaworaset P. Sleep Quality and Burnout Syndrome among Residents in Training at the Faculty of Medicine, Prince of Songkla University. Siriraj Med

    J. 2020;72(4):307-14.

14. Norphun N, Pitanupong J, Jiraphan A. Stress and Coping Strategies among Thai Medical Students in a Southern Medical School. Siriraj Med J. 2020;72(3):238-44.

15. Pitanupong J, Sathaporn K. The Prevalence and Factors Associated with Mistreatment Perception among Thai Medical Students in a Southern Medical School. Siriraj Med J. 2019;71(4):310-7.

16. Charan J, Biswas T. How to calculate sample size for different study designs in medical research?. Indian J Psychol Med. 2013;35(2): 121-126.

17. Kwon M, Kim DJ, Cho H, Yang S. The smartphone addiction scale: Development and validation of a short version for adolescents. PLoS One. 2013;8:e83558.

18. Kwon M, Lee JY, Won WY, Park JW, Min JA, Hahn C, et al. Development and validation of a smartphone addiction scale (SAS). PLoS One. 2013;8:e56936.

19. Johns MW. A new method for measuring daytime sleepiness: The Epworth Sleepiness Scale. Sleep. 1991; 14(6):540-5.

20. Dagnew B, Andualem Z, Dagne H. Excessive daytime sleepiness and its predictors among medical and health science students of University of Gondar, Northwest Ethiopia: institution-based cross-sectional study. Health Qual Life Outcomes. 2020;18(1):299.

21. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001;16(9): 606-13.

22. Pentapati SSK, Debnath DJ. Updated BG Prasad's classification for the year 2022. J Family Med Prim Care. 2023;12(1):189-90

23. Choudhury S, Saha I, Som TK, Ghose G, Patra M, Paul B. Mobile phone involvement and dependence among undergraduate medical students in a Medical College of West Bengal, India. J Educ Health Promot. 2019;8:1.

24. Ghosh T, Sarkar D, Sarkar K, Dalai CK, Ghosal A. A study on smartphone addiction and its effects on sleep quality among nursing students in a municipality town of West Bengal. J Family Med Prim Care. 2021;10(1):378-86.

25. Sethuraman AR, Rao S, Charlette L, Thatkar PV, Vincent V. Smartphone addiction among medical college students in the Andaman and Nicobar Islands. Int J Community Med Public Health. 2018;5:4273-7.

26. Chatterjee S, Kar SK. Smartphone addiction and quality of sleep among Indian medical students. Psychiatry. 2021;84(2): 182-91.

27. Dutta G, Rajendran N, Kumar T, Varthya SB, Rajendran V. Prevalence of Depression Among Undergraduate Medical Students in India: A Systemic Review and Meta-Analysis. Cureus. 2023;15(1):e33590.

28. Santander-Hernández FM, Peralta CI, Guevara-Morales MA, Díaz-Vélez C, Valladares-Garrido MJ. Smartphone overuse, depression & anxiety in medical students during the COVID-19 pandemic. PLoS One. 2022;17(8):e0273575.

Clinical Efficacy of Andrographis paniculata Extracted Scrub Compared With 4% Chlorhexidine Scrub in Burn Wounds: A Prospective Randomized Controlled Trial

Pattraporn Vangchanachai, M.D.*, Suttipong Tianwattanatada, M.D.*, Nantaporn Namviriyachote, M.D.*, Vich Thampanya, M.D.**, Natthida Owattanapanich, M.D.*, Kusuma Chinaroonchai, M.D.*, Suchada Kittidacha, M.D.*, Anchan Ketmek, M.D.*, Pornprom Muangman, M.D.*

*Division of Trauma Surgery, Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand, **Division

of Internal Medicine, Chiangrai Prachanukroh Hospital, Chiangrai 57000, Thailand.

ABSTRACT

Objective: The primary objective of this study is to compare the healing rate between AP soap and 4% Chlorhexidine solution in superficial second-degree burn wounds. The secondary objectives include the analgesic effect and moisturization of these two products.

Materials and Methods: Data was collected between 2019 and 2021. Patients aged 18 years and above, with

superficial second-degree burns including at least 20% of TBSA, and admitted to the Burn Unit within 24 hours of injury were included. They were randomly assigned to two groups: Andrographis paniculata with Perilla oil liquid soap group (AP group) and 4% Chlorhexidine group (control group). The measurements included percentage of epithelialization, pain score during wound cleansing, itching score after wound cleansing, and dry skin specified symptoms. All patients received standard care for burn wound treatment.

