Siriraj Medical Journal
SMJ
Volume 73, Number 12, December 2021
E-ISSN 2228-8082
The world-leading biomedical science of Thailand
By Doonyaporn Wongsawaeng, et al.
MONTHLY
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ORIGINAL ARTICLE
REVIEW ARTICLE
Siriraj Medical Journal
SMJ
Volume 73, Number 12, December 2021
ORIGINAL ARTICLE
777 Incidence and Risk Factors of Retinopathy of Prematurity, a 10-year Experience of
a Single-center, Referral, Hospital
Kanya Chutasmit, et al.
786 Magnetic Resonance Hippocampal Subfield Volumetric Analysis for Differentiating among
Healthy Older Adults and Older Adults with Mild Cognitive Impairment or Major
Depressive Disorder
Doonyaporn Wongsawaeng, et al.
793 Psychometric Properties of the PHQ-9, HADS, and CES-D Questionnaires and
the Prevalence of Depression in Patients with Cancer Receiving Radiotherapy
Kantanut Yutrirak, et al.
801 The Efficacy of Follow-up Phone Calls for Capillary Blood Glucose Lowering in Diabetic
Patients in Primary Care Unit
Possatorn Wongwutthiwet, et al.
808 Factors Associated with Severe Lower Respiratory Tract Infection from Respiratory
Syncytial Virus (RSV) in Thai Children
Atipotsawee Tungsupreechameth, et al.
815 Clinical Outcomes and Cost of Ventilator Weaning and Endotracheal Extubation Guided
by an Established Ventilator Weaning Protocol in Patients Undergoing Elective Cardiac
Surgery
Supanan Innok, et al.
823 Cost-effectiveness Analysis Comparing Vonoprazan-based Triple Therapy with Proton
Pump Inhibitor-based Therapy in the Treatment of Helicobacter pylori Infection in
Thailand
Jadesada Lertsirimunkong, et al.
832 The Relationship between Mental Health with the Level of Empathy Among Medical
Students in Southern Thailand: A University-Based Cross-Sectional Study
Katti Sathaporn, et al.
REVIEW ARTICLE
841 Melasma Clinical Features, Diagnosis, Epidemiology and Etiology: An Update Review
Mohammad Ahmad Abdalla
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Philip Board (Australian National University, Australia)
Richard J. Deckelbaum (Columbia University, USA)
Yozo Miyake (Aichi Medical University, Japan)
Yik Ying Teo (National University of Singapore, Singapore)
Harland Winter (Massachusetts General Hospital, USA)
Philip A. Brunell (State University of New York At Bualo, USA)
Noritaka Isogai (Kinki University, Japan)
Yuji Murata (Aizenbashi Hospital, Japan)
Keiichi Akita (Tokyo Medical and Dental University Hospital, Japan)
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David S. Sheps (University of Florida, USA)
Robin CN Williamson (Royal Postgraduate Medical School, UK)
Tai-Soon Yong (Yonsei University, Korea)
Anusak Yiengpruksawan (e Valley Robotic Institute, USA)
Stanlay James Rogers (University of California, San Francisco, USA)
Kyoichi Takaori (Kyoto University Hospital, Japan)
Tomohisa Uchida (Oita University, Japan)
Yoshiki Hirooka (Nagoya University Hospital, Japan)
Hidemi Goto (Nagoya University Graduate School of Medicine, Japan)
Kazuo Hara (Aichi Cancer Center Hospital, Japan)
Shomei Ryozawa (Saitama Medical University, Japan)
Christopher Khor (Singapore General Hospital, Singapore)
Yasushi Sano (Director of Gastrointestinal Center, Japan)
Mitsuhiro Kida (Kitasato University & Hospital, Japan)
Seigo Kitano (Oita University, Japan)
Ichizo Nishino (National Institute of Neuroscience NCNP, Japan)
Masakazu Yamamoto (Tokyo Women’s Medical University, Japan)
Dong-Wan Seo (University of Ulsan College of Medicine, Korea)
George S. Baillie (University of Glasgow, UK)
G. Allen Finley (Delhousie University, Canada)
Sara Schwanke Khilji (Oregon Health & Science University, USA)
Matthew S. Dunne (Institute of Food, Nutrition, and Health, Switzerland)
Marianne Hokland (University of Aarhus, Denmark)
Marcela Hermoso Ramello (University of Chile, Chile)
Ciro Isidoro (University of Novara, Italy)
Moses Rodriguez (Mayo Clinic, USA)
Robert W. Mann (University of Hawaii, USA)
Wikrom Karnsakul (Johns Hopkins Children’s Center, USA)
Frans Laurens Moll (University Medical Center Ultrecht, Netherlands)
James P. Dolan (Oregon Health & Science University, USA)
John Hunter (Oregon Health & Science University, USA)
Nima Rezaei (Tehran University of Medical Sciences, Iran)
Dennis J. Janisse (Subsidiary of DJO Global, USA)
Folker Meyer (Argonne National Laboratory, USA)
David Wayne Ussery (University of Arkansas for Medical Sciences, USA)
Intawat Nookaew (University of Arkansas for Medical Sciences, USA)
Victor Manuel Charoenrook de la Fuente
(Centro de Oalmologia Barraquer, Spain)
Karl omas Moritz
(Swedish University of Agricultural Sciences, Sweden)
Nam H. CHO (University School of Medicine and Hospital, Korea)
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Surapol Issaragrisil (Siriraj Hospital, Mahidol University,ailand)
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Suneerat Kongsayreepong (Siriraj Hospital, Mahidol University, ailand)
Pornchai O-Charoenrat (Siriraj Hospital, Mahidol University, ailand)
Nopphol Pausawasdi (Siriraj Hospital, Mahidol University, ailand)
Supakorn Rojananin (Siriraj Hospital, Mahidol University, ailand)
Jarupim Soongswang (Siriraj Hospital, Mahidol University, ailand)
Suttipong Wacharasindhu (Chulalongkorn University, ailand)
Prapon Wilairat (Mahidol University, ailand)
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Ampaiwan Chuansumrit
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(Ramathibodi Hospital, Mahidol University, ailand)
Vitoon Chinswangwatanakul
(Siriraj Hospital, Mahidol University, ailand)
SMJ
Volume 73, No.12: 2021 Siriraj Medical Journal
https://he02.tci-thaijo.org/index.php/sirirajmedj/index
777
Original Article
SMJ
Kanya Chutasmit, M.N.S., Pimol Wongsiridej, M.D. , Kanokwan Sommai, M.Sc. (Applied Statistics), Supharat
Siriwaeo, B.N.S., Pranchalee Insawang, B.N.S., Ratchada Kitsommart, M.D.
Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, ailand.
Incidence and Risk Factors of Retinopathy of
Prematurity, a 10-year Experience of a Single-center,
Referral, Hospital
ABSTRACT
Objective: To explore the incidence and trend of ROP over the past 10 years. e secondary objective was to identify
any association between clinical variables and threshold ROP.
Materials and Methods: A cross-sectional, retrospective study of infants with <33 weeks’ gestational age (GA) or
birth weight (BW) ≤1,500g were screened for ROP between January 2010 and December 2019 Infants who had
threshold ROP, labelled as the T-group, were compared against non-threshold infants (either normal or prethreshold
ROP), or the NT-group.
Results: Of the 1,247 infants who were screened for ROP, 174 (14%) tested positive for ROP while 26 (2.1%) had
threshold ROP. Infants who had ROP had a mean ±standard deviation (SD) GA 27.2 ± 2.2 weeks and 115 (66.1%)
were <1000g at birth. Advanced GA was independently associated with lower risk of threshold ROP [adjusted odds
ratio (95% condence interval, CI); 0.71 (0.52, 0.98), p=0.04]. ere was no dierence in respiratory and hemodynamic
outcomes between the T and NT-group, except for longer hospitalization (median [P25, P75]; 121[106.3, 160.5]
and 93.5[72.3, 129] days, p=0.003]. Culture-positive septicemia was independently associated with threshold ROP
[adjusted odds ratio (95% CI); 4.48 (1.72, 11.68), p=0.002].
Conclusion: e incidence of dierent stages of ROP in infants was 14% and 2.1% for severe ROP which required
treatment. Lower GA and positive-culture septicemia was associated with a higher incidence of severe ROP.
Keywords: Incidence; preterm infants; retinopathy of prematurity; screening; threshold disease (Siriraj Med J 2021;
73: 777-785)
Corresponding author: Ratchada Kitsommart
E-mail: ratchada.kit@mahidol.ac.th, rkitsommart@hotmail.com
Received 24 February 2021 Revised 30 June 2021 Accepted 30 June 2021
ORCID ID: http:orcid.org/0000-0002-7592-9899
http://dx.doi.org/10.33192/Smj.2021.101
INTRODUCTION
Retinopathy of prematurity (ROP) is the most
common cause of avoidable severe visual impairment
or blindness regardless of socioeconomic status.
1-3
is
condition has been well-documented in aecting not only
visual outcomes but also neurodevelopmental outcomes.
4,5
Multifactorial factors have been proposed as both risk
factors and preventative measures of severe ROP such as
oxygen management, transfusion practices, nutritional
and postnatal growth status, and infections. Hence, ROP
is inevitably associated with premature birth as postnatal
retinal vessel development is hastened due to postnatal
oxygen exposure and lack of placental factors to promote
normal growth of vessels, leading to an abnormal pattern
of vessels. erefore, despite improvements in perinatal
and neonatal care in a bid to minimize the amount and
duration of oxygen supplementation, retinal examinations
for ROP screening remains a mandatory strategy to
prevent severe ROP.
Volume 73, No.12: 2021 Siriraj Medical Journal
https://he02.tci-thaijo.org/index.php/sirirajmedj/index
778
Chutasmit et al.
While the incidence of very preterm infant birth has
increased this century, advancements in perinatal care has
provided hope in improving their associated morbidities,
including severe ROP. Eye examinations screening for
ROP require an interdisciplinary approach of pediatricians,
ophthalmologists, and caregivers. International guidelines
provide a strategy on how to screen for ROP in at-
risk preterm infants at a certain postnatal age (PNA).
6,7
Incidences of ROP vary among countries depending on
socioeconomic status and accessibility to ophthalmologic
examinations.
1
Interestingly, genetic factors have also
been proven to have an eect on ROP rates in dierent
racial groups.
8,9
Therefore, understanding the local
incidence rate of ROP is important in order to guide
strategic planning to minimize or eliminate the disease.
Unfortunately, problems related to awareness of ROP in
caregivers and a lack of experienced ophthalmologists
leads to inadequate coverage of a screening program
10
,
particularly in middle and low-income countries where
preterm infants are more likely to exposed to risk factors,
especially inadequate oxygen monitoring and oxygen
titration devices or availability of experienced caregivers
to monitor and control oxygenation throughout their
postnatal period.
We, therefore, wanted to explore incidence of ROP
from 2010 until 2019 and identify risk factors associated
with severe ROP cases.
MATERIALS AND METHODS
is was a retrospective, cross-sectional, comparative
study at the Division of Neonatology, Department of
Pediatrics, Faculty of Medicine at Siriraj Hospital, Mahidol
University, Bangkok, ailand. As a teaching and regional
tertiary referral hospital, patients in the study were both
inborn and outborn infants who ranged between low-risk
to high-risk. Preterm infants born <28 days before due
date were admitted into a one of several neonatal wards,
i.e; a neonatal intensive care unit (NICU), intermediate
care unit, or high-risk nursery, depending on birth
weight (BW) and respiratory or hemodynamic status,
regardless of primary diagnosis.An ACOG guidance for
antenatal corticosteroids administrations and intrapartum
antibiotics
11
was used throughout the study period.
We followed the International Liaison Committee of
Resuscitation (ILCOR) guideline for birth resuscitation.
12,13
Respiratory management included encouraging the use
of non-invasive ventilation (NIV) and oxygen titration
and oxygen monitoring devices were available at delivery
suites and neonatal wards. Surfactant replacement therapy
was used in infants with a clinical diagnosis of surfactant
deciency and requiring FiO
2
>0.6 (between 2013 to
2015) or >0.4 (from 2016 onwards) under NIV. Oxygen
management for preterm infants was targeted between
88%-93% until mid-2013 at which point it was changed
to 90%-95%. Nutritional management included early
parenteral nutrition within the rst few hours of life
and encouraging early trophic feeding. Human-milk
fortication was added once infants could tolerate 100
mL/kg/day feeds. Vitamin E 25 IU/day was also prescribed
aer infants were fully-fed until the 40-week PMA.
According to institutional guidelines for screening
of ROP, infants born prior to <33 weeks’ gestation or
with a birth weight ≤1,500g are required to be screened.
All eye examinations were performed under indirect
ophthalmoscopy at the bedside by- or under the direct
supervision of the pediatric ophthalmologist. The
rst examination was scheduled during the 4
th
week
of chronological age. Subsequent examinations were
scheduled over the next 1-4 weeks depending on previous
ndings and a plan of management was manually recorded
following each examination as part of a quality improvement
policy. e cases in which infants who had abnormal eye
examination reached threshold levels between January
2010 to December 2019 (the threshold, T-group) were
explored along with their associated risk factors. Each
case was selectively matched with 4 controls of normal
or pre-threshold ROP (the non-threshold, NT- group)
using the same GA strata (≤27 or >27 weeks-GA) and
admitted next to the corresponding case to minimize
selective bias from level of prematurity and variation
of general care practices over time. Infants who had
normal eye examinations were prioritized in the NT
group. However, in case there were not enough normal
controls, which occurred in the ≤27 weeks-strata, infants
who had abnormal examinations but did not meet the
criteria for threshold (pre-threshold ROP) were selected.
erefore, the NT-group consisted of both normal and
pre-threshold ROP disease. Clinical variables of eligible
infants were extracted using pre-specied outcomes by
an individual chart review for analysis.
Incidence and demographic characters were presented
as a number and percentage for categorical variables and
as mean ± standard deviation (SD) or median [percentile
25
th
(P25), percentile 75
th
(P75)]. Comparisons of infants’
clinical and ophthalmologic outcomes between groups of
gestational age (GA) ≤27 weeks and >27- weeks’ groups
was done using the Chi-square test, Fisher’s exact test,
paired t-test, and Mann-Whitney U test depending on
the type and distribution of each variable. A univariate
logistic regression analysis evaluated factors associated
with occurrence of threshold ROP using the crude odds
ratio (OR) with 95% condence interval (CI) and adjusted
Volume 73, No.12: 2021 Siriraj Medical Journal
https://he02.tci-thaijo.org/index.php/sirirajmedj/index
779
Original Article
SMJ
OR for signicantly dierent demographic variables with
multivariate logistic regression analysis. All statistical
analyses were performed using SPSS Statistics version
18.0 (SPSS, Inc., Chicago, IL, USA). A p-value of <0.05
was considered statistically signicant.
RESULTS
e study protocol was approved by the institutional
IRB. From January 2010 to December 2019, there were
1247 infants screened for ROP. Of these, 174 (14%)
had ROP at various stages. Our annual incidence rate
ranged from 9.2% to 24.4% (Fig 1). e mean ± standard
deviation (SD) GA of 174 infants who had abnormal eye
examinations was 27.2 ± 2.2 weeks and their mean ± SD
birth weight was 923.0 ± 257.4 g. One-hundred and een
(66.1%) infants had BW <1,000 g. One-hundred and
sixty-six (95.4%) were inborn infants, 32 (18.4%) were
small-for-gestational age and 34 (19.5%) were born from
multifetal pregnancies. reshold ROP occurred in 26
infants (2.1%) and 14.9% of infants were in the T-group
(those with ROP at dierent stages). Twenty-ve infants
had laser surgery performed, 5 received both laser surgery
and intravitreal anti-VEGF therapy, and one infant received
only anti-VEGF therapy. Of the 104 infants in the NT-
group, 31 had normal eye examinations (11 infants with
GA ≤27 weeks and 20 infants with GA >27 weeks) and
73 with prethreshold ROP (all GA ≤27 weeks). Table 1
compares baseline demographic characteristics between
the T and NT-group. Although attempts were made to
match GA, the median [P25, P75] GA of the T-group
was signicantly lower than the NT-group, 25.5 [25,
26] versus 26 [25, 27], p=0.02, and their corresponding
BW was marginally dierent (775 [707.5, 932.5] and 870
[770, 1115], respectively; p=0.05). e other baseline
characteristics were not signicantly dierent. Table 2
demonstrates clinical outcomes during hospitalization
at birth between the groups. ere were no dierences
in respiratory and hemodynamic outcomes between the
groups. However, infants in the T-group had a higher
rate of culture-positive septicemia (46.2% versus 17.3%,
p=0.004) and a longer median hospitalization stay, 121
days [106.3, 160.5] and 93.5 days [72.3, 129], p=0.003].
Among infants who had ROP at various stages,
the median [P25, P75] postnatal age (PNA) of initial
eye examination was 30 days [28, 32] at 31 [30, 33]
weeks’ postmenstrual age (PMA). e PNA of the rst
abnormal examination was 50 days [40, 58] at PMA at
34 weeks [32, 36]. Table 3 compares the characteristics
of eye examinations between the groups. PNA and PMA
of initial examinations and the rst abnormal detection
were not dierent between the groups. e T-group
had a signicantly higher number of eye examinations
during birth hospitalization (12[9, 13.3] versus 8 [5, 11.8],
respectively, p<0.001). Table 4 identies the potential risk
factors of developing threshold ROP. Culture-positive
septicemia was independently associated with threshold
ROP [adjusted OR (95%CI) 4.48 (1.72, 11.68), p =0.002]
while advanced GA was associated with lower risk of
threshold ROP [adjusted OR (95%CI) 0.71 (0.52, 0.98)
for each week, p <0.001].
Fig 2 demonstrates the proportion of ROP screening
results based on GA. e incidence trend of ROP at any
stage or at threshold were inversely high with lower GA.
(Table 5) compares characteristics of eye examinations
and the outcomes of ROP in 174 infants based on GA
strata. Infants ≤27 weeks GA had earlier both PMA for
initial eye examination and rst abnormal detection
(30 [29, 31] versus 33 [32, 34] and 33 [31, 34] versus 35
[34, 37] weeks, respectively, both p<0.001). Infants ≤27
weeks GA had a higher rate of threshold ROP (19.8%
versus 7.4%, p=0.03) and borderline dierent rates of
laser therapy (18.9% versus 7.4%, p=0.05].
Fig 1. Trend in the incidences of
retinopathy of prematurity from 2010
to 2019 (N=1,247)
Volume 73, No.12: 2021 Siriraj Medical Journal
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780
Chutasmit et al.
Variable Threshold disease Normal or p-value
(n = 26) prethreshold disease
(n = 104)
Gestational age (week) 25.5 [25, 26] 26 [25, 27] 0.02*
Birth weight (g) 775 [707.5, 932.5] 870 [770, 1115] 0.05
Small-for-gestational age 4 (15.4) 12 (11.5) 0.59
Large-for-gestational age 0 2 (1.9) 0.48
Inborn 25 (96.2) 102 (98.1) 0.56
Multiples 4 (15.4) 19 (18.3) 0.73
Cesarean section 10 (38.5) 67 (64.4) 0.03
Maternal complications (n =128) (n = 26) (n = 102)
Hypertension 2 (7.7) 18 (17.6) 0.36
Diabetes 3 (11.5) 12 (11.8) 1.00
Antepartum hemorrhage 3 (11.5) 4 (3.9) 0.15
Chorioamnionitis / infection 6 (23.1) 20 (19.6) 0.79
TABLE 1. Baseline demographic characteristics.