Results: A total enrollment was 23 patients in this study (12 in the AP group and 11 in the control group). The median age was 38.5 years. There were no statistically significant differences in age, %TBSA, and initial wound size between both groups (p > 0.05). Although the healing time was similar in both groups, (18.5 vs. 20.1, p=0.347), the AP group had a significantly lower pain score than the control group (4.7 vs. 5.4, p=0.020). Moreover, the AP group demonstrated significant improvements in itching score and SRRC score at 14 days compared to the control group (5.1 vs. 6.0, p 0.039 and 1.08 vs. 1.55, p 0.020, respectively). There were no adverse effects during this study. Conclusion: Patients treated with Andrographis paniculata with Perilla oil liquid soap experienced less pain and better moisturization compared to those treated with the standard 4% chlorhexidine solution, while achieving a comparable healing rate. A future large-scale prospective trial is recommended.

Keywords: Andrographis paniculata; wound cleansing; second degree burn (Siriraj Med J 2023; 75: 809-816)

INTRODUCTION

Superficial second-degree burn wounds primarily affect the epidermis and superficial dermis.1 The dermal layer has the ability to produce epithelial cells in order to replace the lost ones, leading to complete epithelialization of wounds

within 3 weeks2 without any surgical intervention. The primary objective of burn wound care is to achieve rapid wound closure. The treatment involves wound cleansing for optimal wound bed preparation and application of temporary dressings, and infection prevention to create

Corresponding author: Pornprom Muangman E-mail: pmuangman@yahoo.com

Received 19 August 2023 Revised 24 September 2023 Accepted 8 October 2023ORCID ORCID ID:http://orcid.org/0000-0001-9828-0060 https://doi.org/10.33192/smj.v75i11.264451

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

a protective environment that facilitates the normal wound healing process.3-5

Wound bed preparation plays a crucial role in wound management as it enables assessment and treatment of patients with wounds. Wound cleansing is an integral component of wound bed preparation as it leads to an optimized wound environment by removing debris, reducing bacterial load, preventing biofilm activity and maintaining wound moisturization.6 The standard cleansing treatment for burn wounds has been the use of 4% Chlorhexidine solution. It has a wide range spectrum of anti-bacterial effects and serves as a prophylactic agent against infections of burn wounds - serious problem that can lead to conversion of partial-thickness to full- thickness burn wounds. Literature recommends the use of Chlorhexidine to maintain wound disinfection6, and two publications suggesting its use only for superficial burns wounds.7,8 However, the disadvantages of Chlorhexidine solution include pain during wound cleansing and tissue irritation in individuals with dry skin that can potentially delay the wound healing process.9,10

Andrographis paniculata known as Fa-Ta-Lai-

Jone, is a medicinal plant listed on the World Health Organization’s (WHO) 2002 catalogue.11 It has anti- oxidant properties12 and exhibits antimicrobial and anti-inflammatory effects13,14 Phytochemical analysis of extracted A. paniculata has revealed that it has several bioactive molecules, for example, andrographolides and flavonoids.15 These phytochemical constituents may contribute to the plant’s wound-healing activity. Andrographolide - the main compound of Andrographis

paniculata has been reported to decrease inflammation14,16

caused by dimethyl benzene, histamine, and adrenaline.17,18 It also demonstrates significant antibacterial activity in its extracted solution.19,20 Flavonoids, which are known for their antimicrobial properties, have been found to promote the wound-healing process by enhancing wound contraction and epithelialization.21

Perilla oil has been shown to suppress production of chemical mediators involved in allergic pathways and inflammatory responses. Essential fatty acids present in Perilla oil offer a wide range of benefits, including anti- inflammatory, antimicrobial, and anticancer properties. In vivo, polyunsaturated omega-3 fatty acids are primarily metabolized into docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), which are incorporated into cell membranes throughout the body. These specific omega-3 fatty acid metabolites play a role in preventing abnormal clotting, reducing inflammation, relaxing blood vessels, and improving ventilatory parameters.22 Therefore, Andrographis paniculata with Perilla oil

liquid soap (AP soap) is a novel product used for wound cleansing and moisturizer, with potential pain-relieving properties. However, there is a lack of published data regarding its effectiveness in treating burn patients. The objective of this study is to assess the clinical efficacy of AP soap in promoting the healing of superficial second- degree burns, in comparison to the standard cleansing, 4% Chlorhexidine solution.

MATERIALS AND METHODS

A prospective, randomized controlled trial was designed, involving 23 patients who were admitted to the Burn unit at Siriraj Hospital between June 2019 and February 2021. Ethical approval for this study was obtained from the Siriraj Institutional Ethical Review Board (SIRB) (COA no. Si 684/2019). Written consent was obtained from all participating patients after providing them with detailed information. The inclusion criteria was patients between 18 and 60 years of age, presenting with superficial second degree burns within 24 hours of sustaining the injury. The burn wounds covered areas at least 20% of the total body surface area (TBSA). Patients who have underlying medical conditions that could affect the wound healing process such as diabetes mellitus, end-stage renal disease, post-radiation therapy, immunosuppressive drug use, or immunocompromised diseases were excluded, as were pregnant or lactating individuals and those with known hypersensitivity to herbal products. The patients were randomly assigned to one of two treatment groups: the Andrographis and Perilla oil liquid soap (AP soap) group (12 patients) and 4% Chlorhexidine-treated group (11 patients). Demographic data including gender, age, causes of burn, %TBSA, and initial wound area were collected. All patients received initial treatment and underwent wound examination by experienced burn surgeons and nurses who were blinded to the assigned treatment group. The patients were treated following standard burn wound care treatment protocol and wound cleansing procedure as flow chart described in Fig 1 below.

1. Wound bed preparation

   The wounds were cleansed using sterile normal saline solution and wrapped to remove excessive discharge from the wound.

   
   

2. Wound assessment

   The wounds were evaluated. Unfavorable clinical symptoms, complications, or side effects were reported to burn surgeon. A nurse, who was not part of the treatment team, obtained the wound size by placing a sterile transparent

   
   

   Fig 1. Study protocol.

   
   

   
   

   film on the wound base and measuring its dimensions using a 0.4 mm pinpoint marker. The wound size was recorded. Wound healing was quantified as a percentage of epithelialization, following a previously established protocol23 using the formula below

   (Area of initial wound - Area of wound at

   
   

   Analog Scale 0-10” on Days 3, 7, 14, 21 of treatment.

   
   

   7. SRRC score assessment

   Experienced burn surgeons and nurses evaluated the specified symptoms of dry skin at Days 3, 7, 14 of the treatment.

   Critically ill-patient treatments, such as volume

   %Epithelialization=

   
   

3. Wound cleansing

   examination date) Area of initial wound

   x 100

   resuscitation, nutrition, and analgesia were same

   administered in both groups following standard approach.

   The primary outcome of this study was to compare the treatment outcomes of Andrographis paniculata extract scrub and 4% Chlorehexidine scrub in the healing

   Wound cleansing was performed using either AP soap or a 4% Chlorhexidine solution, based on the assigned treatment group.

   
   

4. Wound closure

   Sterile gauze was applied to the wound and secured with adhesive tape as per the standard treatment.

   
   

5. Pain assessment

   Patients were asked to rate their pain levels at thirty minutes after wound dressing using the “Pain Numeric Rating Scale 0-10” on Days 3, 7, 14, 21 of treatment.

   
   

6. Itching assessment

   Patients were asked to rate their itching score at 30 minutes after wound dressing using the “Itching Visual

   of superficial second-degree burn wounds, specifically in terms of healing time and the percentage of gross epithelialization. The secondary outcomes were as follows:

   • To compare pain between the two treatments: as rated by patients using the “Pain Numeric Rating Scale 0-10” (scaling on a straight line from 0 to 10 where 0 = no pain, 5 = moderate pain, and 10 = worst possible pain).

   • To compare wound moisturization after wound cleansing, assessed using the “Itching Visual Analog Scale 0-10” (scaling on a straight line from 0 to 10 where 0 = no itching; 1-3 = mild itching, 4-6 = moderate itching, and 7-10 = severe itching) and SRRC rating score (assess dry skin-specific symptoms such as scaling, roughness, redness and cracks after wound cleansing).

Statistical analysis

Statistical data analysis was conducted using SPSS version 18.0. Student’s t-test was used to assess the difference in means, while the χ2 test was utilized to determine relationships between parameters. All p values were two-sided. Statistically significant was considered as p values less than 0.05. Kaplan-Meier analysis was performed to compare the healing time between two groups.

RESULTS

A total of twenty-three patients were included in this study, with random allocation into two groups: the AP group consisting of 12 patients, and the control group comprising 11 patients. The median age of all patients was 38.5 years. In the AP group, 66.7% of patients were male, while in the control group, the percentage was 63.6%. Scald burns were the predominant cause in both groups, accounting for 75% in the AP group and 63% in the control group. The mean total body surface area (TBSA) affected was 33% and 35% in the AP and control groups respectively. The mean initial wound size was 171 and 157 square meters in the AP and control groups, respectively. There were no statistically significant

differences in sex, age, cause of burn, %TBSA, and initial wound area between the AP and control groups (p > 0.05). The demographic data is shown in Table 1 below.