TABLE 2. Clinical characteristics during hospitalization at birth.
Data presented as number (percentage) or median [P25, P75].
*A p-value<0.05 indicates statistical signicance.
Variable Threshold disease Normal or p-value
(n = 26) prethreshold disease
(n = 104)
Respiratory support
Non-invasive ventilation 25 (96.2) 100 (96.2) 1.00
Mechanical ventilation 25 (96.2) 88 (84.6) 0.19
Received theophylline 21 (80.8) 90 (86.5) 0.54
Surfactant administration 11 (42.3) 34 (32.7) 0.49
Pneumothorax 2 (7.7) 6 (5.8) 0.66
Bronchopulmonary dysplasia 23 (88.5) 75 (72.1) 0.13
Cardiovascular
Inotropic agent (s) 17 (65.4) 50 (48.1) 0.13
Medical ligation 15 (57.7) 58 (55.8) 1.00
Surgical ligation 7 (26.9) 31 (29.8) 0.82
Infection
Positive blood culture 12 (46.2) 18 (17.3) 0.004*
Parenteral antibiotics 26 (100) 104 (100)
GI & Nutrition
Breast milk 25 (96.2) 100 (96.2) 1.00
Pasteurized donor milk 2 (7.7) 6 (5.8) 0.66
Formula 23 (88.5) 90 (86.50 1.00
Diagnosis of NEC 8 (30.8) 40 (38.5) 0.51
Surgical NEC 0 7 (6.7) 0.34
Days of mechanical ventilation 41 [21.0 , 61.0] 30 [10.8 , 56.5] 0.21
Days of hospitalization 121 [106.3, 160.5] 93.5 [72.3, 129] 0.003*
Death during birth hospitalization 1 (3.8) 5 (4.8) 0.28
Data presented as number (percentage) or median [P25, P75].
*A p-value<0.05 indicates statistical signicance.
(Abbreviations: CPAP, continuous positive-airway pressure; CSF, cerebrospinal uid; HFNC, high-ow nasal cannula; NEC, necrotizing
enterocolitis; NIPPV, nasal intermittent positive-airway pressure)
Volume 73, No.12: 2021 Siriraj Medical Journal
https://he02.tci-thaijo.org/index.php/sirirajmedj/index
777
Original Article
SMJ
Kanya Chutasmit, M.N.S., Pimol Wongsiridej, M.D. , Kanokwan Sommai, M.Sc. (Applied Statistics), Supharat
Siriwaeo, B.N.S., Pranchalee Insawang, B.N.S., Ratchada Kitsommart, M.D.
Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, ailand.
Incidence and Risk Factors of Retinopathy of
Prematurity, a 10-year Experience of a Single-center,
Referral, Hospital
ABSTRACT
Objective: To explore the incidence and trend of ROP over the past 10 years. e secondary objective was to identify
any association between clinical variables and threshold ROP.
Materials and Methods: A cross-sectional, retrospective study of infants with <33 weeks’ gestational age (GA) or
birth weight (BW) ≤1,500g were screened for ROP between January 2010 and December 2019 Infants who had
threshold ROP, labelled as the T-group, were compared against non-threshold infants (either normal or prethreshold
ROP), or the NT-group.
Results: Of the 1,247 infants who were screened for ROP, 174 (14%) tested positive for ROP while 26 (2.1%) had
threshold ROP. Infants who had ROP had a mean ±standard deviation (SD) GA 27.2 ± 2.2 weeks and 115 (66.1%)
were <1000g at birth. Advanced GA was independently associated with lower risk of threshold ROP [adjusted odds
ratio (95% condence interval, CI); 0.71 (0.52, 0.98), p=0.04]. ere was no dierence in respiratory and hemodynamic
outcomes between the T and NT-group, except for longer hospitalization (median [P25, P75]; 121[106.3, 160.5]
and 93.5[72.3, 129] days, p=0.003]. Culture-positive septicemia was independently associated with threshold ROP
[adjusted odds ratio (95% CI); 4.48 (1.72, 11.68), p=0.002].
Conclusion: e incidence of dierent stages of ROP in infants was 14% and 2.1% for severe ROP which required
treatment. Lower GA and positive-culture septicemia was associated with a higher incidence of severe ROP.
Keywords: Incidence; preterm infants; retinopathy of prematurity; screening; threshold disease (Siriraj Med J 2021;
73: 777-785)
Corresponding author: Ratchada Kitsommart
E-mail: ratchada.kit@mahidol.ac.th, rkitsommart@hotmail.com
Received 24 February 2021 Revised 30 June 2021 Accepted 30 June 2021
ORCID ID: http:orcid.org/0000-0002-7592-9899
http://dx.doi.org/10.33192/Smj.2021.101
INTRODUCTION
Retinopathy of prematurity (ROP) is the most
common cause of avoidable severe visual impairment
or blindness regardless of socioeconomic status.
1-3
is
condition has been well-documented in aecting not only
visual outcomes but also neurodevelopmental outcomes.
4,5
Multifactorial factors have been proposed as both risk
factors and preventative measures of severe ROP such as
oxygen management, transfusion practices, nutritional
and postnatal growth status, and infections. Hence, ROP
is inevitably associated with premature birth as postnatal
retinal vessel development is hastened due to postnatal
oxygen exposure and lack of placental factors to promote
normal growth of vessels, leading to an abnormal pattern
of vessels. erefore, despite improvements in perinatal
and neonatal care in a bid to minimize the amount and
duration of oxygen supplementation, retinal examinations
for ROP screening remains a mandatory strategy to
prevent severe ROP.
Volume 73, No.12: 2021 Siriraj Medical Journal
https://he02.tci-thaijo.org/index.php/sirirajmedj/index
778
Chutasmit et al.
While the incidence of very preterm infant birth has
increased this century, advancements in perinatal care has
provided hope in improving their associated morbidities,
including severe ROP. Eye examinations screening for
ROP require an interdisciplinary approach of pediatricians,
ophthalmologists, and caregivers. International guidelines
provide a strategy on how to screen for ROP in at-
risk preterm infants at a certain postnatal age (PNA).
6,7
Incidences of ROP vary among countries depending on
socioeconomic status and accessibility to ophthalmologic
examinations.
1
Interestingly, genetic factors have also
been proven to have an eect on ROP rates in dierent
racial groups.
8,9
Therefore, understanding the local
incidence rate of ROP is important in order to guide
strategic planning to minimize or eliminate the disease.
Unfortunately, problems related to awareness of ROP in
caregivers and a lack of experienced ophthalmologists
leads to inadequate coverage of a screening program
10
,
particularly in middle and low-income countries where
preterm infants are more likely to exposed to risk factors,
especially inadequate oxygen monitoring and oxygen
titration devices or availability of experienced caregivers
to monitor and control oxygenation throughout their
postnatal period.
We, therefore, wanted to explore incidence of ROP
from 2010 until 2019 and identify risk factors associated
with severe ROP cases.
MATERIALS AND METHODS
is was a retrospective, cross-sectional, comparative
study at the Division of Neonatology, Department of
Pediatrics, Faculty of Medicine at Siriraj Hospital, Mahidol
University, Bangkok, ailand. As a teaching and regional
tertiary referral hospital, patients in the study were both
inborn and outborn infants who ranged between low-risk
to high-risk. Preterm infants born <28 days before due
date were admitted into a one of several neonatal wards,
i.e; a neonatal intensive care unit (NICU), intermediate
care unit, or high-risk nursery, depending on birth
weight (BW) and respiratory or hemodynamic status,
regardless of primary diagnosis.An ACOG guidance for
antenatal corticosteroids administrations and intrapartum
antibiotics
11
was used throughout the study period.
We followed the International Liaison Committee of
Resuscitation (ILCOR) guideline for birth resuscitation.
12,13
Respiratory management included encouraging the use
of non-invasive ventilation (NIV) and oxygen titration
and oxygen monitoring devices were available at delivery
suites and neonatal wards. Surfactant replacement therapy
was used in infants with a clinical diagnosis of surfactant
deciency and requiring FiO
2
>0.6 (between 2013 to
2015) or >0.4 (from 2016 onwards) under NIV. Oxygen
management for preterm infants was targeted between
88%-93% until mid-2013 at which point it was changed
to 90%-95%. Nutritional management included early
parenteral nutrition within the rst few hours of life
and encouraging early trophic feeding. Human-milk
fortication was added once infants could tolerate 100
mL/kg/day feeds. Vitamin E 25 IU/day was also prescribed
aer infants were fully-fed until the 40-week PMA.
According to institutional guidelines for screening
of ROP, infants born prior to <33 weeks’ gestation or
with a birth weight ≤1,500g are required to be screened.
All eye examinations were performed under indirect
ophthalmoscopy at the bedside by- or under the direct
supervision of the pediatric ophthalmologist. The
rst examination was scheduled during the 4
th
week
of chronological age. Subsequent examinations were
scheduled over the next 1-4 weeks depending on previous
ndings and a plan of management was manually recorded
following each examination as part of a quality improvement
policy. e cases in which infants who had abnormal eye
examination reached threshold levels between January
2010 to December 2019 (the threshold, T-group) were
explored along with their associated risk factors. Each
case was selectively matched with 4 controls of normal
or pre-threshold ROP (the non-threshold, NT- group)
using the same GA strata (≤27 or >27 weeks-GA) and
admitted next to the corresponding case to minimize
selective bias from level of prematurity and variation
of general care practices over time. Infants who had
normal eye examinations were prioritized in the NT
group. However, in case there were not enough normal
controls, which occurred in the ≤27 weeks-strata, infants
who had abnormal examinations but did not meet the
criteria for threshold (pre-threshold ROP) were selected.
erefore, the NT-group consisted of both normal and
pre-threshold ROP disease. Clinical variables of eligible
infants were extracted using pre-specied outcomes by
an individual chart review for analysis.
Incidence and demographic characters were presented
as a number and percentage for categorical variables and
as mean ± standard deviation (SD) or median [percentile
25
th
(P25), percentile 75
th
(P75)]. Comparisons of infants’
clinical and ophthalmologic outcomes between groups of
gestational age (GA) ≤27 weeks and >27- weeks’ groups
was done using the Chi-square test, Fisher’s exact test,
paired t-test, and Mann-Whitney U test depending on
the type and distribution of each variable. A univariate
logistic regression analysis evaluated factors associated
with occurrence of threshold ROP using the crude odds
ratio (OR) with 95% condence interval (CI) and adjusted
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OR for signicantly dierent demographic variables with
multivariate logistic regression analysis. All statistical
analyses were performed using SPSS Statistics version
18.0 (SPSS, Inc., Chicago, IL, USA). A p-value of <0.05
was considered statistically signicant.
RESULTS
e study protocol was approved by the institutional
IRB. From January 2010 to December 2019, there were
1247 infants screened for ROP. Of these, 174 (14%)
had ROP at various stages. Our annual incidence rate
ranged from 9.2% to 24.4% (Fig 1). e mean ± standard
deviation (SD) GA of 174 infants who had abnormal eye
examinations was 27.2 ± 2.2 weeks and their mean ± SD
birth weight was 923.0 ± 257.4 g. One-hundred and een
(66.1%) infants had BW <1,000 g. One-hundred and
sixty-six (95.4%) were inborn infants, 32 (18.4%) were
small-for-gestational age and 34 (19.5%) were born from
multifetal pregnancies. reshold ROP occurred in 26
infants (2.1%) and 14.9% of infants were in the T-group
(those with ROP at dierent stages). Twenty-ve infants
had laser surgery performed, 5 received both laser surgery
and intravitreal anti-VEGF therapy, and one infant received
only anti-VEGF therapy. Of the 104 infants in the NT-
group, 31 had normal eye examinations (11 infants with
GA ≤27 weeks and 20 infants with GA >27 weeks) and
73 with prethreshold ROP (all GA ≤27 weeks). Table 1
compares baseline demographic characteristics between
the T and NT-group. Although attempts were made to
match GA, the median [P25, P75] GA of the T-group
was signicantly lower than the NT-group, 25.5 [25,
26] versus 26 [25, 27], p=0.02, and their corresponding
BW was marginally dierent (775 [707.5, 932.5] and 870
[770, 1115], respectively; p=0.05). e other baseline
characteristics were not signicantly dierent. Table 2
demonstrates clinical outcomes during hospitalization
at birth between the groups. ere were no dierences
in respiratory and hemodynamic outcomes between the
groups. However, infants in the T-group had a higher
rate of culture-positive septicemia (46.2% versus 17.3%,
p=0.004) and a longer median hospitalization stay, 121
days [106.3, 160.5] and 93.5 days [72.3, 129], p=0.003].
Among infants who had ROP at various stages,
the median [P25, P75] postnatal age (PNA) of initial
eye examination was 30 days [28, 32] at 31 [30, 33]
weeks’ postmenstrual age (PMA). e PNA of the rst
abnormal examination was 50 days [40, 58] at PMA at
34 weeks [32, 36]. Table 3 compares the characteristics
of eye examinations between the groups. PNA and PMA
of initial examinations and the rst abnormal detection
were not dierent between the groups. e T-group
had a signicantly higher number of eye examinations
during birth hospitalization (12[9, 13.3] versus 8 [5, 11.8],
respectively, p<0.001). Table 4 identies the potential risk
factors of developing threshold ROP. Culture-positive
septicemia was independently associated with threshold
ROP [adjusted OR (95%CI) 4.48 (1.72, 11.68), p =0.002]
while advanced GA was associated with lower risk of
threshold ROP [adjusted OR (95%CI) 0.71 (0.52, 0.98)
for each week, p <0.001].
Fig 2 demonstrates the proportion of ROP screening
results based on GA. e incidence trend of ROP at any
stage or at threshold were inversely high with lower GA.
(Table 5) compares characteristics of eye examinations
and the outcomes of ROP in 174 infants based on GA
strata. Infants ≤27 weeks GA had earlier both PMA for
initial eye examination and rst abnormal detection
(30 [29, 31] versus 33 [32, 34] and 33 [31, 34] versus 35
[34, 37] weeks, respectively, both p<0.001). Infants ≤27
weeks GA had a higher rate of threshold ROP (19.8%
versus 7.4%, p=0.03) and borderline dierent rates of
laser therapy (18.9% versus 7.4%, p=0.05].
Fig 1. Trend in the incidences of
retinopathy of prematurity from 2010
to 2019 (N=1,247)
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Chutasmit et al.
Variable Threshold disease Normal or p-value
(n = 26) prethreshold disease
(n = 104)
Gestational age (week) 25.5 [25, 26] 26 [25, 27] 0.02*
Birth weight (g) 775 [707.5, 932.5] 870 [770, 1115] 0.05
Small-for-gestational age 4 (15.4) 12 (11.5) 0.59
Large-for-gestational age 0 2 (1.9) 0.48
Inborn 25 (96.2) 102 (98.1) 0.56
Multiples 4 (15.4) 19 (18.3) 0.73
Cesarean section 10 (38.5) 67 (64.4) 0.03
Maternal complications (n =128) (n = 26) (n = 102)
Hypertension 2 (7.7) 18 (17.6) 0.36
Diabetes 3 (11.5) 12 (11.8) 1.00
Antepartum hemorrhage 3 (11.5) 4 (3.9) 0.15
Chorioamnionitis / infection 6 (23.1) 20 (19.6) 0.79
TABLE 1. Baseline demographic characteristics.
TABLE 2. Clinical characteristics during hospitalization at birth.
Data presented as number (percentage) or median [P25, P75].
*A p-value<0.05 indicates statistical signicance.
Variable Threshold disease Normal or p-value
(n = 26) prethreshold disease
(n = 104)
Respiratory support
Non-invasive ventilation 25 (96.2) 100 (96.2) 1.00
Mechanical ventilation 25 (96.2) 88 (84.6) 0.19
Received theophylline 21 (80.8) 90 (86.5) 0.54
Surfactant administration 11 (42.3) 34 (32.7) 0.49
Pneumothorax 2 (7.7) 6 (5.8) 0.66
Bronchopulmonary dysplasia 23 (88.5) 75 (72.1) 0.13
Cardiovascular
Inotropic agent (s) 17 (65.4) 50 (48.1) 0.13
Medical ligation 15 (57.7) 58 (55.8) 1.00
Surgical ligation 7 (26.9) 31 (29.8) 0.82
Infection
Positive blood culture 12 (46.2) 18 (17.3) 0.004*
Parenteral antibiotics 26 (100) 104 (100)
GI & Nutrition
Breast milk 25 (96.2) 100 (96.2) 1.00
Pasteurized donor milk 2 (7.7) 6 (5.8) 0.66
Formula 23 (88.5) 90 (86.50 1.00
Diagnosis of NEC 8 (30.8) 40 (38.5) 0.51
Surgical NEC 0 7 (6.7) 0.34
Days of mechanical ventilation 41 [21.0 , 61.0] 30 [10.8 , 56.5] 0.21
Days of hospitalization 121 [106.3, 160.5] 93.5 [72.3, 129] 0.003*
Death during birth hospitalization 1 (3.8) 5 (4.8) 0.28
Data presented as number (percentage) or median [P25, P75].
*A p-value<0.05 indicates statistical signicance.
(Abbreviations: CPAP, continuous positive-airway pressure; CSF, cerebrospinal uid; HFNC, high-ow nasal cannula; NEC, necrotizing
enterocolitis; NIPPV, nasal intermittent positive-airway pressure)
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TABLE 3. Characteristics of eye examinations (N=130).
TABLE 4. Risk factors of threshold ROP.
Threshold Normal or
Variable disease prethreshold disease p-value
(n = 26) (n = 104)
Postnatal age of rst eye examination, day 30 [28, 32.5] 29 [27.3, 32] 0.43
Postmenstrual age of rst eye examination, week 29.5 [28.8, 32] 30 [29, 31] 0.09
Postnatal age of rst abnormal detection, day (n = 99) 50 [44, 53] 52 [44.5, 61] 0.11
Postmenstrual age of rst abnormal detection, week (n = 99) 32 [31, 34] 33 [31.5, 34] 0.16
Number of examinations during birth hospitalization 12 [9, 13.3] 8 [5, 11.8] <0.001*
Data presents as median [P25, P75].
*A p-value<0.05 indicates statistical signicance.
Variables OR (95%CI) P-value AOR (95%CI) p-value
Gestational age
(every week increment) 0.75 (0.56, 0.99) 0.05 0.71 (0.52, 0.98) 0.04*
Birth weight
(every 100-g increment) 0.84 (0.69, 1.02) 0.07 0.95 (0.72, 1.28) 0.75
Mechanical ventilation 4.55 (0.57, 35.97) 0.15 2.42 (0.28, 21.28) 0.43
Surfactant administration 1.51 (0.63, 3.64) 0.36 1.03 (0.39, 2.72) 0.95
Days of mechanical ventilation 1.00 (0.99, 1.01) 0.33 0.99 (0.98, 1.01) 0.78
Did not receive breast milk 1.00 (0.11, 9.34) 1.00 0.68 (0.07, 6.89) 0.75
Culture-positive septicemia 4.10 (1.63, 10.31) 0.003 4.48 (1.72, 11.68) 0.002*
Medical ligation for PDA 1.08 (0.45, 2.58) 0.86 0.64 (0.24, 1.70) 0.37
Surgical ligation for PDA 0.87 (0.33, 2.27) 0.77 0.54 (0.19, 1.54) 0.25
Inotropic agents 2.04 (0.83, 4.99) 0.12 1.11 (0.41, 3.01) 0.84
AOR, adjusted odds ratio, were adjusted by gestational age and positive blood culture.
*A p-value<0.05 indicates statistical signicance.