The mean healing time in the AP soap-treated group was 18.5 days, while it was 20.1 days in the control group. There was no statistically significant difference in healing time between these two groups (p 0.347). All patients in this study achieved complete epithelialization of their wounds within 4 weeks after injury. The percentage of gross wound epithelialization on day 14 was statistically significantly higher in the AP soap-treated group compared to the control group, with values of 87% and 82%, respectively (p-value of 0.027). On day 21, the percentage of gross wound epithelialization was 97.8% in the AP soap-treated group and 96.77% in the control group, with a p-value of 0.58. Tables 2 provides details on the percentage of epithelialization. Kaplan-Meier analysis demonstrated no statistically significant difference in wound epithelialization between the two groups as shown in Fig 2. The healing time after treatment was 18 and 20 days, respectively, with no statistically significant difference. Hospital stay did not significantly differ between the two groups (46.7 and 50.5 days, p-value = 0.64). There was no instance of burn wound infection among the patients.

Fig 2. Percent Epithelialization on days 3, 7, 14, 21 after treatment

Pain assessment during wound cleansing

The mean of pain analog scores assessed between the AP soap-treated group and the control group during the initial treatment period (days 1-3) showed no significant differences. However, the pain score was significantly lower in the AP soap-treated group at 7 days (4.7 vs. 5.4, p=0.020), and 14 days (2.6 vs. 3.5, p=0.011) after treatment, as shown in Table 3.

Wound moisture after wound cleansing

The AP soap-treated group demonstrated a significant improvement in itching score, indicating enhanced wound moisturization at 14 days compared to the control group (5.1 vs. 6.0, p=0.039). Although the SRRC score could

not be evaluated during the first 3 days after treatment due to excessive wound discharge, the, the AP soap group exhibited a significantly lower SRRC score than the control group at 14 days post-treatment treatment (1.08 vs. 1.55, p=0.020). Table 3 presents the pain score, itching score, and SRRC score.

Cases demonstration

Patients received standard care for burn wound treatment, with the exception of the cleansing process which depended on the assigned treatment group. The procedure for wound cleansing using AP soap is demonstrated in Fig 3. An example of wound healing progression using AP soap is shown in Fig 4.

TABLE 3. Percent epithelialization at days 3, 7, 14, 21 after treatment, healing time, and length of stay.

Fig 3. The application of AP-soap started with rinsing AP soap. Wet gauze was used for scrubbing and then the wound was cleaned.

Fig 4. Example of an AP soap treatment group patient.

DISCUSSION

The use of Chlorhexidine solution as a standard topical wound cleansing treatment for partial thickness burns has been established for decades. However, there are some disadvantages such as wound base tissue irritation and pain during wound cleansing.10,24 This study aimed to evaluate the clinical efficacy of Andrographis paniculata and Perilla oil liquid soap (AP soap) in the healing of superficial second-degree burn wounds. The results demonstrated comparable wound healing outcomes with reduced pain during wound cleansing, and more moisturization compared to the standard cleansing Chlorhexidine solution. Thus, AP soap appeared to address the disadvantages associated with Chlorhexidine solution. Al-Bayaty et al, reported the effects of topically applied A. paniculata leaf extract on wound healing in rat models. The macroscopic examination revealed the significantly faster wound healing rate in rats with extracted A. paniculata dressing compared to placebo.25 This study showed no significant differences in time required to complete gross epithelialization, representing the healing time of burn wounds, between the AP soap- treated group and 4% Chlorhexidine-treated group (control group), which were 18.5 days and 20.1 days, respectively (p=0.347). However, on day 14 of treatment, the epithelialization rate was higher, suggesting that AP soap may accelerate the wound healing process. No

significant difference was found on day 21, as wounds tended to heal naturally, and the small sample size may have contributed to the lack of statistical significance. Significant differences may be identified in a randomized controlled trials with larger number of enrolled patients. This study also reported no significant differences in the length of stay between the groups (AP soap 46.7 ± 18.8 vs. Control group 50.5 ± 20.8, p= 0.643). No adverse side effects of AP soap were observed in this study.