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Chutasmit et al.
Fig 2. Incidences of retinopathy of prematurity by gestational age (N=1,247)
TABLE 5. Characteristics of abnormal eye examinations (N=174).
GA ≤27 weeks GA >27 weeks p-value
(n = 106) (n = 68)
PNA of rst eye examination (days) 30 [28, 33] 30 [28 ,32] 0.88
PMA of rst eye examination (weeks) 30 [29, 31] 33 [32, 34] <0.001*
PNA of rst abnormal detection (days) (n = 99) 51 [44, 59.3] 42.5 [32.3, 53.8] <0.001*
PMA age of rst abnormal detection (weeks) (n = 99) 33 [31, 34] 35 [34, 37] <0.001*
Number of examinations during hospitalization 10 [8, 13] 6 [4, 9] <0.001*
Threshold disease 21 (19.8) 5 (7.4) 0.03*
Laser therapy 20 (18.9) 5 (7.4) 0.05*
PNA of LASER therapy (days) 75.5 [66.8, 85.8] 68 [38, 88] 0.37
Intravitreous anti-VEGF therapy 5 (4.7) 1 (1.5) 0.41
PNA of anti-VEGF therapy (days) 69 [61, 108] 43 [43, 43] 0.33
Data presents as median [P25, P75] or number (percentage). *A p-value<0.05 indicates statistical signicance.
Abbreviations: PMA, postmenstrual age; PNA, postnatal age; VEGF, vascular endothelial growth factor
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DISCUSSION
Retinopathy of prematurity (ROP) remains an important
morbidity factor in extremely preterm infants. Since its risk
is the result of premature birth, total elimination of ROP
remains a challenge even though various strategies have
been attempted to minimize the risk of the disease. In fact,
a standard screening program is mandatory to explore the
magnitude of the disease and, more importantly, to identify
early abnormal vessels to allow for early management
that can save an infant’s long-term vision. Relatively
recent reports about incidence of ROP at any stage of
the disease ranges between 9% to 27%.
14-17
However, it is
a challenge to compare results because such a big range
of incidence can be explained by a few possibilities. e
rst, and most important reason, is the availability to
provide care for very premature infants and associated
risk factors. Middle-income countries especially have a
high burden of ROP due to improvements in survival
rate of extremely premature infants, however, they still
have limited resources to monitor and titration of oxygen
devices.
1
is phenomenon has been noted aer studies
have revealed the incidence of ROP in middle-income
countries was as high as 69% in extremely-low birthweight
infants.
18
Second, criteria for ROP screening suggested
from dierent expertise groups are not uniform, mainly
included GA and BW.
6,19
Generally, ROP screening is
suggested for infants with GA ≤30 or 32 weeks or a BW
of ≤1,500 g. Although we perform screening for all <33
weeks’ gestation or ≤1,500 g BW infants, only 7 out of
130 (5.4%) who were 31 to 32 weeks’ GA and had BW
>1,500 g. So, proportion of at-risk infants who were
screened overall should be comparable to the other reported
incidence using minor dierent criterion. ird, various
denitions of severe ROP were selected in each report
and used treatment requiring ROP or threshold ROP to
represent the severity. Our incidence of ROP at any stage
of the disease was 14%, which was relatively low when
compared to other upper middle-income countries where
the incidence ranges between 19% to 33%.
17,20,21
In fact, our
incidence showed ROP rates decreased from 2010 to 2013.
However, there was a sharp increase in ROP rate from
9.3% in 2013 to 14.3% in 2014. We suspect this rise was
secondary due to changes of targeted oxygen saturation
which was reported in a previous study.
22,23
However,
our incidence of threshold ROP at 2.1% was relatively
stable throughout the study period and comparable to
the other reports from developed countries.
14
Timing of abnormal neovascularization usually found
during vasoproliferative phase of ROP.
19,24
We found
median PNA of initial abnormal vessels detection were
50 days in threshold ROP and 52 days for prethreshold
ROP which were correspondence to 32- and 33-weeks
PMA. Since their PNA and PMA were comparable
between the groups, timing of initial abnormal detection
cannot predict their subsequent results of abnormal
vessels which emphasize the importance of subsequent
follow-up examinations until full development of retinal
vessels.
Observational studies have shown several risk factors
associated with either ROP at various stages of disease
progression or threshold ROP. e most potent risk of
baseline characteristics is premature birth,
10,14,25
which
was also demonstrated in our study [adjusted OR 0.71
(0.52, 0.98), p=0.04]. Although 66.1% of ROP cases in
our study were extremely premature infants (birth weight
<1,000 g), we did not nd any signicant association
between BW and threshold ROP. So, premature birth
is a more potent risk factor than intrauterine growth.
Dysoxemia and clinical unstable are proposed to be
at-risk for ROP.
26-29
We did not nd any dierences
in respiratory outcomes such as intubation, duration
of mechanical ventilation, surfactant administration,
pneumothorax, or bronchopulmonary dysplasia or in
hemodynamic parameters (inotropic agents or treatment
of patent ductus arteriosus) in infants with threshold
ROP and the control group. Postnatal nutrition plays
an important role on normal retinal vessels via optimal
level of IGF-1 and antioxidative factors in breast milk.
30
Hence, we did not nd dierent rate of threshold ROP in
infants who received maternal breast milk or pasteurized
donor milk (PDM [adjusted OR 0.68 (0.07, 6.89), p=0.75].
However, due to the limited number of infants who did
not receive breast milk, this phenomenon is deserved to
be explored further with adequate sample size.
e meta-analysis showed signicant association
between chorioamnionitis and severe ROP,
31
but no study
has found a similar association for postnatal septicemia.
Interestingly, we noticed positive-culture septicemia as
a risk factor [adjusted OR 4.48 (1.72, 11.68), p=0.002].
e possibility of this relationship can be attributed to
inammation cascade suppressed early retinal vascularization
and cause severe neovascularization later or secondary to
systemic instability during sepsis contributed to retinal
hypoxia and develop ROP later.
32
We reported our incidence rate in a large number
of at-risk infants from the tertiary care referral center in
ailand where the ROP screening program, including
patient selections, examination maneuvers and recording,
follow-up practices and therapy is already established.
All eye examinations were interpreted by only one
pediatric ophthalmologist which ensured internal validity.
However, some limitations must be considered. First,
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Chutasmit et al.
due to our cross-sectional design, we could not ensure
timely association or if some variables occurred before
or aer detection of abnormal retinal vessels. erefore,
our results assumed association between these variables
and ROP occurrence. Hence, PNA of abnormal ndings
occurred around 50 days when most clinical stability was
already established or had subsided. is was assumed to
occur before any ndings of ROP. Second, our patients
were mainly inborn infants where physicians, caregivers,
devices, and monitoring equipment were available. Our
incidence rate may not reect the true incidence rate in
the country, especially in rural areas where resources are
limited, especially in coverage of the screening program.
CONCLUSION
In conclusion, during the past 10 years, our incidence
of ROP at any stage in infants born <33 weeks or with
a BW <1,500 g was 14% and 2.1% for threshold ROP
requiring treatment. Lower GA and positive-culture
septicemia were found to be associated with occurrence
of threshold ROP.
ACKNOWLEDGEMENTS
We gratefully give thanks to Professor La-Ongsri
Atchaneeyasakul for her contribution in performing eye
examination throughout the study period.
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Vis Sci. 1999;40:804-9.
29. Holmes JM, Zhang S, Leske DA, Lanier WL. Carbon dioxide-
induced retinopathy in the neonatal rat. Curr Eye Res. 1998;17:
608-16.
30. Zhou J, Shukla VV, John D, Chen C. Human milk feeding as
a protective factor for retinopathy of prematurity: a meta-
analysis. Pediatrics. 2015;136:e1576-86.
31. Villamor-Martinez E, Cavallaro G, Raaeli G, Mohammed
Rahim OMM, Gulden S, Ghazi AMT, et al. Chorioamnionitis
as a risk factor for retinopathy of prematurity: An updated
systematic review and meta-analysis. PLoS One. 2018;13:1-20.
32. Lundgren P, Klevebro S, Brodin P, Smith LEH, Hallberg B,
Hellstrom A. Leucocytosis is associated with retinopathy of
prematurity in extremely preterm infants. Acta Paediatr. 2019;
108:1357-8.
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Doonyaporn Wongsawaeng, M.D.*, Orasa Chawalparit, M.D.*, Siriwan Piyapittayanan, M.D.*, Tanyaluck
ientunyakit, M.D.*, Weerasak Muangpaisan, M.D.**, Kitikan ana-udom, M.D. ***, Panida Charnchaowanish,
B.Sc*, Chanon Ngamsombat, M.D.*
*Department of Radiology, **Department of Preventive and Social Medicine, ***Department of Psychiatry, Faculty of Medicine Siriraj Hospital,
Mahidol University, Bangkok 10700, ailand.
Magnetic Resonance Hippocampal Subeld
Volumetric Analysis for Differentiating among
Healthy Older Adults and Older Adults with Mild
Cognitive Impairment or Major Depressive Disorder
ABSTRACT
Objective: Depression among older adults is frequently an early symptom of cognitive decline, and is believed to
be a risk factor for Alzheimer’s disease (AD). Hippocampal subeld volume loss is found in both mild cognitive
impairment (MCI) and major depressive disorder (MDD). We aimed to investigate the potential of MR hippocampal
subeld volumetry for discriminating among healthy older adults (HOA) and older adults with MCI or MDD.
Materials and Methods: Seventy age-matched subjects (29 non-depressed MCI, 12 MDD, and 29 HOA) underwent
3-Tesla MR imaging (MRI) with high-resolution 3D-T1W-TFE whole brain. Hippocampal subeld volumetric
measurements were performed using FreeSurfer soware to distinguish among MCI, MDD, and HOA. Subgroup
analysis with amyloid PET result was also performed.
Results: Signicantly smaller bilateral hippocampal tail volume was observed in MCI compared to HOA (p=0.004
and p=0.04 on the le and right side, respectively). e same comparative nding was observed at le HATA
(hippocampus-amygdala-transition-area) of MCI (p=0.046). Other regions showed non-signicantly smaller size
in MCI than in HOA [le molecular layer HP (p=0.06), le whole hippocampus (p=0.06), and le CA1 (p=0.07)].
ere was a non-signicant trend toward smaller size in almost all 13 subeld hippocampal regions of MCI compared
to MDD, even in subgroup analysis with amyloid PET result.
Conclusion: MR hippocampal subeld volumetry may have value in routine clinical practice for screening individuals
with MCI, and may be a valuable adjunct to amyloid PET study for very early-stage diagnosis of AD.
Keywords: Magnetic resonance hippocampal subeld volumetric analysis, mild cognitive impairment (MCI), major
depressive disorder (MDD), healthy older adults (HOA) (Siriraj Med J 2021; 73: 786-792)
Corresponding author: Chanon Ngamsombat
E-mail: ngamsombatc@gmail.com
Received 9 March 2021 Revised 29 June 2021 Accepted 1 July 2021
ORCID ID: https://orcid.org/0000-0001-5055-0711
http://dx.doi.org/10.33192/Smj.2021.102
INTRODUCTION
Mild cognitive impairment (MCI) is diagnosed
when people have measurable changes in thinking ability
noticed by the person affected, family members, or
friends even though the observed impairment does
not aect the individual’s activities of daily living.
1
e
2011 recommendations from the National Institute on
Aging-Alzheimer’s Association diagnostic guideline for
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Alzheimer’s disease (AD) working groups suggest that
some MCI cases reect the early stage of AD.
2
Depression,
especially in older adults, frequently develops concomitantly
with cognitive impairment, and it may be a psychological
reaction or a risk factor for AD.
3
One of the most mentioned structures in limbic
system is hippocampus, which is known to involve in both
neurodegenerative disease, especially AD, and emotional
regulation.
4
Hippocampal atrophy is usually detected
in late stage of AD. Previous study found that subeld
hippocampal atrophy evidenced by magnetic resonance
imaging (MRI) might be helpful for early detection of
mild cognitive impairment who have converted to AD
(MCI-c).
5
Concerning mood regulation, a previous meta-
analysis found more hippocampal volume loss in MDD
than in the control; however, the impact of illness on
hippocampal volume is probably related to duration
and severity.
6
To date, no study has compared subeld hippocampal
volume between MCI and MDD in older adults. Accordingly,
the aim of this study was to investigate the potential of
MR hippocampal subeld volumetry for discriminating
among older adults with non-depressed MCI, older
adults with treatment-naïve MDD, and healthy older
adults (HOA).
MATERIALS AND METHODS
Study population
is retrospective study reviewed the MRI DICOM
les, clinical information, and neuropsychological test
results of 72 subjects (30 MCI, 12 MDD, and 30 HOA)
who were recruited at a single national tertiary referral
center in ailand during January 2016 to September
2020. e protocol for this study was approved by the
Siriraj Institutional Review Board (SIRB) of the Faculty of
Medicine Siriraj Hospital, Mahidol University, Bangkok,
ailand (Si 1037/2020).
e 30 MCI and 30 HOA subjects, recruited from
neurology and geriatric clinics at our center, were part
from the SIRB-approved study (Si 137/2015). Clinical
evaluation of MCI and HOA subjects was performed by
a senior geriatric neurologist (WM) who specializes in
dementia.
e 12 MDD subjects, rst-diagnosed treatment-
naïve patients, recruited from the psychiatric clinic at
our center, were part from a dierent SIRB-approved
study (Si 239/2016). Diagnosis and severity of depression
were determined by a board-certied psychiatrist.
Two out of 72 subjects (1 MCI and 1 HOA) were
excluded due to aws in their MRI DICOM les. e
remaining 70 subjects (29 MCI, 12 MDD, and 29 HOA)
were included and analyzed. e amyloid PET result for all
of the 29 MCI patients were recorded and subcategorized
as PET positive MCI (PET+ve MCI; n=12) or PET negative
MCI (PET-ve MCI; n=17) patients. Age, gender, education
level, ai Mental State Examination (TMSE)
7
, Clinical
Dementia Rating Scale (CDR), and Hamilton Rating
Scale for Depression (HAM-D)
8
were also collected and
recorded. Two years of clinical follow-up among the
29 MCI subjects was achieved by the end of September
2020.
Operational denitions
1. Criteria for mild cognitive impairment (MCI)
1) Age equal to or greater than 60 years
2) Subjective memory complaint by the patient,
family member, or clinician with preserved activities of
daily living (ADL)
3) CDR score of 0.5
4) Absence of dementia by National Institute of
Neurological and Communicative Disorders and Stroke
and the Alzheimer’s Disease and Related Disorders
Association (NINCDS-ADRDA) criteria
5) TMSE score from 24 to 30
6) No history of depressive symptom
2. Criteria for major depressive disorder (MDD)
1) Age equal to or greater than 60 years
2) First diagnosed approaching fulllment of the
Diagnostic and Statistical Manual of Mental Disorders,
5
th
Edition (DSM-5) criteria for MDD
9
3) Depression severity was measured by HAM-D
4) TMSE score from 24 and 30
5) No other psychiatric disorders, antidepressant
drug use, currently unstable medical or neurological
condition
3. Criteria for healthy older adults (HOA)
1) Age equal to or greater than 60 years
2) TMSE score from 24 to 30
3) CDR score of 0
4) No neurological or psychiatric illness, non-
demented, and normal ADL
Magnetic resonance imaging (MRI) acquisition
All 70 enrolled subjects underwent 3T MRI scans
(Ingenia, Philips Medical System, Best, the Netherlands)
with a 32-channel head coil. e MRI protocol included
a 3D high-resolution T1W-TFE sequence covering whole
brain (eld-of-view (FOV) 230×230×172 mm
3
, matrix
size 352x352, voxel size 0.72×0.72×0.65 mm
3
, echo time
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(TE)/repetition time (TR) 4.8/9.8 ms, ip angle 8°, scan
time 6 min). All MRI DICOM les were transferred to
hippocampal subeld segmentation process.
Hippocampal subeld segmentation
e FreeSurfer image analysis pipeline (version
6.0)
10
was used for automated hippocampal subeld
segmentation. e validated ultra-high resolution 13
subeld hippocampal regions (Fig 1) were, as follows:
presubiculum, subiculum, parasubiculum, cornu ammonis
(CA)1, CA2/3, CA4, molecular layer hippocampus (HP),
GC-ML-DG (granule cell layer and molecular layer
of dentate gyrus), HATA (hippocampus-amygdala-
transition-area), hippocampal tail, mbria, hippocampal
ssure, and the whole hippocampus, bilaterally.
e raw volume data each of subeld was displayed
and then normalized according to each subject’s intracranial
volume (ICV) derived from FreeSurfer soware via this
following formula: volume normalized = volume raw
data x 1,000/ICV in cm
3
.
10,11
[18F] Florbetapir PET/CT to detect cerebral amyloid
deposition
All 29 MCI patients also underwent amyloid positron
emission tomography (PET) study with administration
of our proprietary [18F] orbetapir biomarker
12
shortly
before or aer MRI scan. Our specic PET/CT scan
(Discovery STE; GE Healthcare, Chicago, IL, USA)
acquisition and image protocols are described in ADNI
GO
13
and ADNI 2.
14
In the present study, two nuclear
medicine physicians who were blinded to patient clinical
information reached a consensus decision regarding who
was amyloid positive and who was amyloid negative
according to the published criteria.
15
(Fig 2)
Fig 2. e transaxial images of [F-18] orbetapir PET brain study in two dierent patients with mild cognitive impairment (MCI) showing
positive brain amyloid deposition due to mildly increased radiotracer uptake at bilateral temporal cerebral cortices (A), and negative amyloid
deposition due to clear gray-white matter discrimination without abnormal cortical uptake (B).
Fig 1. Coronal view MRI bilateral hippocampi of a 72-year-old male with mild cognitive impairment (amyloid PET positive) (A), and a
68-year-old male with rst diagnosis treatment-naïve MDD (B) shown in T1-weighted image (le), and T1-weighted image with subeld
hippocampal segmentations (right).
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Statistical analysis
All statistical analyses were performed using SPSS
Statistics version 18.0 (SPSS, Inc., Chicago, IL, USA).
Continuous variables were analyzed by analysis of variance
(ANOVA) with Bonferroni post hoc comparisons, and
the categorical variables were analyzed by chi-square
test. A p-value <0.05 was considered to be statistically
signicant.
RESULTS
1. Demographics, clinical and neuropsychological data
Seventy age-matched subjects were included in
this study (MCI=29, MDD=12, HOA=29). e mean
± SD age of these 3 groups was 68.1±4.3, 70.8±6.0, and
68.7±4.8 years, respectively. As expected, there were no
statistically signicant dierences in TMSE score among
the 3 study groups (Table 1). Six of the 29 MCI patients
had clinically proven AD-converted MCI by the end of
the 2-year follow-up, and all 6 of those patients had an
initial amyloid PET result that was positive.
2. Hippocampal subelds
2.1 Comparison between MCI and HOA (Table 2)
e bilateral hippocampal tails showed signicantly
smaller volume in the MCI group compared to the HOA
group (p=0.004 and p=0.04 on the le and right side,
respectively), as well as at the le HATA (hippocampus-
amygdala-transition-area) (p=0.046). We also observed
a trend towards signicantly smaller size in the MCI
group compared to the HOA group for le molecular
layer HP (p=0.06), le whole hippocampus (p=0.06),
and le CA1 (p=0.07).
2.2 Comparison between MCI and MDD (Tables
2, 3)
ere was a non-signicant trend toward smaller
size in almost all of the 13 subeld hippocampal regions
when compared between MCI and MDD subjects – even
in subgroup analysis (MCI PET+ve and MCI PET-ve).
2.3 Comparison between MDD and HOA (Table 2)
ere was no signicant dierence between the
MDD and HOA groups for any subeld hippocampal
regions.
2.4 Comparison between MCI PET+ve and HOA
(Table 3)
In subgroup analysis combined with amyloid
PET result, we found that the bilateral hippocampal
tails showed a signicantly smaller volume in the MCI
PET+ve group than in the HOA group (p=0.002 and
p=0.02 on the le and right side, respectively). e le
whole hippocampus (p=0.05), le molecular layer HP
(p=0.07), and le subiculum (p=0.07) all demonstrated
smaller volume among MCI PET+ve subjects compared
to HOA subjects.
2.5 Comparison between MCI PET-ve and HOA
(Table 3)
No statistically signicant dierence in hippocampal
subeld volumes was observed between these two groups.
TABLE 1. Demographic, clinical and neuropsychological data of MCI, MDD, and HOA subjects.
Subject data
MCI MDD HOA
(n=29) (n=12) (n=29)
p
Gender (male/female), n 15/14 5/7 10/19 0.41
Age (years), (mean±SD) 68.1±4.3 70.8±6.0 68.7±4.8 0.26
Education, n (%) <0.0001
- High school or lower 2 (6.9%) 8 (66.7%) 16 (55.2%)
- Higher than high school 27 (93.1%) 4 (33.3%) 13 (44.8%)
TMSE (mean±SD) 27.3±1.6 26.8±2.0 27.9±1.9 0.17
HAM-D (mean±SD) NA 24.5±4.3 NA NA
A p-value<0.05 indicates statistical signicance
Abbreviations: MCI, mild cognitive impairment; MDD, major depressive disorder; HOA, healthy older adults; SD, standard deviation;
TMSE, ai Mental State Examination, HAM-D; Hamilton Rating Scale for Depression; NA, not applicable
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TABLE 2. Normalized hippocampal subeld volume compared among MCI, MDD, and HOA subjects.
TABLE 3. Hippocampal subeld volume compared among MCI PET +ve, MCI PET -ve, MDD, and HOA subjects.
Parameters MCI (n=29) MDD (n=12) HOA (n=29) P (MCI vs HOA)
Left hippocampal tail 323.4±67.2 342.4±70.2 383.0±67.5 0.004
a
Right hippocampal tail 345.3±78.2 368.0±54.0 392.4±70.1 0.04
a
Left HATA 37.4±7.5 43.7±13.9 42.3±7.4 0.046
a
Left molecular layer HP 352.1±67.7 385.6±88.0 394.1±58.2 0.06
Left whole hippocampus 2,151.5±376.2 2,338.6±521.6 2,396.6±337.1 0.06
Left CA1 394.4±79.9 435.0±88.3 440.8±68.5 0.07
a
Statistically signicant dierence (p<0.05) between the MCI and HOA groups
Abbreviations: MCI, mild cognitive impairment; MDD, major depressive disorder; HOA, healthy older adults; HATA, hippocampus-
amygdala-transition-area; HP, hippocampus; CA1, cornu ammonis 1
MCI PET+ve MCI PET-ve MDD HOA
P (MCI
Parameters
(n=12) (n=17) (n=12) (n=29)
PET+ve
vs HOA)
Left hippocampal tail 297.5±79.1 341.7±52.4 342.4±70.2 383.0±67.5 0.002
a
Right hippocampal tail 318.2±87.5 364.4±67.0 368.0±54.0 392.4±70.1 0.02
a
Left whole hippocampus 2,035.4±380.4 2,233.5±361.8 2,338.6±521.6 2,396.6±337.1 0.05
Left molecular layer HP 334.3±66.8 364.6±67.5 385.6±88.0 394.1±58.2 0.07
Left subiculum 261.9±56.5 292.6±50.6 310.1±78.2 311.6±48.4 0.07
a
Statistically signicant dierence (p<0.05) between the MCI PET+ve and HOA groups
Abbreviations: MCI, mild cognitive impairment; MDD, major depressive disorder; HOA, healthy older adults; HP, hippocampus
DISCUSSION
Interestingly, the signicantly smaller volume of
the bilateral hippocampal tails in the MCI compared
to the HOA group, as well as in subgroup analysis, was
observed in the MCI PET+ve, but not in the MCI PET-
ve group. Previous study
16,17
reported some dierences
in functionality between the ventral (anterior) and the
dorsal (posterior) hippocampus in which the posterior
part primarily performs cognitive functions, such as
learning and memory, whereas the anterior part is more
related to stress and emotion. Our 2-year clinical follow-
up data showed that about 20% of our MCI patients (6/29
subjects) converted to clinically diagnosed Alzheimer’s
disease (AD). More importantly, all 6 of those AD-
converted MCI patients (MCI-c) also had an initial
amyloid PET result that was positive. We propose that
the structural change of the hippocampus demonstrated
by MRI volumetric analysis, especially the small size of
the hippocampal tail, might be a predictor of conversion
to AD among MCI patients.
e relatively smaller volume of the le molecular layer
HP, le CA1, le subiculum, and le whole hippocampus
in the MCI group (especially MCI PET+ve) compared
to HOA subjects suggests that other hippocampal
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subeld regions might also be aected in the early stage
of neurodegenerative disease. Scharfman, et al. reported
that neurons in the entorhinal cortex, especially the
supercial layer, were believed to be particularly vulnerable
to adverse eect in the early stage of Alzheimer’s disease
(AD)
18
and have been found interconnecting to axons
within the hippocampal formation.
From neuroanatomy, the subiculum is the grey
structure that is located above the parahippocampal
gyrus, which is part of the entorhinal cortex, and it
superolaterally connects to the CA1 region. We postulate
that the change in the entorhinal cortex in early AD
might also propagate eect to the subiculum and CA1,
as well as to the molecular layer HP adhering to both
subiculum and CA1.
In older adults, depression oen develops concomitantly
with cognitive impairment. is is likely a psychological
reaction to cognitive decline, so it may manifest as an
early symptom in early-stage dementia patients. However,
recent data suggests that depression, particularly late-life
depression, can also be a risk factor for AD.
3
Two prior studies
19,20
reported signicant volume
change in some subeld hippocampal regions in MDD
patients with some specic conditions, such as recurrent
episode of depressive symptom (decreased volume as the
number of prior episodes increased)
19
, or continuous
remission of drug-naive disease (increased volume in
MDD patients who were in remission at least 6 months).
Concerning our result, there was no statistically signicant
dierence in volumetric analysis compared between
rst-diagnosed and untreated MDD and either MCI or
HOA subjects. is may suggest that the hippocampus
has some plasticity, especially relative to volumetric
change in depressive condition, but not in early or late-
stage neurodegenerative disease, which known to be
associated with progressive permanent neuronal loss.
Strengths and limitations
e strengths of our study were: 1) Clinical evaluation
of MCI and HOA subjects was performed by a senior
geriatric neurologist (WM) who specializes in dementia;
2) Amyloid-PET result was available for all MCI patients;
and, 3) All MDD patients had rst-diagnosed and untreated
status without any confounding factors, such as repeated
episode of depressive symptom or treatment-related
issues.
Limitations of the present study include 1) A lack
of data specic to depressive illness duration, which may
aect hippocampal subeld volume change as found
from prior study
21
; 2) e fact that our MDD patients
had only mild to moderate depressive severity, which
may not clearly demonstrate alteration of hippocampal
volume; 3) Our study’s single-center retrospective design;
and, 4) our overall small size and small group sample
sizes may have limited the statistical power of our study
to identify all signicant dierences between and among
groups.
CONCLUSION
MR hippocampal subeld volumetry may have
value in routine clinical practice for screening individuals
with MCI, and may be a valuable adjunct to amyloid
PET study for very early-stage diagnosis of AD. Future
study in subeld hippocampal volumetry compared
between MCI patients with and without codepressive
symptoms will further clarify the inuence of depression
on hippocampal atrophy, especially in some specic
subeld regions. is information will improve our
understanding of the underlying pathophysiology, and
will help us to better guide disease management in the
future.
ACKNOWLEDGEMENTS
e authors gratefully acknowledge Dr. Orawan
Supapueng for assistance with statistical analysis and
Mrs. Angkana Jongsawaddipatana for assistance with
data collection.
Conict of interest declaration: All authors declare
no personal or professional conicts of interest, and no
nancial support from the companies that produce and/
or distribute the drugs, devices, or materials described
in this report.
Funding disclosure: DW, OC, SP, TT, WM, KT, and
CN were each supported by a Chalermprakiat Grant
from the Faculty of Medicine Siriraj Hospital, Mahidol
University, Bangkok, ailand.
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Kantanut Yutrirak, M.D.*, Woraphat Ratta-apha, M.D., Ph.D.*, Pittaya Dankulchai, M.D.**, Panate Pukrittayakamee, M.D.*
*Department of Psychiatry, **Division of Radiation Oncology, Department of Radiology, Faculty of Medicine Siriraj Hospital, Mahidol University,
Bangkok 10700, ailand.
Psychometric Properties of the PHQ-9, HADS,
and CES-D Questionnaires and the Prevalence of
Depression in Patients with Cancer Receiving
Radiotherapy
ABSTRACT
Objective: e primary aim was to compare the psychometric properties among the Patient Health Questionnaire
(PHQ-9) (both including and excluding somatic symptom items), the depression subscale of the Hospital Anxiety
and Depression Scale (HADS-D), and the Center for Epidemiologic Studies Depression Scale (CES-D) in detecting
depression in cancer patients receiving radiotherapy. e secondary aim was to investigate the prevalence of
depression in this group of patients.
Materials and Methods: Overall, 198 participants with cancer diagnosis from a radiotherapy clinic took part in
the study. ey completed PHQ-9, HADS-D, and CES-D questionnaires and were interviewed in line with the
Mini-International Neuropsychiatric Interview (M.I.N.I.) to conrm the diagnosis. e PHQ-9 was analyzed for
three scoring methods: sum-score, inclusive (including all items), and exclusive (excluding 4 somatic symptom
items) methods. e psychometric properties of each questionnaire were analyzed. e prevalence of depression
measured by the M.I.N.I. was evaluated.
Results: e sum-score method of the PHQ-9 had an equal sensitivity (100%) to the HADS-D and CES-D, and had
a slightly higher specicity (91.1%) than the HADS-D (87.4%) and CES-D (90.6%). When compared results within
the PHQ-9, the sum-score method had greater sensitivity than the inclusive (71.4%) and exclusive (42.9%) methods,
and had a slightly lower specicity than the inclusive (96.9%) and exclusive (97.4%) methods. e prevalence of
depression assessed by the M.I.N.I was 3.5%.
Conclusion: e sum-score method of the PHQ-9 seemed to be the best tool to use for depression screening in
cancer patients receiving radiotherapy due to its excellent sensitivity and specicity.
Keywords: PHQ-9; HADS; CES-D; Depression; Cancer; Radiotherapy (Siriraj Med J 2021; 73: 793-800)
Corresponding author: Panate Pukrittayakamee
E-mail: panate.puk@mahidol.ac.th
Received 8 April 2021 Revised 8 September 2021 Accepted 5 October 2021
ORCID ID: https://orcid.org/0000-0001-8776-2427
http://dx.doi.org/10.33192/Smj.2021.103
INTRODUCTION
Depression is a common problem in patients with
cancer. In one meta-analysis, the prevalence of depression
among cancer patients was found to be 14.9%.
1
It has
been reported that depression increases the mortality
rate
2
, decreases the quality of life
3
, and decreases the will
to live of patients with cancer.
4,5
So, eective screening
for depression is required among patients with cancer.
e depression screening tools commonly used in
patients with cancer include the Patient Health Questionnaire
(PHQ-9)
6
, Hospital Anxiety and Depression Scale (HADS)
7
,
and Center for Epidemiologic Studies Depression Scale
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794
(CES-D).
8
e PHQ-9 was developed based on the major
depressive episode criteria of the Diagnostic and Statistical
Manual of Mental Disorders (DSM IV-TR). It is a 9-item
self-report questionnaire, which can be scored using a
sum-score method or a DSM IV-TR-based algorithm.
It has shown satisfactory concurrent and discriminant
validity and also reliability when validated in patients with
cancer.
9
e HADS is also a self-report questionnaire,
consisting of 14 items divided into depression and anxiety
subscales. It was developed for screening depression
and anxiety in a general medical population. Validation
studies of the HADS in cancer patients showed it had a
stable factor structure, moderate to high discriminant
validity, and adequate internal consistency.
9
e CES-D
is a 20-item self-report questionnaire developed for
screening depression in a general medical population and
in patients with cancer.
10
Results from validation studies
in cancer patients demonstrated its good sensitivity,
specicity, and internal consistency.
9
Although all these
three self-report questionnaires are easy to complete by
patients with physical illnesses and have been validated
in cancer populations, there is no consensus on which
screening tool is preferred for screening depression in
cancer patients.
Screening as well as diagnosing depression in patients
with cancer is challenging as cancer can produce somatic
symptoms that are similar to somatic symptoms of
depression, such as a decreased appetite, weight loss,
sleep problems, and fatigue.
11
Suggestions have been
made to exclude these somatic symptoms when evaluating
depression in cancer patients. Indeed, a previous study of
the PHQ-9 tried to explore the eect of excluding somatic
symptom items on detecting depression. In that study,
4 somatic symptom items, namely decreased appetite,
sleep problems, fatigue, and psychomotor retardation,
were excluded from the questionnaire and depression
was diagnosed when 3 of the remaining 5 items were
present. e results demonstrated that excluding those
items when assessing somatic symptoms of depression
had very little eect on detecting depression.
12
However,
the limitation of that study was that the gold standard
used for validity testing was not a structured diagnostic
interview.
Since there is insucient evidence for making a
recommendation about which depression screening tool
should be used in patients with cancer, this study
aimed to
compare the psychometric properties of the PHQ-9, HADS,
and CES-D in detecting depression in cancer patients in a
radiotherapy clinic. is study focused on cancer patients
in a radiotherapy clinic because these patients represent
variations in cancer type and stage. Furthermore, evidence
regarding the eect of excluding somatic symptom items
from the PHQ-9 remains inconclusive due to the lack
of using a diagnostic interview as the gold standard in
validity testing. Hence, this study also aimed to compare
the psychometric properties of the PHQ-9 between
including and excluding somatic symptom items by using
a structured diagnostic interview as a gold standard.
Finally, this study aimed to investigate the prevalence
of depression in cancer patients receiving radiotherapy.
MATERIALS AND METHODS
Participants
Cancer patients with any type and any stage of cancer
receiving treatment in a radiotherapy clinic of a tertiary
care hospital were recruited from January to April 2020.
e calculated sample size was 195. is sample size was
calculated by using the Wayne formula and based on a
prevalence of depression of 14.9% in cancer patients.
1
Measures
e ai version of the PHQ-9, the depression
subscale of the HADS (HADS-D), and CES-D were
used to assess depression. e ai version of the Mini-
International Neuropsychiatric Interview (M.I.N.I.) was
used as the gold standard to conrm a diagnosis of major
depressive episodes.
1) PHQ-9
e PHQ-9 is a 9-item self-report questionnaire
which can be scored using two methods: a sum-
score method with a cut-o score and an algorithm
scoring method. In the sum-score method, each
item can be rated from 0 to 3, with the total score
ranging from 0 to 27. Patients are classied
as having depression when the total score of the
ai version of the PHQ-9 is 9 or more.
13
However,
the cut-o score used in this study was re-calculated
to nd the most appropriate cut-o score for
cancer patients in this study. In the algorithm
scoring method, each item of the PHQ-9 is
counted as meeting a criterion if it is rated as 2
or 3. Patients are classied as having depression
when 5 of 9 items meet the criteria, one of which
must be item 1 (loss of pleasure in doing things)
or 2 (depressed mood).
6,14
e algorithm scoring
method in this study was split into two sub-
methods for analysis: an inclusive and exclusive
method. In the inclusive method, all 9 items
of the PHQ-9 were included in the assessment. In
the exclusive method, 4 items assessing somatic
symptoms of depression were excluded in order
to prevent false-positive results. ese items
Yutrirak et al.
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were item 3 (sleep problems), 4 (fatigue), 5
(appetite changed), and 8 (psychomotor retardation).
Patients were classied as having depression
when 3 of the remaining 5 items met the criteria,
one of which must be item 1 or 2.
11,12,15
2) HADS
e HADS is a 14-item self-report questionnaire,
with 7 items for the anxiety subscale and 7
items for the depression subscale.
7
However,
only the depression subscale of HADS (HADS-D)
was used in this study. For each subscale, each
item can be rated from 0 to 3, with the total
score ranging from 0 to 21. A sum score of 11
or more in the ai version of the HADS represents
depression.
16
However, the cut-o score used in
this study was re-calculated, as was also done
with the PHQ-9.
3) CES-D
e CES-D is a 20-item self-report questionnaire.
Each item can be rated from 0 to 3, with the
total score ranging from 0 to 60.
8
A sum score of
19 or more in the ai version of the CES-D
represents depression.
17
However, the cut-o
score used in this study was re-calculated, as
was also done with the PHQ-9 and the HADS.
4) M.I.N.I.
e ai version of the M.I.N.I. was translated from
the M.I.N.I. 5.0.0/DSM-IV. It is a structured
diagnostic interview comprising 16 modules for
assessing common psychiatric disorders. In this
study, the major depressive episode module was
used as the diagnostic tool. is module had a
sensitivity of 98% and specicity of 94%.
18
Data collection
Ethics approval was obtained from the Siriraj
Institutional Review Board. All the participants completed
the demographic data, PHQ-9, HADS-D, and CES-D
questionnaires. ey were interviewed using the M.I.N.I.
either by a psychiatric resident or a psychologist who had
been trained and certied in M.I.N.I.. Both interviewers
were blinded from the result of the self-rated questionnaires.
If depression was conrmed by M.I.N.I., the interviewers
would notify the attending physician to consider referring
the participant to consult psychiatrist for evaluation
and proper treatment. Data about cancer type, stage,
treatment, pain score, and opioid use were obtained
from the patients’ medical records.
Statistical analysis
e analysis was done with SPSS version 24. By
using the M.I.N.I. as the gold standard, the cut-o scores
of the PHQ-9, HADS-D, and CES-D were determined
by plotting their receiver operating characteristic (ROC)
curves. e psychometric properties of each questionnaire
were analyzed and demonstrated in terms of sensitivity,
specicity, positive predictive value (PPV), negative
predictive value (NPV), and likelihood ratio. Convergent
validity between the PHQ-9 and HADS-D, between PHQ-
9 and CED-D, and between HADS-D and CES-D were
analyzed by Spearman’s rho correlation. e internal
consistency of each questionnaire was analyzed by
Cronbach’s alpha. e prevalence of depression measured
by each questionnaire and the M.I.N.I. were evaluated.
RESULTS
In total, 198 participants were enrolled on the study,
and their demographic data are shown in Table 1. ere
was nearly an equal number of female (53.3%) and male
(46.5%) participants. Half the participants were more than
60 years old. e majority of participants (86.9%) were
recruited from an outpatient clinic. e most common
cancer types were breast (27.3%), prostate (13.6%), oro-
pharyngo-laryngeal (12.1%), and gastrointestinal cancer
(10.1%). e most common stage was the non-metastatic
stage (83.8%). Most of the participants did not have pain
(62.6%) and did not receive opioids (91.9%).
e most appropriate cut-o scores were 11 for
the PHQ-9, 7 for the HADS-D, and 20 for the CES-D.
e ROC curves for these cut-o values are displayed
in Fig 1. e area under the curve values for each were
0.97 (SD = 0.01; 95% CI 0.94 to 0.99) for the PHQ-9,
0.95 (SD = 0.02; 95% CI 0.91 to 0.98) for the HADS-D,
and 0.98 (SD = 0.01; 95% CI 0.95 to 1.00) for the CES-D.