Pain management remains a challenging aspect in burn patient care. Recurrent pain exposures in burn patients can lead to secondary hyperalgesia and contribute to chronic pain issues, significantly affecting quality of life.26 Wound cleansing, in particular, is a procedure that can produce severe pain, as patients often have to endure it more frequently compared to other treatments. Previous studies have explored several of methods and wound cleansing products to address this problem. Although achieving completely pain-free wound cleansing products remains elusive, advancements in dressing material have shown promise in reducing pain and discomfort during wound dressing changes. Our study demonstrated that pain during wound cleansing was significantly lower in the AP soap treated group compared to the 4% Chlorhexidine–treated group at 7 days and 14 days after treatment, during the period when wounds had not fully epithelialized. This finding was supported by

patient experiences and the numeric pain score ratings, indicating that AP soap was less painful and provided a more comfortable experienced for patients.

For optimal wound healing, a moist environment is known to facilitate faster and less painful hearing compared to a dry environment, which can lead to cell dehydration and death. This often results in the formation of a scab or crust over the wound, hindering healing. By maintaining proper hydration with a moisture-retentive dressing, migration of epidermal cells is enhanced, encouraging epithelialization.9 The itching visual analog scale, as suggested by Reich, et al27 is an appropriate parameter for evaluating skin conditions. In this study, the itching visual analog scale demonstrated significantly lower scores in the AP soap-treated group compared to the control group at 14 days after treatment (5.1 vs. 6.0, p=0.039), indicating improved moisturization with AP soap.

The specified symptom sum score (SRRC) system, acknowledged by the European group on Efficacy Measurement of Cosmetics and other topical products (EEMCO), assesses skin-specific symptoms such as scaling, roughness, redness, and cracks or SRRC; to evaluate the effects of topical products.28,29 In this study, statistically significant improvements in the SRRC rating score were observed in the AP soap-treated group at 14 days after treatment (p-value 0.020).

This research was conducted in randomized controlled trial design to reduce bias. However, the small sample size limited the ability to detect significant differences in certain measurements. These findings highlight the need for well-designed studies to further investigate the efficacy of the Andrographis paniculata and Perilla oil liquid soap as a wound cleansing agent for partial thickness burn wounds. A future large prospective study is warranted.

CONCLUSION

Andrographis paniculata and Perilla oil liquid soap, a novel natural product for epithelialization of wounds demonstrated comparable wound healing rates to chlorhexidine solution, with the added benefits of reduced pain and better moisturization.

Declaration of conflicting interests

The author(s) declare no potential conflicts of interest according to the research, authorship, and/or publication of this article.

ACKNOWLEDGEMENTS

The authors would like to thank the Burn Unit, Division of Trauma Surgery, Department of Surgery,

Faculty of Medicine Siriraj Hospital, Thailand for their support and dedicated care of patients.

The authors would like to express our gratitude to the dedication of Assoc. Prof. Dr. Watcharee Khunkitti for being consultant of soap product development.

REFERENCES

1. Matthews JB, Mandell SP, Gibran NS. Burns. In: Brunicardi FC, editor. Schwartz’s Principle of Surgery. 1. 11 ed. United States: McGraw-Hill Educaion; 2019. p. 251-69.

2. Courtney M. Townsend KLM. Sabiston Textbook of Surgery. 20 ed. Philadelphia: Elsevier Inc; 2017. p. 505-31.

3. Hayek S, El Khatib A, Atiyeh B. Burn wound cleansing - a myth or a scientific practice. Ann Burns Fire Disasters. 2010;23(1): 19-24.

4. Guidelines IBP, Atiyeh B, Barret JP, Greenfield E, Dahai PH, Duteille PF, et al. Best Practice Guidelines : Effective skin and wound management of non- complex burns. Wounds International. 2014.

5. Chuntrasakul C, Muangman P, Benjathanung R, Suvanchote S, Boonpamee S, Jantarapakdee S, et al. Clinical Experience of ActicoatTM Treatment in Extensive Burn Wounds. Siriraj Med J. 2007;59(2):47-51.

6. Falanga V. Wound bed preparation: science applied to practice. In: Calne S, editor. European Wound Management Association position document: Wound bed preparation in practice. London: MEP Ltd; 2004.

7. D’Avignon LC, Saffle JR, Chung KK, Cancio LC. Prevention and management of infections associated with burns in the combat casualty. J Trauma. 2008;64(3 Suppl):S277-86.

8. DeSanti L. Pathophysiology and Current Management of Burn Injury. 2005;18(6):323-32.

9. Hess CT. Checklist for factors affecting wound healing. Adv Skin Wound Care. 2011;24(4):192.

10. Liu JX, Werner J, Kirsch T, Zuckerman JD, Virk MS. Cytotoxicity evaluation of chlorhexidine gluconate on human fibroblasts, myoblasts, and osteoblasts. J Bone Jt Infect. 2018;3(4):165-72.