All of these values show high accuracy.
19
The psychometric properties of the PHQ-9,
HADS-D, and CES-D are listed in Table 2. e sum-
score method used for the PHQ-9, the HADS-D, and
the CES-D demonstrated good sensitivity (100%) and
good specicity (91.1%, 87.4%, and 90.6%, respectively).
Although the inclusive and exclusive methods of the
PHQ-9 demonstrated slightly higher specicity than the
sum-score method (96.9% for the inclusive method and
97.4% for the exclusive method), their sensitivities were
much lower (71.4% for the inclusive method and 42.9%
for the exclusive method). Comparing the inclusive and
exclusive method, the inclusive method demonstrated
greater sensitivity with similar specicity. Convergent
validity testing showed good correlations between the
PHQ-9 and HADS-D (r = 0.67, p < 0.01), between the
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TABLE 1. Demographic data.
Characteristics (n = 198) n (%)
Gender
Female 106 (53.5)
Male 92 (46.5)
Age (mean 59.4, SD 13.3)
Education
High school or less 119 (60.1)
Undergraduate degree or more 79 (39.9)
Setting
Outpatient 172 (86.9)
Inpatient 26 (13.1)
Cancer type
Breast 54 (27.3)
Prostate 27 (13.6)
Oro-pharyngo-laryngeal 24 (12.1)
Gastrointestinal 20 (10.1)
Gynecologic 19 (9.6)
Lung 16 (8.1)
Brain 14 (7.1)
Others* 24 (12.0)
Disease stage
Non-metastasis 166 (83.8)
Metastasis 32 (16.2)
Treatment
Radiotherapy 16 (8.1)
Radiotherapy + Surgery 59 (29.8)
Radiotherapy + Chemotherapy 42 (21.2)
Radiotherapy + Surgery + Chemotherapy 81 (40.9)
Pain (mean 1.76, SD 2.8)
No pain 124 (62.6)
Mild (Pain score 1-3) 30 (15.2)
Moderate (Pain score 4-6) 23 (11.6)
Severe (Pain score 7-10) 21 (10.6)
Opioids use
No 182 (91.9)
Yes 16 (8.1)
*yroid 7, Hematologic 7, Liver 2, Urinary tract 3, Anus 1, Cholangiocarcinoma 1, Nasal cavity 1, Epithelioid tumor 1, Multiple
primary 1.
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TABLE 2. Psychometric properties.
Sensitivity Specicity PPV NPV + likelihood - likelihood Internal
consistency
(Cronbach’s alpha)
PHQ-9
Sum-score 100 91.1 29.2 100 11.2 0 0.804
(cut-off 11)
Algorithm scoring
Inclusive 71.4 96.9 45.5 98.9 22.7 0.3 -
Exclusive 42.9 97.4 37.5 97.9 16.4 0.6 -
HADS-D (cut-off 7) 100 87.4 22.6 100 8 0 0.772
CES-D (cut-off 20) 100 90.6 28 100 10.6 0 0.815
PHQ-9 and CES-D (r = 0.68, p < 0.01), and between
HADS-D and CES-D (r = 0.74, p < 0.01). e internal
consistencies of the PHQ-9 and CES-D were good
(Cronbach’s alpha = 0.80 and 0.82, respectively), while
the internal consistency of the HADS-D was acceptable
(Cronbach’s alpha = 0.77).
20
e prevalence of depression measured by each
questionnaire and the M.I.N.I. are presented in Table 3.
e prevalence measured by the inclusive method (5.6%)
and exclusive method (4.0%) of the PHQ-9 were close to
the prevalence measured by the M.I.N.I. (3.5%), which
represents the gold standard. However, the prevalence
measured by the sum-score methods of the PHQ-9
(12.1%), HADS-D (15.7%), and CES-D (12.6%) were
much higher than the prevalence measured by the M.I.N.I..
DISCUSSION
e study aimed to test the psychometric properties
of the three self-rating questionnaires PHQ-9, HADS-D,
and CES-D for screening depression in cancer patients
receiving radiotherapy. e results showed that the
psychometric properties, both validity and reliability, of
all questionnaires were nearly equivalent. Comparing
the sum-score methods of the PHQ-9, HASD-D, and
CES-D, the sum-score method of PHQ-9 is recommended
for depression screening in cancer patients receiving
radiotherapy because it showed high sensitivity and
the highest specicity and all of its items are similar to
the major depressive disorder criteria of the DSM-5.
14
In addition, because the PHQ-9 consists of 9 items that
can be completed within a few minutes, it is convenient
Fig 1. ROC curve
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for patients with physical illness. Although the CES-D
showed a similar specicity to the sum-score method
of the PHQ-9, the major limitation of the CES-D is it is
time consuming to complete because it consists of 20
items.
Regarding the PHQ-9, its sum-score method
demonstrated a much higher sensitivity but with a similar
specicity when compared to the algorithm scoring
methods. is nding suggested that the sum-score
method is better than the algorithm scoring methods for
screening depression in patients with cancer. Comparing
the methods within the algorithm scoring methods, the
exclusive method had a much lower sensitivity than the
inclusive method. is result reected that the items
concerning the somatic symptoms of depression should
not be excluded from the PHQ-9 when screening for
depression in cancer patients. is nding is supported
by evidence from another study which demonstrated
that the somatic symptoms of depression were more
likely to be present in depressed than in non-depressed
cancer patients.
21
The cut-off scores of the screening tools were
dierent from the recommendation from the previous
study. According to our ndings, the cut-o scores of
the PHQ-9, HADS-D, and CES-D were 11, 7 and 20,
respectively, while the cut-o scores of the ai version
recommended in previous studies were 9, 11, and 19,
respectively.
13,16,17
One of the reasons for this disparity may
be the dierence in somatic symptoms in the population
between the studies. Previous studies of the ai version
of the PHQ-9 was conducted in family medicine clinic
and the CES-D was conducted in general populations
which tend to have less somatic symptoms. While the
ai HADS-D study was conducted in in-patients with
cancer which tend to have more somatic symptoms.
To the best of our knowledge, the present study is the
rst one to investigate the cut-o score in this specic
population.
The prevalence of depression assessed by the
structured interview (M.I.N.I.) was nearly equal to the
prevalence assessed by the algorithm scoring methods of the
PHQ-9. is may be explained by the high specicity of
the algorithm scoring methods. Comparing the methods
within the algorithm scoring methods, the inclusive method
is preferred for assessing the prevalence or diagnostic
purpose due to its high specicity and higher sensitivity
than the exclusive method. However, inspection of the
raw data showed that some patients had a diagnostic
mismatch between the M.I.N.I. assessment and the
PHQ-9 algorithm scoring methods. us, evaluation of the
psychometric properties through a diagnostic interview
conducted by a psychiatrist as the gold standard should
be conducted in a further study in order to conrm
whether the PHQ-9 algorithm scoring methods are
appropriate for assessing the prevalence of depression
in patients with cancer.
In contrast, the prevalence as assessed by the PHQ-9
sum-score method, HADS-D, and CES-D was relatively
high when compared with the M.I.N.I. due to the false-
positive cases. Since these three questionnaires are scored
using a sum-score method, the severity ratings of the
somatic symptoms that overlap with cancer symptoms
need to be taken into account. As a consequence, cancer
symptoms may have an inuence on increasing the somatic
symptoms scores, leading to false-positive results.
12
We suggest that these three questionnaires may not be
appropriate for assessing the prevalence of depression
in patients with cancer.
Yutrirak et al.
TABLE 3. Prevalence.
%
M.I.N.I. 3.5
PHQ-9
Sum-score method 12.1
Algorithm scoring methods
Inclusive method 5.6
Exclusive method 4.0
HADS-D 15.7
CES-D 12.6
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e prevalence of depression assessed by the M.I.N.I.
in our study was lower than the average prevalence in
a meta-analysis in the literature (3.5% vs. 14.9%).
1
is
discrepancy may be due to the dierence in cancer stage
of participants among the studies. Our study and the
studies with a similar prevalence were conducted in
patients with cancer of any type and stage, mostly the
non-metastatic stage.
22-25
In contrast, the studies with a
prevalence of around 14.9% were conducted in cancer
patients within 12 months of diagnosis
26
, post-treatment
cancer patients
27
, and patients with recurrent or metastatic
cancer.
28
is may imply that patients are more likely to
develop depression when initially facing cancer diagnosis
and when facing advanced cancer. erefore, depression
screening should be performed within the rst year of
cancer diagnosis and upon progressing to an advanced
stage. Moreover, a systematic review reported that the
rate of depression is higher in adolescents and young
adults with cancer because of the disruptions in their
school life, career path, or early marital life.
29
It can be
implied that if we include more young age patients in
the study, we will gain more prevalence of depression.
Further study should be designed to include patients in
all age groups to improve the precision of the results.
Study limitations
Several limitations in the present study should be
considered. We use the M.I.N.I. as the gold standard
for depression diagnosis instead of using the standard
interview by psychiatrists because it consumed much less
time when must deal with the high volume of participants.
erefore, it could have some false positive and false
negative cases. e sensitivity and specicity in this
study may be dierent from a previous study conducted
in a population with a higher prevalence of depression.
30
Hence, further studies should be investigated in cancer
patients with a higher prevalence of depression, such as
newly diagnosed cancer patients, post-treatment cancer
patients, and patients with more advanced-stage cancer.
Furthermore, patients in a surgery and chemotherapy
clinic should be recruited to apply the results more
broadly.
CONCLUSION
e sum-score method of the PHQ-9 seemed to
be the best tool to use for depression screening among
cancer patients receiving radiotherapy. e inclusive
method of the PHQ-9 may be useful for prevalence
studies or could serve a diagnostic purpose due to its
high specicity and acceptable sensitivity. e prevalence
of depression assessed by the M.I.N.I. was 3.5%, nearly
equal to the prevalence assessed by the inclusive method
of the PHQ-9, which was 5.6%.
ACKNOWLEDGEMENTS
e authors would like to thank the Department of
Radiology for allowing us to collect the data. We would
like to thank Lakkhana ongchot, psychologist, for
helping collect the data and we also would like to thank
to Naratip Sanguanpanich, statistician, for statistical
analysis advice.
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Variation of a test’s sensitivity and specicity with disease
prevalence. CMAJ 2013;185(11):E537-E544.
Yutrirak et al.
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Possatorn Wongwutthiwet, M.D.* Tatree Bosittipichet, M.D.**, anakamon Leesri, Ph.D.***
*Bangkruai Hospital, Nontaburi 11130, ailand. **Department of Social Medicine, Phra Nakhon Si Ayutthaya Hospital, Phra Nakhon Si Ayutthaya
13000, ailand. ***Department of Community Health Nursing, Institute of Nursing, Suranaree University of Technology, Nakorn Ratchasima 30000,
ailand.
The Efcacy of Follow-up Phone Calls for
Capillary Blood Glucose Lowering in Diabetic
Patients in Primary Care Unit
ABSTRACT
Objective: To study the eect of telephone call intervention on glycemic control in diabetic patients for 2 months
Materials and Methods: e quasi-experimental research included 130 Patients from January 2020 to March
2020 in primary care. e 115 patients were divided into 2 groups through a simple randomization process, 61 in
experimental group and 54 in control group aer exclusion. 115 Patients will be tested for Capillary blood glucose
(CBG) level at a period of 0-month, 1-month and 2-months. CBG level were presented in mean ± SD, mean dierence
± SD and analyzed by Independent t-test and Paired t-test.
Results: e phone call intervention can lower CBG level compared to the control group. Mean dierence of CBG
between 0 month and 2 months follow-up in phone calls group vs control group (-6.80 ± 4.86 vs -2.96 ± 4.82 mg/dL)
and mean dierence CBG level between 1 month and 2 months follow-up in phone calls group vs control group
(-5.77 ± 4.09 vs -4.22 ± 5.10 mg/dL) but had no signicant dierence (p >0.05)
Conclusion: e follow-up phone calls can lower CBG level in the experimental group more than the control group,
but there is no signicant dierence.
Keywords: Diabetes mellitus type 2; phone call; glycemic control (Siriraj Med J 2021; 73: 801-807)
Corresponding author: anakamon Leesri
E-mail: thanakamon@sut.ac.th
Received 18 May 2021 Revised 2 September 2021 Accepted 21 September 2021
ORCID ID: https://orcid.org/0000-0003-2841-5729
http://dx.doi.org/10.33192/Smj.2021.104
INTRODUCTION
It is expected that ailand will completely enter an
aging society by 2022, and elderly people will account for
20 percent of all ai population.
1
Non-communicable
diseases (NCDs), such as diabetes and hypertension, would
be an inevitable case for an aging society. Diabetes
2
is a
condition that impairs the body cell’s ability to convert
sugar to energy which will be stored at liver, muscle
and fat. ese cause high blood sugar levels. Diabetes
is currently a crucial non-communicable disease, and
e World Health Organization (WHO) attaches great
importance to the promotion, prevention and control of
disease to avoid complications. In Western Pacic, it was
found that there were 162 million patients with diabetes
in 2019
3
, and ailand ranked fourth regionally, coming
aer China, Indonesia and Japan as there were 4.4 million
patients with diabetes found in ailand. According to
Health Data Center
4
under the Department of Public
Health, it was found that patients having well-controlled
diabetes made up for only 28.32 percent (while the target
proportion was 40 percent). In Nonthaburi Province,
there were 45,457 patients with diabetes whereas only
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12,252 of them had well-controlled diabetes, accounting
for 26.95 percent. In Bang Kruai District, there were 4,580
patients with diabetes whereas only 4,232 of them had
well-controlled diabetes, accounting for 26.03 percent.
In Bang Kruai Health Promoting Hospital, there were
401 patients with diabetes whereas only 100 of them had
well-controlled diabetes, accounting for 24.94 percent.
Without a good control of a blood sugar level, patients
can suer from the complications and premature death.
Comparing to the previous years, it is found that incidence
of diabetes increases in a wider age range. Furthermore,
according to the data from National Economic and Social
Development Board (NESDB) in 2008
5
, it was found
that in ailand, for Out Patients Department (OPD),
the average medical fee of diabetes was 1,173 Baht per
patient whereas for In Department Patients (IPD), the
average medical fee was 10,217 Baht per patient. e
total average medical fee was 3,984 million Baht per
year. Hence, if there are 3 million patients with diabetes
receiving medical service from healthcare centers, it will
cost 47,596 million Baht per year for medical fees.
Poor-controlled diabetes is caused by many reasons
such as patient’s lack of knowledge regarding of self-care
or lack of awareness in danger and severity of diabetes.
By these reasons, it results in discontinuity of medicine
taking, missing doctor’s appointments and inability to
adjust eating or exercising habits, and this can lead to
many complications such as chronic kidney disease
(CKD), Diabetic Retinopathy (DR), Diabetic Ulcer and
Cardiovascular Disease (CVD). ese complications
could worsen patient’s quality of life as well as nancial
burdens.
erefore, the researcher recognizes the signicance
of patient’s awareness, and many relevant studies also
indicate that many patients with diabetes lack a good
understanding of their conditions. The researcher,
hence, decides to study about the eect of follow-up
phone calls for glycemic control of diabetic patient.
Currently, there is an involvement of technology in a
medical treatment to enhance its eciency, and it is
found that the majority of people carry mobile phones
with them most of the time. is study is conducted to
provide guidance in giving care to patients with diabetes
and boosting patient’s awareness of the disease, and
this could encourage patients to adjust their habits and
control their sugar blood level better. Furthermore, it
could reduce patient’s risks of having complications
and enhance their living standards. It could also reduce
expenses given by patients for receiving medical service
and commuting to hospital, given by family to provide care
for patients, given by hospitals to treat several dierent
complications, and given by the nation to provide health
welfare to patients. Accordingly, the aims of this study
to investigate the ecacy of follow-up phone calls for
Capillary blood glucose lowering in diabetic patients in
primary care setting
MATERIALS AND METHODS
Study design & population
This study is quasi-experimental research with
two groups of samples, and there is an application of
Pretest-Posttest Design with nonequivalent groups. e
samples include 130 patients with diabetes who were 30
years old and older and continually received medical
service at Bang Kruai Health Promoting Hospital, Bang
Kruai District, Nonthaburi Province between January
2020 and March 2020. e Inclusion Criteria include
abilities in understanding ai language and using phones
as well as their voluntariness of consent to research.
e Exclusion Criteria are participant’s discontinuity
in receiving medical treatment according to doctor’s
appointment, their withdraw from the research and
ineligibility. Some participants might be found ineligible
later because they fail to meet inclusion criteria, and
this could result from participant’s mistakes in giving
information or researcher’s errors.
Study size
Study size was estimate from the study of phone call
intervention on glycemic control in diabetes patients.
6
e hypothesis is that patient’s HbA1c level decrease by
<7%. For the control group, it is 35.7%, while it is 60.9%
in the phone call intervention group (p value <0.001), this
is a two-sided experiment with type 1 error, signicance
at 5% and power at 80%. e sample size is calculated
to be 122 participants, and 5 percent is calculated added
in case of data loss. erefore, the population was 130
participants divided by simple randomization into 65
participants in each intervention group and a control
group.
Measurement and tools
Measurement in this study consisted of a patient’s
general data record, including gender, age, education level,
monthly income, chronic disease, height, weight, and
body mass index (BMI), as well as a record of patient’s
CBG level and blood pressure noted at starting point
(which will be referred as the 0 month) then one and
two-month aer that (or the 1 month and 2 months).
is e participants were instructed to fast up to 8 hours
before a blood test. is measurement was performed
the same in both intervention and control groups.
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e intervention group received follow-up phone
calls every two weeks, accounting for 4 times across
the whole study period. mean CBG of both the phone
calls and control groups were assessed and compared
at 0-month, 1 month and 2 months.
e follow-up call consists of a procedure for asking
about symptoms and details about taking medication.
Primary outcome was mean dierence of CBG
between 0-month, 1 month and 2 months and secondary
outcomes were mean CBG at 0-month, 1 month and
2 months, mean systolic and diastolic blood pressure
at 0-month, 1 month and 2 months, mean dierence of
systolic and diastolic blood pressure between 0-month,
1 month and 2 months.
Study Flow
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Data analysis
e data are analyzed by statistical analysis soware,
approved and recorded in a form of le by the following
statistical analysis soware: Patient’s general data are
presented in number (percentage), mean ± standard
deviation, median (inter quartile range), and the data
are analyzed by Chi-square test, Independent t-test,
Mann-Whitney U test. Patient’s data of blood sugar
level and blood pressure level (systolic and diastolic) are
presented in mean ± standard deviation, and the data
are analyzed by Independent t-test and Paired t-test.
Ethical statements
is study has been approved by the committee of
research ethics regarding to human study of Nonthaburi
Public Health Oce. (e number of projects: 2/2563,
certied at January 14, 2020).
RESULTS
Patient characteristics
A total of 115 diabetic patients between January
2020 and March 2020. 61 patients in phone call group
and 54 patients in control group. Table 1 provides the
demographic details and information of each group.
Aer comparing between the two study groups, beyond
the education level, there were no dierences found
related to patient characteristics and baseline clinical data
including mean HbA1C, mean systolic blood pressure,
mean diastolic blood pressure and mean LDL
TABLE 1. e general information of the sample size (N = 115).