11. 2002 WHOG. WHO monographs on selected medicinal plants. World Health Organization. 2002;2:12-24.

12. Trivedi NP, Rawal UM, Patel BP. Hepatoprotective effect of andrographolide against hexachlorocyclohexane-induced oxidative injury. Integr Cancer Ther. 2007;6(3):271-80.

13. Chang H-MAB, Paul Pui-Hay, A Yao, Sih-Cheng, A Wang, Lai- Ling, A Yeung, Shem Chang-Shing. Pharmacology and Applications of Chinese Materia Medica. World Scientific, Singapore, 1986.

14. Farnsworth NR, Krause EC, Bolton JL, Pauli GF, van Breemen RB, Graham JG. The University of Illinois at Chicago/National Institutes of Health Center for Botanical Dietary Supplements Research for Women’s Health: from plant to clinical use. Am J Clin Nutr. 2008;87(2):504S-8S.

15. Koteswara Rao Y, Vimalamma G, Rao CV, Tzeng YM. Flavonoids andandrographolidesfromAndrographispaniculata.Phytochemistry. 2004;65(16):2317-21.

16. Zou W, Xiao Z, Wen X, Luo J, Chen S, Cheng Z, et al. The anti- inflammatory effect of Andrographis paniculata (Burm. f.) Nees on pelvic inflammatory disease in rats through down-regulation of the NF-kappaB pathway. BMC Complement Altern Med. 2016; 16(1):483.

    
    

17. Jarukamjorn K, Nemoto N. Pharmacological Aspects of Andrographis paniculata on Health and Its Major Diterpenoid Constituent Andrographolide. Journal of Health Science. 2008; 54:370-81.

18. Hidalgo MA, Romero A, Figueroa J, Cortes P, Concha, II, Hancke JL, et al. Andrographolide interferes with binding of nuclear factor-kappaB to DNA in HL-60-derived neutrophilic cells. Br J Pharmacol. 2005;144(5):680-6.

19. Jayakumar T, Hsieh CY, Lee JJ, Sheu JR. Experimental and Clinical Pharmacology of Andrographis paniculata and Its Major Bioactive Phytoconstituent Andrographolide. Evid Based Complement Alternat Med. 2013;2013:846740.

20. Singha PK, Roy S, Dey S. Antimicrobial activity of Andrographis paniculata. Fitoterapia. 2003;74(7):692-4.

21. Tsuchiya H, Sato M, Miyazaki T, Fujiwara S, Tanigaki S, Ohyama M, et al. Comparative study on the antibacterial activity of phytochemical flavanones againt methicillin-resistant Staphylococcus aureus. J Ethnopharmacol. 1996;50(1):27-34.

22. Asif M. Health effects of omega-3,6,9 fatty acids: Perilla frutescens is a good example of plant oils. Orient Pharm Exp Med. 2011;11(1):51-9.

23. Tianwattanatada S, Namviriyachote N, Chinaroonchai K, Owattanapanich N, Nair HKR, Muangman P. Clinical Efficacy

    Test of Polyester Dressing Containing Herbal Extracts and Silver Sulfadiazine Cream Compared with Silver Sulfadiazine Cream in Healing Burn Wounds: A Prospective Randomized Controlled Trial. Siriraj Med J. 2021;73(11):752-7.

24. Abdel-Sayed P, Tornay D, Hirt-Burri N, de Buys Roessingh A, Raffoul W, Applegate LA. Implications of chlorhexidine use in burn units for wound healing. Burns. 2020;46(5):1150-6.

25. Al-Bayaty FH, Abdulla MA, Hassan MIA, Ali HM. Effect of Andrographis paniculata leaf extract on wound healing in rats. Nat Prod Res. 2012;26(5):423-9.

26. Norman AT, Judkins KC. Pain in the patient with burns. Continuing Education in Anaesthesia Critical Care & Pain. 2004; 4(2):57-61.

27. Reich A, Heisig M, Phan NQ, Taneda K, Takamori K, Takeuchi S, et al. Visual analogue scale: evaluation of the instrument for the assessment of pruritus. Acta Derm Venereol. 2012;92(5):497- 501.

28. Serup J. EEMCO guidance for the assessment of dry skin (xerosis) and ichthyosis: clinical scoring systems. Skin Res Technol. 1995;1(3):109-14.