Phone calls Control
n=61 n=54
p-value
Sex
Male 21 (34.4) 16 (29.6) 0.583
Female 40 (65.6) 38 (70.4)
Age (years old) 63.16±8.65 66.0±7.48 0.064
Educational Level
None 2 (3.3) 3 (5.6) < 0.05*
Pre-Primary School 9 (14.8) 20 (37.0)
Primary School 17 (27.9) 6 (11.1)
Pre-Secondary School 16 (26.2) 5 (9.3)
Secondary School 11 (18.0) 13 (24.1)
Bachelor degree 6 (9.8) 7 (13.0)
Income (bath) 2,500 (700, 6,500) 2,350 (700, 7,000) 0.772
Hypertension 54 (88.5) 44 (81.5) 0.288
Height (cm.) 158.89±7.33 159.52±8.06 0.660
Weight (kg.) 69.28±17.29 68.70±15.19 0.849
BMI (kg./m.
2
)
< 18.5 1 (1.6) 1 (1.6) 0.916
18.5 – 22.9 10 (16.4) 7 (13.0)
23.0 – 24.9 14 (23.0) 15 (27.8)
≥ 25 36 (59.0) 31 (57.4)
HbA1c (mg%) 7.83±1.48 7.45±1.29 0.940
Systolic blood pressure (mmHg) 141.16±18.54 144.26±16.59 0.350
Diastolic blood pressure (mmHg) 74.10±11.16 73.85±10.97 0.905
LDL (mg/dL) 106.64±33.73 110.17±33.83 0.577
*Chi-square test, Independent t-test, Mann-Whitney U test
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Capillary blood glucose level outcome
Table 2 e mean dierence of CBG between 0
month and 2 months in 2 groups showed that the mean
dierence of CBG in the phone calls group was greater
than in the control group with no signicance (-5.77±4.09
vs -4.22±5.10 P=0.812). Likewise, the mean dierence
of CBG between 0 month and 1 months in 2 groups
showed the same trend with no signicance (-6.80±4.86
vs -2.96.22±4.82 P=0.577) but the mean dierence of CBG
between 1 month and 2 months in 2 groups showed that
the mean dierence of CBG in the phone calls group was
less than in the control group (1.03±4.09 vs -1.26±5.10
P = 0.724).
Table 3 the mean CBG level at 0-month, 1-month
and 2-months in the phone calls group was less than in the
control group with no signicance (CBG M
0
144.49±33.54
vs 149.13±35.31 P= 0.472, CBG M
1
137.69±37.35 vs
146.17±37.59 P= 0.228, CBG M
2
138.72±32.66 vs
144.91±36.11, P= 0.337).
Systolic blood pressure (SBP) outcome
Table 2 e mean dierence of SBP between 0
month and 2 months in 2 groups showed that the mean
dierence of SBP in the phone calls group was lesser than
in the control group with no signicance (-9.33±1.64
vs -12.43±2.40 P=0.280). Likewise, the mean dierence
of SBP between 0 month and 1 months in 2 groups
showed the same trend with no signicance (-7.36±1.58
vs -11.44±2.55 P=0.166) but the mean dierence of CBG
between 1 month and 2 months in 2 groups showed that
the mean dierence of CBG in the phone calls group
was greater than in the control group (-1.97±1.48 vs
-0.98±2.04 P = 0.692).
Table 3 the mean SBP level at 0 month and 2 months
in the phone calls group was less than in the control group
with no signicance (SBP M
0
141.07±17.14 vs 144.50±16.49
P= 0.227, SBP M
2
131.74±14.23 vs 132.07±14.59, P=
0.901) and the mean SBP level at 1 month the phone calls
group was slightly greater than in the control group with
no signicance (SBP M
1
133.70±16.14 vs 133.06±13.55
P= 0.817)
Diastolic blood pressure (DBP) outcomes
Table 2 The mean difference of DBP between
0 month and 2 months in 2 groups showed that the mean
dierence of DBP in the phone calls group was greater
than in the control group with no signicance (-6.82±1.18
vs -5.91±1.43 P=0.622). Likewise, the mean dierence
of DBP between 0 month and 1 months in 2 groups
showed the same trend with no signicance (-3.57±1.16
vs -1.24±1.71 P=0.218) but the mean dierence of CBG
between 1 month and 2 months in 2 groups showed
that the mean dierence of CBG in the phone calls
group was lesser than in the control group (-3.07±1.03
vs -4.67±1.56 P = 0.383).
Table 3 the mean DBP level at 0 month in the
phone calls group was slightly greater than in the control
group with no signicance (DBP M
0
74.23±10.08 vs
TABLE 2. e comparation between Means of CBG level with blood pressure level (diastolic and systolic).
Phone calls Control
n=61 n=54
p-value
Mean Difference of CBG Level (mg/dL)
Month 0 and 1 -6.80±4.86 -2.96±4.82 0.577
Month 1 and 2 1.03±4.64 -1.26±4.45 0.724
Month 0 and 2 -5.77±4.09 -4.22±5.10 0.812
Systolic blood pressure (mmHg)
Month 0 and 1 -7.36±1.58 -11.44±2.55 0.166
Month 1 and 2 -1.97±1.48 -0.98±2.04 0.692
Month 0 and 2 -9.33±1.64 -12.43±2.40 0.280
Diastolic blood pressure (mmHg)
Month 0 and 1 -3.75±1.16 -1.24±1.71 0.218
Month 1 and 2 -3.07±1.03 -4.67±1.56 0.383
Month 0 and 2 -6.82±1.18 -5.91±1.43 0.622
* Analyzed by Independent t-test, Paired t-test
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TABLE 3. e comparison of CBG level with blood pressure level separated with systolic and diastolic blood pressure.
Phone calls Control
n=61 n=54
p-value
CBG Level (mg/dL)
0 month (CBG M
0
) 144.49±33.54 149.13±35.31 0.472
1 month (CBG M
1
) 137.69±37.35 146.17±37.59 0.228
2 months (CBG M
2
) 138.72±32.66 144.91±36.11 0.337
Systolic blood pressure (mmHg)
0 month (SBP M
0
) 141.07±17.14 144.50±16.49 0.227
1 month (SBP M
1
) 133.70±16.14 133.06±13.55 0.817
2 months (SBP M
2
) 131.74±14.23 132.07±14.59 0.901
Diastolic blood pressure (mmHg)
0 month (DBP M
0
) 74.23±10.08 74.19±11.13 0.982
1 month (DBP M
1
) 70.48±9.51 72.94±14.21 0.271
2 months (DBP M
2
) 67.41±9.13 68.28±10.70 0.640
74.19±11.13 P= 0.982) and the mean DBP level at 1
month and 2 months the phone calls group was lesser
than in the control group with no signicance (DBP M
1
70.48±9.51 vs 72.94±14.21 P= 0.271, DBP M
2
67.41±9.13
vs 68.28±10.70, P= 0.640)
DISCUSSION
Before the study, there was no dierence in the average
of blood sugar level (mg/DL) of phone calls and control
groups (p>0.05). However, when comparing the average
of blood sugar levels (mg/DL) recorded in the 0 month
and 1 month, it was found that the phone calls group’s
average blood sugar level decreased by a more substantial
amount than that of the control group (-6.80±4.86 vs
-2.96±4.82, p value = 0.577). Comparing the average of
blood sugar levels (mg/DL) in the 0
th
and 2
nd
months, it
was similarly found that the intervention group’s average
blood sugar level decreased by a more substantial amount
than that of the control group (-5.77±4.09 vs -4.22±5.10
p value = 0.812). erefore, it could be concluded that
there is clinical signicance of the intervention group
who received follow-up phone calls. is corresponds
with Naeti Suksomboon’s study
6
which conducted a
systematic review and meta-analysis of follow-up phone
calls as a way to control blood sugar levels, and it was
found that follow-up phone calls might not be more
eective in helping controlling blood sugar levels when
comparing to those who were not given follow-up phone
calls. However, it is still benecial for people living in
a country with small to medium incomes.
e reason why there was no statistical signicance
between two groups of the participants in the mentioned
study might be because of too small sample size, insucient
time of research, too short time of phone calls, insucient
information instructed to patients via phone calls, infrequent
phone calls or a lack of other media to follow up patients.
ese reasons might result in ineciency in controlling of
blood sugar levels. According to the study of Rattanaporn
Jeerawattana
7
, with motivation-promoting activities
and diabetes-instructing trainings before giving the
participants phone calls, it was found that the intervention
group’s average blood level decreased more signicantly
than that of the control group (11.43±1.92 vs 7.29±1.32
P<0.001). Likewise, according to Bogner’s study
8
, the
overall phone calls given to participants were two times,
and they lasted for 15 minutes, and this also included
three direct talks which lasted for 30 minutes, given
during three-month period. e ndings indicated that
the intervention group can control their blood sugar levels
more eectively than the control group do (Achieved
HbA1c <7%: 67 participants (60.9%) vs 25 participants
(35.7%), p value <.001).
Currently, technology plays a crucial role in
people’s life and most people are able to use phones for
communicative purposes. e researcher, therefore,
aims that this study could be guidance of how to provide
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more eective treatments to patients. Nevertheless, there
are some limitations including insucient samples and
limited time for phone calls. Also, three-month period for
follow-up might be insucient, so the ndings indicate
no statistical signicance. is study covers patients
from only one medical center, so it might not be able
to represent overall populations. However, since the
ndings illustrate that the intervention group has a more
ecient control of blood sugar levels than the control
group, the researcher would suggest that there should
be an increase of study populations, areas and time
period. Also, there should be some adjustments of the
directions for follow-up phone calls, such as an increase
in contents or time period. is would help follow-up
phone calls to work more eectively.
CONCLUSION
is quasi-experimental study’s results show that
follow-up phone calls can assist patients with diabetes
to control their blood sugar levels more eectively than
the control group, but there is no statistical signicance.
Further studies may be needed for more explicit data.
REFERENCES
1. Foundation of ai Gerontology Research and Development
Institute (TGRI) Institute for Population and Social Research,
Mahidol University. Situation of ai Elderly 2017 (1
st
Edition).
Nakornpathom: Printory Company, 2018.
2. Diabetic Association of ailand under the Patronage of Her
Royal Highest Princess Maha Chakkri Siridhron. Clinical
Practice Guideline for Diabetes 2017. Bangkok: Romyen Media
Company; 2016.
3. International Diabetes Federation. IDF DIABETES ATLAS
Ninth edition 2019[Internet]. 2019 [cited 10 January 2020].
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2019/IDF_Atlas_9th_Edition_2019.pdf
4. Hdcservice.moph.go.th [Internet]. ailand: e percentage of
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5. e Oce of the National Economic and Social Development
Boar, MOPH, ailand. ailand Healthy Lifestyle Strategic
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from: http://wops.moph.go.th/ops/oic/data/20110316100703_1_.
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6. Suksomboon N, Poolsup N, Nge YL. Impact of Phone Call
Intervention on Glycemic Control in Diabetes Patients: A
Systematic Review and Meta-Analysis of Randomized, Controlled
Trials. PLoS ONE 2014;9(2):e89207.
7. Jerawatana R, Reutrakul S, Siripitayakunkit A. e Eect of
Advanced Practice Nurse-Led Intervention Program on
Outcomes in Diabetes Patients with Complex Problems. Rama
Nurs J 2018;24(1):51-68.
8. Bogner HR, Morales KH, de Vries HF, Cappola AR. Integrated
management of type2 diabetes mellitus and depression treatment
to improve medication adherence: a randomized controlled
trial. Ann Fam Med 2012;10:15–22.
9. Dale J, Caramlau I, Sturt J, Friede T, Walker R. Telephone
peer delivered intervention for diabetes motivation and support:
the telecare exploratory RCT. Patient Educ Couns 2009;75:91–98.
10. Walker EA, Shmukler C, Ullman R, Blanco E, Scollan-Koliopoulus
M, et al. Results of a successful telephonic intervention to
improve diabetes control in urban adults: a randomized trial.
Diabetes Care 2011;34:2–7.
11. eeraakarawipas N. Eectiveness of a Model of Care for
Diabetis Mellitus Patient Who Could not Control Blood Sugar.
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12. American Diabetes Association. 2. Classication and diagnosis
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13. omas R. Freeman. McWhinney’s Textbook of Family Medicine.
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808
Atipotsawee Tungsupreechameth, M.D., Klaita Srisingh, M.D.
Department of Pediatrics, Faculty of Medicine, Naresuan University, Phitsanulok 65000, ailand.
Factors Associated with Severe Lower Respiratory
Tract Infection from Respiratory Syncytial Virus
(RSV) in Thai Children
ABSTRACT
Objective: To determine the factors associated with severe ALRTI from RSV in children.
Materials and Methods: A retrospective study of children aged 1-60 months were conducted from 2014 to 2018.
Out of 269 patients diagnosed with RSV ALRTI, 100 children were enrolled in the study, 20 had severe RSV
ALRTI, while 80 had non-severe RSV ALRTI as identied by the ReSVinet scale. A multivariable logistic model
was conducted to select signicant variables.
Results: During the study period, 269 patients were diagnosed with RSV ALRTI. Mean age was 10.45 ± 3.53 months.
Clinical manifestations of severe RSV ALRTI group had signicant dierence in abnormal general condition
(P < 0.001), tachypnea (P < 0.001), SpO
2
< 85% (P < 0.001), poor air entry in lungs (P < 0.001), and retraction
(P < 0.001). e factors associated with severe RSV ALRTI group, were underlying congenital heart disease [aOR
32.45; 95% CI 3.38-311.87, P = 0.003] and duration of hospital stay >5 days [aOR 19.56; 95% CI 1.81-212.05,
P = 0.014].
Conclusion: Factors associated with severe RSV ALRTI in children were underlying congenital heart disease and
duration of hospital stay >5 days.
Keywords: Lower respiratory tract infections; respiratory syncytial virus; risk factor (Siriraj Med J 2021; 73: 808-814)
Corresponding author: Klaita Srisingh
E-mail: klaitas@nu.ac.th
Received 28 May 2021 Revised 6 September 2021 Accepted 21 September 2021
ORCID ID: https://orcid.org/0000-0001-6398-9555
http://dx.doi.org/10.33192/Smj.2021.105
INTRODUCTION
RSV Acute lower respiratory tract infection (ALRTI)
causes severe lower respiratory tract illness in the acute
phase, leading to hospitalization, higher hospitalization costs,
and high mortality rates, especially in young children.
1-4
Approximately 66,000-199,000 died with RSV and 99%
of these deaths occurred in developing countries.
5
A
study in ailand reported an annual incidence rate of
RSV ALRTI was 5.8-534 cases per 100,000 populations;
however, the incidence rate may vary depending on
the age demographic and the area where the study is
conducted.
6-10
ailand is one of the developing countries facing
RSV ALRTI problems and there were limited data
about severe RSV ALRTI. e data available on RSV
infection are insucient to cause change in the country’s
policy.
6-10
ailand has no specic medical treatment
and currently using supportive care as the mainstay of
management for children with RSV ALRTI, identical
to other developing countries.
11
Prophylactic passive
immunotherapy using palivizumab - a monoclonal
antibody against RSV infection is a costly treatment in
ailand. Presently, palivizumab is not routinely used
in ai children and in other countries. ere are many
socio-cultural, demographic and environmental risk
factors that predispose children to acquire respiratory
tract infections especially RSV ALRTI.
12
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Since there are no updated data for severe RSV
ALRTI in ailand or information about the factors
related to severe infection, this study aimed to identify
the factors associated with severe RSV ALRTI in children.
e benets of this study include documentation and data
conrmation in order to recommend policy changes in
ailand about vaccine prioritization plan or palivizumab
dispensation for prophylaxis of the RSV ALRTI.
MATERIALS AND METHODS
Study design and setting
A retrospective case-control study was performed
on children were admitted to the the Naresuan University
Hospital from 2014 - 2018. e Ethics Committee approved
study protocol of the Human Research Study of Naresuan
University (No.0897/2019).
Denition
Weight and height of preterm in this study refer
to the weight and height of patients’ corrected age.
Corrected age is used to adjust the age of preterm
participants calculated using the equation: [corrected
age = Chronological age + (40 - Gestational age)]
Hospital-acquired pneumonia (HAP) refers to a
pneumonia with clinical evidence of a new lung inltrate
caused by an infectious agent (new onset of fever, purulent
sputum, leukocytosis, and a decrease in oxygenation)
that occurs 48 hours or more aer hospital admission
and is not incubating at the time of admission. Cultures
obtained from endotracheal aspirates are used to identify
etiologic agents.
Eligibility criteria
is study enrolled children aged between 1-60
months with acute lower respiratory tract infection
(ALRTI) diagnosis from Respiratory Syncytial Virus
(RSV) at time of data collection period.
Selection of cases and controls
e data collectors identied children diagnosed
with RSV ALRTI then used the ReSVinet scale as the
clinical scoring method to assess the disease severity.
13
e subjects were divided into two groups: the severe RSV
ALRTI group (cases) and non-severe RSV ALRTI group
(controls). e evaluation process utilized 7 parameters
(feeding intolerance, medical intervention, respiratory
diculty, respiratory frequency, apnea, general condition,
fever) that were assigned dierent values (from 0 to 3)
for a total of 20 points. A score greater than or equal to
14 is classied as severe RSV ALRTI. e control group
was selected based on ReSVinet scale score below 14
points, and applied gender matching.
Laboratory method
Nasopharyngeal swab specimens are processed
using the Quick Navi
TM
-RSV2 immunoassay (immuno-
chromatographic assay technique) (Denka Seiken Co.,
Ltd., Tokyo, Japan) to identify RSV.
Sample size determination
Population was estimated from the study of Zhang XB
and et al.
14
using a case-control study with binary formula
outcomes. Low birthweight, congenital heart disease,
bronchopulmonary dysplasia, and airway abnormalities
were found to be risk factors for severe respiratory syncytial
virus-associated acute lower respiratory tract infections
(p < 0.001).
P(exposure|case) = e proportions of exposure to
severe respiratory syncytial virus-associated acute lower
respiratory tract infections was 0.315.
P(exposure|control) = e proportions of exposure
to non- severe respiratory syncytial virus-associated
acute lower respiratory tract infections was 0.685.
Twenty patients from case group (severe RSV ALRTI)
and 80 patients from control group (non-severe RSV ALRTI)
were results of the calculations using P(exposure|case) =
0.315, P(exposure|control) = 0.685, Ratio (case:control)
= 1:4, Alpha = 0.05, Beta = 0.20.
Sampling procedure
e subjects were patients diagnosed with RSV
ALRTI. ose who scored greater than or equal to 14
in the ReSVinet scale were assigned to the severe RSV
ALRTI group (case group), while subjects with scores
below 14 points were in the non-severe RSV ALRTI
(control group). Matlab-program
15
was used to generate
a 1:4 (case: control) ratio, matching the sex and age of
the participants at random to complete the data.
Collected data
Naresuan University Hospital is a tertiary-care
University hospital in the lower northern part of ailand,
all admissions were recorded in the hospital’s database.
Coders enter the of clinical diagnoses information using
the International Classication of Disease 10
th
revision
(ICD-10). We identified subjects with a principal
diagnosis of acute bronchitis, bronchiolitis, pneumonia,
laryngotracheobronchitis and epiglottitis using the ‘J20,
J21, J12, J05’ ICD-10 codes (J205- acute bronchitis due
to respiratory syncytial virus, J209 - acute bronchitis,
unspecied, J210-acute bronchiolitis due to respiratory
syncytial virus, J219-acute bronchiolitis, unspecied;
J121- Respiratory syncytial virus pneumonia, J129
-viral pneumonia, unspecied; J050-Acute obstructive
laryngitis[croup], J051-Acute epiglottitis). We conrmed
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810
the RSV diagnosis through laboratory reports. Data
gathered were reviewed from the medical records.