29. Al-Kotb H, Abdel-Aziz H. Effect of Standardized Skin Care Guidelines on Skin Dryness among Elderly People at Ismailia City. Journal of Nursing and Health Science. 2017;6:12-8.

Hepatocellular Carcinoma’s Characteristics in an Endemic Country: A Closer Examination of Tumor Grade and Microvascular Invasion

Ignasia Andhini Retnowulan, M.D.*, Marini Stephanie, M.D.*, Nur Rahadiani, M.D., Ph.D.*, Ridho Ardhi Syaiful, M.D.**, Ening Krisnuhoni, M.D., MS*

*Department of Anatomical Pathology, Faculty of Medicine Universitas Indonesia/ Dr. Cipto Mangunkusumo Hospital, Jakarta, Indonesia, **Department of Surgery, Faculty of Medicine Universitas Indonesia/ Dr. Cipto Mangunkusumo Hospital, Jakarta, Indonesia.

ABSTRACT

Objective: Although histological grade and microvascular invasion are known predictors for patient survival and recurrence in hepatocellular carcinoma (HCC), their relationship with various clinical and histomorphological features of HCC remains unclear.

Materials and Methods: Medical records were retrieved from 61 patients who were diagnosed with HCC from

2008-2018. Clinical and histomorphological variables that were hypothesized to be associated with histological grade and microvascular invasion were analyzed statistically using the Chi-square test or the Fisher’s exact test as alternatives. Multivariate analysis was performed with logistic regression model.

Results: The majority of the patients had well to moderately-differentiated HCC (67.2%) with some of them presenting

microvascular invasion (57.4%). Alpha-fetoprotein level (AFP) ≥100 ng/ml (p=0.036), tumor size >7cm (p=0.031) and mitotic index ≥5 per 10 high power field (p=0.009) were significantly correlated with poorly-differentiated HCC. Mitotic Index ≥5 per 10 high power field was an independent factor for poorly differentiated HCC. Meanwhile BCLC stage B and mitotic index were also an independent factor for the presence of microvascular invasion.

Conclusion: Larger tumor size and higher mitotic index was significantly correlated and independent factors for

poorly differentiated HCC and microvascular invasion. In biopsy specimens for which the microvascular invasion is difficult to assess, histological grade, tumor size and mitotic index may be beneficial to depict the prognosis of patients with HCC.

Keywords: Hepatocellular carcinoma; tumor grade; microvascular invasion; Indonesia (Siriraj Med J 2023; 75: 817-826)

INTRODUCTION

Hepatocellular carcinoma (HCC) is the second most frequent cancer in Asia and the second leading cause of cancer-related deaths in East Asia and Sub-Saharan Africa. Moreover, China, Southeast Asia, Japan and Sub-Saharan Africa are areas with a high incidence of HCC with an incidence >20/100,000.1,2

The current HCC diagnostic approach relies on radiologic imaging and the use of histopathology

biopsy is limited to specific cases.1,3 Surveillance through ultrasonography (US) examination and alpha-fetoprotein (AFP) measurement should be carried out every 6 months in individuals with a high risk of HCC to achieve early diagnosis.4 When nodules are found on the liver US with increased AFP level, a computed tomography (CT) scan or three-phase magnetic resonance imaging (MRI) should be performed. Typical features of HCC on CT scan or three-phase MRI are sufficient for diagnosis of

Corresponding author: Marini Stephanie E-mail: marini2sh@gmail.com

Received 21 August 2023 Revised 8 October 2023 Accepted 9 October 2023 ORCID ID:http://orcid.org/0000-0002-5743-688X https://doi.org/10.33192/smj.v75i11.264786

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

HCC, otherwise, tumor biopsy should be carried out for diagnostic purposes.4

Although various therapeutic modalities are available, HCC is generally diagnosed at an advanced stage when curative therapy is not possible. Therefore, at present, the prognosis of HCC remains poor.5 Histopathological examination is involved in determining therapy and prognosis through the assessment of histological parameters which cannot be replaced by radiologic examinations.3 The present study aimed to provide data on the clinical and histomorphology characteristics of HCC and clarify how these relate to important prognostic factors of HCC, particularly histologic grade and microvascular invasion.

MATERIALS AND METHODS

Medical records of 61 patients were retrieved from 2008-2018 archives for consecutive evaluation. Inclusion criteria were all resection cases with a diagnosis of HCC in the Department of Anatomic Pathology, FKUI/ RSCM. Exclusion criteria were biopsy cases, cases with unrepresentative slide and cases with a final diagnosis of non-HCC. The clinical variables assessed were sex, age, hepatitis infection, AFP level, cirrhosis status and Barcelona Clinic Liver Cancer (BCLC) staging. Triphasic CT and additional MRI with contrast for patients with inconclusive CT were performed on all patients and yielded inconclusive radiologic results. Hepatitis infection involves positive serological markers for hepatitis B or C virus (HBV and HCV, respectively) before or during HCC diagnosis. AFP levels were measured at the time of HCC diagnosis. Cirrhosis status was determined radiologically with a US Fibroscan from Echosans and confirmed through histopathological analysis. The BCLC criteria classify clinical stages as 0, A, B, and C.6

Two independent pathologists evaluated the pathology

reports and histologic specimens of all patients. The histomorphology variables assessed were tumor size, histological pattern, mitotic index, special type carcinomas, histological grade and microvascular invasion. Tumor size was defined as the largest dimension from resection or radiologic findings and was categorized based on the Milan criteria.7 The histological patterns that were identified included macrotrabecular, microtrabecular, solid and pseudoglandular. Mitotic index was categorized as low or high and defined as <5 per 10 high power field (HPF) and ≥5 per 10 HPF respectively according to a study by Ha et al.8 Special type carcinomas that were identified included fibrolamellar, scirrhous, undifferentiated carcinoma, lymphoepithelial, sarcomatous, steatohepatitic and macrotrabecular massive. HCC was categorized into good-to-moderate or poor differentiation based on

histological grade. The cells of HCC with well-to-moderate differentiation display mildly to moderately atypical nuclei, often with nucleoli, and copious eosinophilic to basophilic cytoplasm. Meanwhile, the cells of HCC with poor differentiation were anaplastic with pleomorphic and atypical nuclei, and sparse basophilic cytoplasm.9 Malignant cells in peritumoral blood vessels indicate microvascular invasion.

The Statistical Package for Social Sciences software (version 25.0; IBM Corp.) was used for analysis. Variables hypothesized to be associated with histological grade or microvascular invasion were analyzed with the Chi-square test or its alternatives Fisher’s exact test. Multivariate analysis was performed with logistic regression to draw significant factors associated with features of HCC, the variables were selected from bivariate analysis with p-value ≤0.25.

The Ethics Committee of the Faculty of Medicine Universitas Indonesia and Dr. Cipto Mangunkusumo Hospital have granted ethical approval for this study (protocol number 23-01-0066) under the decision number KET-84/UN2.F1/ETIK/PPM.00.02/2023.

RESULTS

Data from 61 patients with HCC were retrieved. Of these, 80% were male with a mean age of 51.8 years ± 15.643, 20% of them were <40 years old and the youngest patient was 17 years old. Most patients had hepatitis infection. Most patients had stage B HCC according to the BCLC staging system (91.8%). Tumor size ranged from 2.5-25 cm. A similar proportion of cirrhotic and non-cirrhotic patients was found. The median AFP level was 113.5 ng/ml. The mean mitosis count was 6.72 over 10 HPF. The most common histological pattern was the microtrabecular pattern (72.1%). Only 5 patients (8.1%) were found to have steatohepatitic HCC. Most patients had well to moderately-differentiated HCC (67.2%). The microvascular invasion was observed in most cases (57.4%). Clinical and histological characteristics of HCC can be seen in Table 1. Representative microscopic images of the HCC found in the current patients can be seen in Fig 1.

Statistical tests examined the association between

sex, age, AFP level, hepatitis infection, BCLC staging, cirrhosis status, tumor size and mitotic index with histological grade, microvascular invasion, and well- differentiated with no microvascular invasion. There was a significant association between AFP level, tumor size and mitotic index with histological grade. AFP level

≥100 ng/ml (p=0.036), tumor size >7cm (p=0.031) and mitotic index ≥5 per 10 HPF (p=0.009) were significantly

TABLE 1. Clinical and histological characteristics of HCC (n=61).

Characteristics n (%)

Sex

Male 49 (80.3)

Female 12 (19.7)

Age in years, mean (SD) 51.80 ± 15.643

Hepatitis infection, n (%)

Non-hepatitis 13 (15.9)

BCLC staging

Stage 0 Stage A Stage B Stage C

0 (0)

5 (8.2)

56 (91.8)

0 (0)

Hepatitis 42 (58.5)

Tumor size

≤7 cm

>7 cm

24 (39.3)

37 (60.7)

Tumor size in cm, median (minimum-maximum) 10.9 (2.0-25)

Cirrhosis status