Collected data comprised of the date of admission,
age, gender, weight, height, preterm birth, underlying
diseases, length of hospital stay, daycare attendance,
history of exposure to sick patients, second-hand smoke,
duration of illness prior to admission. Two physicians
(1 medical doctor, 1 pulmonologist) determined the
ReSVinet scale scores based on the patients admission
records and scores were used to categorize the case and
control groups. e data of illness were collected such
as general condition, fever, respiratory frequency, lung
sound, chest wall retraction, SpO
2
, history of apnea,
decreased appetite, and complications (e.g. secondary
bacterial infection), the clinical course (e.g. requiring
intensive care, mechanical ventilation, requiring oxygen
supplement).
Data and statistical analysis
e patients were divided into two groups, severe
RSV ALRTI and non-severe RSV ALRTI, based on the
score of the ReSVinet scale. Continuous variables were
compared between the two groups using the Student’s
t-test. Categorical variables were compared using the
Chi square test or Fisher’s exact test. Multiple logistic
regression analysis was used to identify the independent
factors associated with severe RSV ALRTI. All potential
risk factors showing a p value of <0.2 in the univariate
analysis were included in the regression model. Odds
ratios (OR) and 95% condence intervals (95% CI) were
calculated. Multiple logistic regression analysis was
performed to evaluate adjusted odds ratio (AOR) and
95% condence interval (95% CI). A two-tailed p-value
of <0.05 was considered statistically signicant. e
statistical analysis was performed using SPSS version
20.0 for Windows (SPSS Inc., Chicago, IL, USA).
RESULTS
Two hundred sixty-nine children between 1-60
months old were diagnosed with RSV ALRTI and were
admitted in Naresuan University hospital during the
course of the study. e participants were divided into
two groups using the ReSVinet scale method: twenty in
the severe RSV ALRTI group and 249 in the non-severe
RSV ALRTI group. e 249 patients in non-severe RSV
ALRTI were further divided using Matlab-program to
generate 80 participants randomly matched by sex and
age, and to satisfy the 1:4 (case:control) ratio (Fig 1). e
record showed RSV ALRTI from March to November, but
the upsurge of cases was between August to November
and documented the highest number in September. Mean
age was 10.45 ± 3.53 months. e mean weight in severe
Fig 1. Method of study.
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RSV ALRTI group was considerably lower than non-
severe RSV ALRTI group (7.20±1.18 kg vs. 9.71±0.45 kg,
P = 0.022). e mean height in the severe RSV ALRTI
group was 67.25±16.12 cm. and non-severe RSV ALRTI
group was 76.03±13.64 cm. (P = 0.015). Non-severe RSV
ALRTI cases group had a higher attendance rate at the
daycare center than severe RSV ALRTI group (32.5%
vs 5.0%, P = 0.013). e age, history of exposure to sick
patients, preterm birth, and second-hand smoke contact
had no signicant dierence in both groups. ere was
a statistically signicant dierence in the proportion of
patients with underlying disease between two groups,
70.0% in severe RSV ALRTI group while only 21.2%
non-severe RSV ALRT group (P < 0.001). Congenital
heart disease and pulmonary disease were the most
prevalent underlying conditions in severe RSV ALRTI
group (30.0% and 20.0%, respectively). e occurrence
bronchopulmonary dysplasia (BPD) in severe RSV ALRTI
group was higher than the non-severe RSV ALRTI group
but not signicantly dierent (10.0% vs 1.3%, P = 0.287).
ere was a substantial dierence in the duration of illness
before hospitalization ≤3 day-period and the duration
of hospital stay in >5 day-period. e respective results
were 65.0% vs. 38.7% (P = 0.034) and 95.0% vs. 62.5%
(P = 0.005) in severe RSV ALRTI group and non-severe
RSV ALRTI group. (Table 1).
TABLE 1. Characteristics data and factors associated of participants with severe RSV ALRTI and non-severe RSV
ALRTI.
Demographic data Severe RSV ALRTI Non-severe RSV ALRTI P value
(n=20) (n=80)
Age (months) (mean, SD) 10.45 (3.53) 14.94 (1.32) 0.160
c
Sex number (%) 0.158
a
Male 6 (30.0%) 24 (30.0%)
Female 14 (70.0%) 56 (70.0%)
Weight (kg) (mean, SD) 7.20±1.18 9.71±0.45 0.022
c
*
Height (cm.) (mean, SD) 67±16.12 76.03±13.64 0.015
c
*
Daycare attendance 1 (5.0%) 26 (32.5%) 0.013
a
*
History of exposure to sick patients 4 (20.0%) 28 (35.0%) 0.198
a
Preterm birth 6 (30.0%) 9 (11.2%) 0.072
b
Exposure to second-hand smoke 0 (0.0%) 0 (0.0%) N/A
Underlying disease 14 (70.0%) 17 (21.2%) <0.001
a
*
Congenital heart disease 6 (30.0%) 3 (3.8%) 0.002
b
*
Pulmonary disease 4 (20.0%) 9 (11.3%) 0.287
b
Asthma and allergic rhinitis 2 (10.0%) 8 (10.0%)
BPD 2 (10.0%) 1 (1.3%)
Hematologic disease 1 (5.0%) 2 (2.5%) 0.492
b
Neurologic disease 2 (10.0%) 2 (2.5%) 0.178
b
Other underlying disease 1 (5.0%) 1 (1.3%) 0.362
b
Duration of illness prior to admission
≤3 days 13 (65.0%) 31 (38.7%) 0.034
a
*
>3 days 7 (35.0%) 49 (61.3%)
Duration of hospital stay >5 days 19 (95.0%) 50 (62.5%) 0.005
a
*
Complications
HAP 19 (95.0) 38 (47.5) < 0.001
a
*
Requiring ICU 18 (90.0) 3 (3.8) < 0.001
a
*
Oxygen supplementation < 0.001
b
*
Low ow 1 (5.0) 74 (92.5)
High ow and non-invasive 5 (25.0) 6 (7.5)
Mechanical ventilator 14 (70.0) 0 (0.0)
a
Chi-Square Tests,
b
Fisher's Exact Test,
c
Independent t-test, *p<0.05,
Abbreviations: N/A = Not available, BPD = Bronchopulmonary dysplasia, HAP= Hospital-acquired pneumonia, ICU= intensive care unit
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On rst-time admission, clinical manifestations
of patients with severe and non-severe RSV ALRTI
had signicant dierences in tachypnea (for infant <2
months, respiratory rate >60 /min; for children 2-12
months, respiratory rate >50 /min; for children >1-5
years, respiratory rate >40 /min) (P < 0.001), SpO
2
<85%
(P < 0.001), lung sound (poor air entry) (P < 0.001),
and all retraction (suprasternal notch, intercostal and
subcostal retraction) (P < 0.001). In contrast, there were
no statistical dierences in relation to abnormal general
condition (e.g. lethargy, discomfort, agitation), fever
and decreased appetite in both groups. No apnea was
observed in all patients.
When compared to patients with non-severe RSV
ALRTI, patients with severe RSV ALRTI had a higher
rate of HAP (95.0% vs. 47.5%, P < 0.001). e common
pathogens of HAP found in our study were aerobic
gram-negative bacilli [Acinetobacter baumannii (95%),
Pseudomonas aeruginosa (2%), Escherichia coli (1.8%),
Klebsiella pneumoniae (1%), Enterobacter spp. (0.2%)].
In addition, the number of patients with severe
RSV ALRTI that required intensive care and mechanical
ventilation was higher than the number of cases of non-
severe RSV ALRTI (90.0% vs 3.8%, P < 0.001 and (70.0%
vs.0.0%, P < 0.001, respectively). All patients needed
oxygen supplementation during admission.
Our research recorded four patient deaths (4.0%),
three of them had underlying congenital heart diseases
[1 case with dextrocardia, ventricular inversion, pulmonary
stenosis (PS), patent ductus arteriosus (PDA); 1 case with
CoA; and 1 case with ventricular septal defect (VSD)],
and one had underlying asthma, all of whom were in
the severe RSV ALRTI group.
e results of the multiple logistic regression analysis
adjusted by sex, age, daycare center attendance, and
duration of illness prior to admission 3 days revealed the
following risk factors for severe RSV ALRTI: underlying
cardiovascular disease [aOR 32.45; 95% CI 3.38-311.87,
P = 0.003], and hospital stay >5 days [aOR 19.56; 95%
CI 1.81-212.05, P = 0.014] (Table 2).
DISCUSSION
is study showed that underlying cardiovascular
diseases particularly congenital heart disease is one of
the risk factors for severe RSV ALRTI (aOR = 32.45),
which is comparable to previous studies.
14,16-21
Infants
with congenital heart disease have increased risk for
severe RSV ALRTI with higher morbidity (need for
assisted ventilation and longer duration of oxygen
supplementation) and higher mortality rate of 37% as
rst reported by MacDonald, et al.
22
Congenital heart
disease and RSV-related rehospitalization rate were
recorded at 3.0-16.4% in developed countries.
16-19,21,23,24
is study supports the hypothesis that congenital heart
disease (CHD) increases the risk for severe RSV ALRTI.
Furthermore, the present study revealed that a hospital
stay of more than 5 days is also a concomitant risk factor
for severe RSV ALRTI, which is approximately 20 times
more common than non-severe RSV ALRTI. is nding
may suggest that care providers pay more attention to this
group due to the slow recovery from disease and the need
to avoid HAP. In our study, HAP was found to be 95.0%
in the severe RSV ALRTI group. As a result, patients may
undergo procedures to avoid disease-related complications,
such as the insertion of intravenous catchers for uid
resuscitation and dehydration, intravenous antibiotics
in case of bacterial superinfection, or airway suctioning
for clearing secretions. Appropriate management which
consists of alcohol-based disinfection and hand washing
with alcohol-based rubs or soaps, is extremely eective in
reducing RSV transmission and preventing nosocomial
infections. We found that nosocomial infection was
associated with severe RSV ALRTI group (P < 0.001) and
the most common pathogen was Acinetobacter baumannii
TABLE 2. Multivariable analysis of risk factors of severe RSV-associated acute lower respiratory tract infections.
Factors
Multivariable analysis
AOR 95% CI P value
Underlying cardiovascular disease 32.45 3.38-311.87 0.003
Duration of hospital stay >5 days 19.56 1.81-212.05 0.014
Adjusted by sex, age, daycare center attendance, duration of illness prior to admission ≤ 3 days
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as reported by other studies.
20,22,25,26
e number of infants
admitted to hospitals during RSV season can be very
high, resulting in overcrowded pediatric wards and an
excessive workload for the sta. Furthermore, staying in
the hospital for longer periods of time may increase the
risk of cross-bacterial antimicrobial resistance infections.
us, the importance of systematic preventive measures
such as isolation of infected infants in single rooms, and
handwashing are highly recommended.
Groothuis, et al
27
were the rst to study the burden
of early rehospitalization in infants with BPD due to
RSV infection. However, we do not consider preterm
birth and BPD as associated factors for severe RSV ALTI
(P 0.287). is is so because our study had recorded
preterm births of 6 out of 20 patients with severe RSV
ALRTI (30.0%) and 9 out of 80 from non-severe RSV
ALRTI group (11.2%) (P = 0.072). Moreover, the number
of patients with underlying BPD was small (2 out of 20
(10.0%) patients from severe RSV ALRTI group and 1
out of 80 (1.3%) from non-severe RSV ALRTI group),
and the majority of the patients in both groups were
born at term (70% in severe RSV ALRTI and 89.8% in
non-severe RSV ALRTI).
Multivariable analysis revealed that daycare attendance,
direct contact with sick patients prior to hospital admission,
duration of illness prior to admission, and history of
exposure to sick patients were not considered as risk
factors for severe RSV ALTI, which contradicted the
results of previous studies conducted in developed
countries.
16,23,28
is is partly explained by the limited
utilization of daycare centers in the study population
particularly in patients with severe RSV ALRTI (5%).
A number of limitations should be considered in
this current study. First, this research is retrospective,
wherein the ReSVinet scores of the participants were
based on their admission records instead on the peak
of severity of the disease. Second, this cross-sectional
study has small sample size. Finally, a full range PCR
for the respiratory viral panel could not be performed.
Notwithstanding these limitations, prospective studies
should be carried out to clarify the correlation of associated
factors.
CONCLUSION
Our study demonstrated that factors associated
with severe RSV ALRTI in children include underlying
cardiovascular diseases and duration of hospital stay >
5 days.
ACKNOWLEDGMENTS
e authors would like to thank Miss Kornthip
Jeephet, Statistics Technical Ocer, Research Center
of the Faculty of Medicine, Naresuan University for
statistical analysis, and Miss Judely Marish Cañete, Miss
Daisy Gonzales, International Relations Section, Faculty
of Medicine, Naresuan University for their assistance in
revising and editing the manuscript.
Conicts of interest: ALL of the authors declare no
conict of interest.
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Supanan Innok, M.N.S*, Witchuda Dokphueng, M.N.S*, Kamol Udol, M.D., M.Sc.**, Worawong Slisatkorn,
M.D.***, Prasert Sawasdiwipachai, M.D.****
*Department of Nursing, Siriraj Hospital, Bangkok 10700, ailand, **Department of Preventive and Social Medicine, ***Department of Surgery,
****Department of Anesthesiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, ailand
Clinical Outcomes and Cost of Ventilator Weaning
and Endotracheal Extubation Guided by An
Established Ventilator Weaning Protocol in Patients
Undergoing Elective Cardiac Surgery
ABSTRACT
Objective: To compare successful early extubation rates, complications, and cost before and aer the use of an
established ventilator weaning protocol in patients undergoing elective cardiac surgery.
Materials and Methods: Subjects were adult patients undergoing elective cardiac surgery who were clinically stable
within 2 hours aer surgery. e control group underwent conventional ventilator weaning at the discretion of their
attending sta. e intervention group underwent protocol-guided ventilator weaning. e primary outcome was
a successful early extubation (within 6 hours aer surgery). Secondary outcomes were complications from weaning
to 24 hours aer surgery, and the relevant cost related to respiratory and cardiovascular care within 24 hours aer
admission to the postoperative intensive care unit.
Results: e primary outcome occurred in 37 out of 65 patients (56.9%) in the intervention group and in 5 out of
65 patients (7.7%) in the control group (adjusted odds ratio 20.6; 95% condence interval 6.7–62.9, p<0.001). e
complication rates were not statistically dierent between the intervention and control groups (26.2% vs. 20.0%,
p=0.41). e relevant cost, approximated by the service charges, related to respiratory and cardiovascular care was
signicantly less in the intervention group than in the control group (median 2,491 vs. 2,711 ai baht, p<0.001).
Conclusion: e use of the established ventilator weaning protocol aer elective cardiac surgery was associated with
a higher rate of successful early extubation and lower cost related to respiratory and cardiovascular care compared
to the conventional practices of ventilator weaning and extubation. e rates of overall complications were not
signicantly dierent.
Keywords: Early extubation; cardiac surgery; ventilator weaning protocol; complication; cost (Siriraj Med J 2021;
73: 815-822)
Corresponding author: Kamol Udol
E-mail: kamol.udo@mahidol.ac.th
Received 18 May 2021 Revised 17 October 2021 Accepted 27 October 2021
ORCID ID: https://orcid.org/0000-0002-1508-7749
http://dx.doi.org/10.33192/Smj.2021.106
INTRODUCTION
Open-heart surgery remains an important treatment
option for patients with coronary artery disease, valvular
heart disease, and congenital heart disease. Aer successful
open-heart surgery, patients oen require further ventilatory
support for a period of time until the eects of general
anesthesia fade and their vital signs are stable. Timely
ventilator weaning and endotracheal extubation is essential
in order to avoid unnecessary prolonged ventilation and,
at the same time, to minimize the adverse eects of too
early weaning and extubation.
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At Siriraj Hospital, the process of ventilator weaning
in elective cardiac surgery patients in the postoperative
intensive care unit (ICU) has conventionally been handled
primarily by the attending nurse, under the supervision
of the attending ICU physician, without any specic
guidance. e nurse initiates the process of ventilator
weaning and regularly monitors the patient’s response
and weaning parameters. When the patient is considered
ready for extubation, the nurse noties the attending
ICU physician to conrm the evaluation and to perform
the extubation. e ventilator weaning process depends
considerably on the individual nurse’s experience and
preference. is leads to a variation in practice and can
result in an unnecessarily prolonged intubation in some
patients, especially those who are ready for extubation
during the night. Prolonged ventilatory support and
delayed endotracheal extubation are associated with an
increase in the length of ICU and hospital stay, adverse
clinical outcomes, including an increase in mortality, and
higher health care costs.
1,2
Previous studies found that
post cardiac surgery patients with stable hemodynamics
could be safely extubated within 4–6 hours aer surgery.
3,4
In order to reduce variations in practice and to avoid
delayed extubation, a team comprising postoperative
ICU nurses, a cardiovascular-thoracic surgeon, and a
cardiovascular anesthesiologist was formed to establish
a protocol for ventilator weaning and extubation for
postoperative cardiac surgery patients. e protocol
species the steps and activities to be followed by the
attending nurse, with an aim for early extubation within
6 hours aer surgery.
We conducted this study to evaluate the eects
of using the established ventilator weaning protocol in
patients undergoing elective cardiac surgery compared
to conventional weaning practices.
MATERIALS AND METHODS
is prospective pre-post intervention study was
conducted at Siriraj Hospital in Bangkok, ailand. e
Institutional Review Board of the Faculty of Medicine
Siriraj Hospital approved the study protocol. All the
subjects provided written informed consent to participate
in the study.
Study participants
Patients were potentially eligible if they had coronary
artery disease, valvular heart disease, or adult congenital
heart disease that required elective cardiac surgery for
the rst time, were aged 18–75 years old, and had a le
ventricular ejection fraction (LVEF) of ≥ 45%, and an
echocardiographically estimated right ventricular systolic
pressure (RVSP) of ≤ 60 mmHg. After the surgery,
patients were admitted to the postoperative ICU. At 2
hours aer surgery, the patients were assessed for their
nal eligibility. Patients were excluded if they met at
least one of the following exclusion criteria at 2 hours
aer surgery: a Richmond Agitation and Sedation Scale
(RASS) of < –2; pulse oximetry oxygen saturation (SpO
2
)
of < 95%; serious cardiac arrhythmia [symptomatic
bradycardia with a heart rate of < 50 beats per minute
(BPM), second- or third-degree atrioventricular block,
atrial brillation with a ventricular rate of > 120 BPM,
atrial utter, supraventricular tachycardia, sustained
ventricular tachycardia, ventricular fibrillation, or
pulseless electrical activity]; unstable hemodynamics
[sustained hypotension (mean arterial pressure (MAP)
of < 65 mmHg or systolic blood pressure (SBP) of < 90
mmHg) for longer than 10 minutes, at least 2 episodes
of hypotension (MAP of < 65 mmHg or SBP of < 90
mmHg) within the previous 2 hours, receiving at least 5
microgram/kg/min of dopamine or dobutamine, or at least
0.1 microgram/kg/min of adrenaline or norepinephrine,
requiring mechanical circulatory support (intra-aortic
balloon pump, ventricular assist device, or extra-corporeal
membrane oxygenation), or had a urine output of < 1
mL/kg/hour]; chest drain content of > 100 mL/hour for
2 consecutive hours; and the occurrence of new stroke.
Patients with a documented diculty in intubation were
also excluded.
Study procedures
Patients enrolled before implementation of the
established ventilator weaning protocol (i.e., the conventional
weaning group) were managed conventionally regarding
ventilator weaning and extubation by the attending nurse
in consultation with the attending ICU physician in the
postoperative ICU. Patients were put on mechanical
ventilation upon ICU admission, usually in the assist/
control mode. e weaning process started with a gradual
reduction of the fraction of inspired oxygen (FiO
2
) to
0.4-0.5 while maintaining the SpO
2
at 95% or higher.
When this level of FiO
2
was achieved and the patient was
clinically stable and conscious, the ventilator mode was
then switched to synchronized intermittent mandatory
ventilation (SIMV) with pressure support (PS). When
the attending sta were condent that the patient could
tolerate this ventilator mode well and was clinically stable,
the patient was put on spontaneous ventilation with either
T-piece or continuous positive airway pressure (CPAP) with
PS. When the patient’s respiratory and clinical conditions
were ready, the attending ICU physician performed the
extubation. e specic details and timing of each step
Innok et al.
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SMJ
were not specied and were le to the discretion of the
attending nurse in consultation with the attending ICU
physician. During the process, the patient’s conditions
were regularly monitored and management was provided
accordingly.
e established ventilator weaning protocol was
implemented in April 2016, and patients enrolled in
the study thereaer comprised the protocol weaning
group. e protocol provides details of and timing for
the activities at each step, together with the criteria for
the assessment of patients during the weaning process.
e protocol aims for extubation to be performed within
6 hours aer surgery if the patients are stable and do not
have major complications. e protocol is summarized
in Fig 1.
Outcomes
e primary outcome was a successful extubation
within 6 hours aer the surgery. Extubation was considered
successful if there were no respiratory, cardiovascular, or
neurological complications until 24 hours aer surgery,
and no re-intubation within 48 hours aer extubation.
Secondary outcomes were complications recorded from
the beginning of ventilator weaning to 24 hours aer
surgery, and the relevant cost related to respiratory and
cardiovascular care within 24 hours aer admission to
the ICU. Respiratory complications included new or
worsening atelectasis, pneumothorax, re-intubation
within 48 hours aer extubation, and moderate or severe
acidosis or alkalosis. Cardiovascular complications included
postoperative myocardial infarction, signicant arrhythmias
(atrial utter, atrial brillation with rapid ventricular
rate, supraventricular tachycardia, sustained ventricular
tachycardia, ventricular brillation, pulseless electrical
activities), and hypotension (MAP < 65 mmHg or SBP
< 90 mmHg for longer than 10 minutes). Neurological
complication was reected by a Glasgow coma scale of
< 13. e cost considered in this study was limited to
that related to inotropic agents, antiarrhythmic agents,
procedures related to respiratory care (endotracheal
intubation, ventilator use, suction, chest x-ray, arterial blood
gas analyses, and intercostal drainage), and cardiovascular
care (intraarterial blood pressure monitoring, use of
infusion pumps, electrocardiography, analyses of cardiac
biomarkers, and electrical cardioversion). For each service
item, we used the service charge determined by Siriraj
Hospital as a proxy for its cost. e service charge for
each service item was xed throughout the study period.
Statistical analyses
On the basis of our local ICU statistics, the rate of
successful extubation within 6 hours aer cardiac surgery
was approximately 25%. To demonstrate a doubling
of the successful extubation rate aer the use of the
established ventilator weaning protocol with the power
of 80% at a two-sided signicance level of 0.05 and the
assumption of a 10% loss of subjects, it was determined
that a sample size of 65 subjects in each group would be
required.
e patients’ characteristics were summarized with
the median and interquartile range (IQR), or number
and percentage, and were compared between groups
using the Mann–Whitney U test, chi-square test, or the
Fisher’s exact test as appropriate. e primary outcome
was analyzed using multiple logistic regression analysis,
adjusted for imbalances in the baseline characteristics
(characteristics with a p-value of < 0.2 in comparisons
between groups). e magnitude of the eect is presented
as an adjusted odds ratio (OR) and its 95% condence
interval (CI). e complication rates were compared
between groups using the chi-square test. e cost was
compared using the Mann–Whitney U test.
RESULTS
In total, 130 patients participated in the study: 65 in
the conventional weaning group and 65 in the protocol
weaning group. All the patients completed the study
protocol and were included in the analyses. e median
age was 61.5 years old and 61.5% were male. Comorbidities
were prevalent; almost 40% of the study participants had
diabetes, about three-quarters had hypertension, and
slightly more than half had dyslipidemia. Coronary artery
bypass gra (CABG) surgery was performed, as a single
procedure or combined with other procedures, in 74%
of the subjects. Valve surgery, alone or combined with
other procedures, was done in 32% of the subjects. e
patients’ baseline characteristics were not statistically
signicantly dierent between the groups (Table 1).
Primary outcome
e median (IQR) duration of intubation was 5.8
(5.3–6.0) hours in the protocol weaning group and 9.0
(7.4–11.1) hours in the conventional weaning group (p <
0.001). e primary outcome (successful extubation within
6 hours aer surgery) occurred in 37 patients (56.9%) in
the protocol weaning group and in 5 patients (7.7%) in
the conventional weaning group (Table 2). e OR for
the primary outcome, adjusted for sex, the presence of
diabetes mellitus, and the presence of coronary artery
disease, was 20.6 (95% CI 6.7–62.9, p < 0.001) for the
intervention group compared to the control group.
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Innok et al.
No
No Yes
Step 4
Post-extubation care
Extubation
Step 3
Perform
extubation
5
th
–6
th
hour
Final assessment
- Spontaneous breathing above the ventilator rate, RR 10–30/min
- Spontaneous TV 5–7 ml/kg, Minute ventilation 5–10 L/min
- SpO
2
≥ 95%
-
RSBI (f/V
T
) ≤ 105
Step 2
Prepare for
extubation
3
rd
–4
th
hour
Initial assessment
- Breathing spontaneously above the ventilator rate, RR 10–30/min
- Spontaneous TV 5–7 ml/kg, Minute ventilation 5–10 L/min
- ABG: pH 7.35–7.45, PaO
2
≥ 90 mmHg, PaCO
2
35–45 mmHg, HCO
3
22–26 mEq/L
- PaO
2
/FiO
2
> 200
- SpO
2
≥ 95%
RR 2 breaths q 15–30 minutes until achieving RR 4–6/min
Pre-extubation
- Upright position
- Clear airway and rest the patient for 30 minutes
- Ask the patient to take deep breaths
O
2
T-Piece 7–10 L/min
After 30 minutes: ABG for evaluation of gas exchange
CPAP + PS 5–8 cmH
2
O
After 30 minutes: ABG for evaluation of gas exchange
Assessment for extubation readiness
- Good consciousness: Alert and cooperative
- Adequate gas exchange: pH 7.35–7.45, PaO
2
≥ 90 mmHg, PaCO
2
35–45 mmHg, HCO
3
22–2 6 mEq/L, SpO
2
≥ 95 %, RR ≤ 24 /min
- Stable hemodynamics: MAP ≥ 65 mmHg, SBP ≥ 90 mmHg, Dobutamine or Dopamine < 5 µg/kg/min, Adrenaline or Norepinephrine < 0.1 µg/kg/min
- No bleeding: Chest tube output < 50 ml/hr
- No significant arrhythmia: Symptomatic bradycardia, A-V Block, AF, Atrial flutter, SVT, Sustained VT, VF, PEA
- No increased work of breathing: No rapid shallow breathing pattern, No paradoxical abdominal movement
- Adequate Pain control: Pain score < 3
- No anxiety
- Rest the patient
- Maintain ventilator setting
- Reassess within 1 hour
(total duration of this stage
3 hours)
- *If necessary, repeat ABG
If PaO
2
≤ 60 mmHg, SpO
2
< 90%
- CXR, ABG
- Consider re-intubation
- PaO
2
≥ 90 mmHg, SpO
2
≥ 95%
- Ability to maintain RR 10–30/min
- Ability to cough and clear secretions
- Deep breathing exercise
Figure 1. Ventilator weaning and extubation protocol after elective cardiac surgery
Step 1
Initiation of
ventilator weaning
1
st
–2
nd
hour
Evaluate physiologic criteria
- Awake: Eye opening, moving spontaneously and following command
- Adequate gas exchange: SpO
2
≥ 95%
- No new onset arrhythmia or serious dysrhythmia: Symptomatic bradycardia, A-V Block, AF, Atrial flutter, SVT, Sustained VT, VF, PEA
- Stable hemodynamics: MAP ≥ 65 mmHg, SBP ≥ 90 mmHg, urine > 1 ml/kg/hr, Dobutamine or Dopamine < 5 µg/kg/min, Adrenaline or
Norepinephrine < 0.1 µg/kg/min, No IABP, No VAD, No ECMO
- No need of reoperation: Chest tube output < 100 ml/hr
- No new stroke
- No difficult intubation
Ventilator setting by anesthesiologist
CMV rate 10–12/min
Verify baseline ABG within 20 minutes
Assessment of airway and cardiac conditions
Titrate FiO
2
to 0.4–0.5
maintain SpO
2
≥ 95%
*Clear airway and confirm CXR if necessary
Wean Ventilator Settings
- SIMV + PS 5–8 cmH
2
O, Limit PEEP ≤ 5 cmH
2
O
- After 30 minutes, ABG for evaluation of gas exchange
- Assess vital signs q 30 minutes
No
- Maintain previous setting
- Minimal sedation just for
comfort
- Upright and comfortable
position
Reassessment until
appropriate conditions are met
Post cardiac surgery
Admission to Postoperative ICU
All criteria met
Weaning as clinically
indicated
Notify Physician
Fig 1. Ventilator weaning and extubation protocol aer elective cardiac surgery
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TABLE 1. Characteristics of the study participants at enrolment.
Characteristic Total Protocol Conventional p-value
a
(n = 130) weaning weaning
(n = 65) (n = 65)
Age (year) – median (IQR) 61.5 60.0 62.0 0.537
b
(54.0–6 7.0) (52.5–67.0) (55.0–67.0)
Male – no. (%) 80 (61.5) 45 (69.2) 35 (53.8) 0.071
Comorbidities – no. (%)
Diabetes mellitus 48 (36.9) 20 (30.8) 28 (43.1) 0.146
Hypertension 99 (76.2) 52 (80.0) 47 (72.3) 0.303
Dyslipidemia 70 (53.8) 36 (55.4) 34 (52.3) 0.725
Chronic kidney disease 8 (6.2) 2 (3.1) 6 (9.2) 0.273
c
COPD/Asthma 5 (3.8) 1 (1.5) 4 (6.2) 0.365
c
eGFR
d
(mL/min/1.73 m
2
) – median (IQR) 75.4 75.8 75.1 0.524
b
(62.6–91.8) (65.2–91.6) (60.8–91.8)
Smoking status – no. (%) 0.639
Current smoker 11 (8.5) 7 (10.8) 4 (6.2)
Ex-smoker 31 (23.8) 15 (23.1) 16 (24.6)
Non-smoker 88 (67.7) 43 (66.2) 45 (69.2)
ASA class – no. (%) 1.000
c
2 5 (3.8) 2 (3.1) 3 (4.6)
3–4 124 (96.2) 63 (95.4) 62 (93.8)
Cardiac condition
e
– no. (%)
Coronary artery disease 96 (73.8) 52 (80.0) 43 (66.2) 0.075
Valvular heart disease 43 (33.1) 19 (29.2) 24 (36.9) 0.351
Congenital heart disease 8 (6.2) 4 (6.2) 5 (7.7) 0.730
c
Type of surgery – no. (%) 0.367
c
Single procedure
CABG surgery 83 (63.8) 44 (67.7) 39 (60.0)
Valve surgery 25 (19.2) 8 (12.3) 17 (26.2)
Closure of septal defect 4 (3.1) 2 (3.1) 2 (3.1)
Combined procedures
CABG and valve surgery 13 (10.0) 8 (12.3) 5 (7.7)
Valve surgery and closure of septal defect 4 (3.1) 2 (3.1) 2 (3.1)
Other 1(0.8) 1 (1.5) 0 (0.0)
Operation time (minutes) – median (IQR) 155 150 170 0.257
b
(120–216) (120–199) (120–235)
a
Conventional weaning vs. Protocol weaning, Chi-square test unless indicated otherwise.
b
Mann–Whitney U test.
c
Fisher’s exact test.
d
Calculated using the CKD–EPI creatinine equation.
e
Listed conditions are not mutually exclusive.
IQR: Interquartile range, COPD: Chronic obstructive pulmonary disease, eGFR: Estimated glomerular ltration rate, CABG: Coronary
artery bypass gra, ASA: American Society of Anesthesiologists.
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Secondary outcomes
Overall, 30 subjects suered at least 1 complication
from the beginning of ventilator weaning to 24 hours
aer the surgery: 17 (26.2%) in the protocol weaning
group and 13 (20.0%) in the conventional weaning group
(p = 0.405) (Table 3). Atrial brillation developed more
frequently in the protocol weaning group than in the
conventional weaning group (8 vs. 3 subjects respectively).
Two subjects in the protocol weaning group required
inotropic agents. In both groups, no subject required
re-intubation within 48 hours.
The service charges related to respiratory and
cardiovascular care within 24 hours aer admission to
the ICU were signicantly less in the protocol weaning
group than in the conventional weaning group [median
(IQR) 2,491 (2,308–2,652) ai baht (THB) vs. 2,711
(2,479–2,945) THB, p < 0.001] (Table 3).
TABLE 2. Primary outcome.
TABLE 3. Secondary outcomes.
Protocol Conventional Adjusted OR
a
p-value
weaning weaning (95% CI)
(n = 65) (n = 65)
Successful extubation within 6 hours 37 (56.9) 5 (7.7) 20.6 < 0.001
after surgery – no. (%) (6.7–62.9)
a
Adjusted for sex, presence of diabetes mellitus, presence of coronary artery disease.
OR: odds ratio, CI: condence interval.
Protocol Conventional p-value
weaning weaning
(n = 65) (n = 65)
Complications
a
– no. (%) 17 (26.2) 13 (20.0) 0.405
Respiratory – no. (%)
Atelectasis 4 (6.2) 4 (6.2)
Pneumothorax 1 (1.5) 1 (1.5)
Acidosis (arterial pH < 7.25) or alkalosis (arterial pH > 7.5) 1 (1.5) 1 (1.5)
Cardiovascular – no. (%)
Atrial brillation 8 (12.3) 3 (4.6)
Supraventricular tachycardia 1 (1.5) 0 (0.0)
Hypotension 3 (4.6) 2 (3.1)
Requirement of inotropic agents 2 (3.1) 0 (0.0)
New pathological Q wave or new LBBB in ECG – no./total (%) 1/52 (1.9) 3/44 (6.8)
Costs
b
(THB) – median (IQR) 2,491 2,711 < 0.001
(2,308–2,652) (2,479–2,945)
a
Complications recorded from the beginning of ventilator weaning to 24 hours aer surgery.
b
Approximated by the service charges related to respiratory and cardiovascular care within 24 hours aer admission to the postoperative
intensive care unit.
LBBB: le bundle branch block, ECG: electrocardiography, THB: ai baht, IQR: Interquartile range.
Innok et al.
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DISCUSSION
In this prospective pre-post intervention study
among patients undergoing elective cardiac surgery, the
implementation of the established ventilator weaning
protocol led to a remarkable increase in the rate of
successful extubation within 6 hours aer surgery and
a decrease in service charges related to respiratory and
cardiovascular care within 24 hours aer admission to the
postoperative ICU, when compared to the conventional
weaning practices. ere was no statistically signicant
increase in the rates of respiratory and cardiovascular
complications.
Early extubation in stable postoperative cardiac
patients, when compared to late extubation, was shown in
previous studies to shorten the length of ICU and hospital
stay, and to reduce healthcare costs.
3,5-9
Strategies that
enhance early extubation would, therefore, be benecial
for both patients and the healthcare system. A number
of studies have found that ventilator weaning guided
by an established weaning protocol shortens the time
to extubation and increases the rate of early extubation
when compared to weaning without a guide among
cardiac patients in a coronary care unit or post cardiac
surgery patients.
10-12
Moreover, early extubation in cardiac
surgery patients was found to lead to a reduction in costs
and an improvement in health resource utilization.
5,9
e results of our study conrm the clinical and cost
benets of protocol-guided ventilator weaning in post
cardiac surgery patients.
Implementing the established ventilator weaning
protocol appeared to be safe. In this study, no patients
required re-intubation within 48 hours aer extubation.
e rates of respiratory and cardiovascular complications
were similar between the 2 groups, except for atrial
brillation, which was higher in the protocol weaning
group. Previous studies did not observe an increased rate
of atrial brillation in patients with early extubation. It is
still not clear whether this increase in atrial brillation in
our study was true or just a chance nding. Additional
information is required before a denite conclusion
regarding this issue can be made.
e established ventilator weaning protocol clearly
species the steps to take and time frames to follow during
the weaning process; thereby reducing the variations in
practice, hastening the process of weaning, and enhancing
the success rate of early extubation. In addition, the
protocol also provides monitoring criteria to determine the
progression of the patients and the actions to be taken if
the patients do not progress as expected. In conventional
weaning practices, extubation in some patients who are
ready during the night may be delayed until the next
morning due to concerns about safety, as the number of
sta during the night may be less than that during the day.
Moreover, it might be perceived that night sta may not
be as vigilant as day sta in detecting complications aer
extubation. Our study provides assurances that following
the established weaning protocol does not increase the
risk of complications aer extubation, regardless of the
time of extubation.
Experts have suggested that a ventilator weaning
protocol should be developed using a multidisciplinary team
approach.
13
e ventilator weaning protocol implemented
in this study was developed by a team of postoperative
ICU nurses, a cardiovascular-thoracic surgeon, and a
cardiovascular anesthesiologist. In our institution, and
in this study, the attending nurse plays a primary role in
the process of ventilator weaning, in consultation with
the attending ICU physician when necessary. Nurses have
important roles to play in various strategies essential for
successful ventilator weaning, including enhancing the
readiness to wean, frequent assessment of the readiness
to wean, encouraging spontaneous breathing during
weaning, and the use of spontaneous breathing trials.
14
Other studies support the success of ventilator weaning
and early extubation when directed by a nurse using a
pre-specied protocol.
12,15
Employing the result of our study to clinical practice
has potential implications for post cardiac surgery
patients and for health care system. For patients, early
ventilator weaning and endotracheal extubation is
likely to reduce discomfort and anxiety associated with
mechanical ventilation and the endotracheal tube. e
length of postoperative ICU stay is likely to be shortened.
Mechanical ventilators and ICU beds could therefore be
utilized more eciently as they become more readily
available to other patients in need. In ailand, about
11,000 adults underwent CABG and/or valve surgery
in 2019.
16
Applying the protocol-guided early ventilator
weaning and extubation could lead to millions of ai
baht being saved each year.
However, our study had some limitations to note.
Group allocations for each subject did not follow a process
of randomization. us, selection bias and some eects
of unmeasured or unknown confounding factors could
not be entirely excluded. e successful extubation rate
within 6 hours aer surgery in the conventional weaning
group (7.7%) was much lower than that estimated in our
sample size calculation (25%). is would indicate bias
in the study and may have led to an overestimation of
the eect of protocol weaning compared to conventional
weaning. e unadjusted OR estimated from the result
of the study was 15.9 (95% CI 5.6–44.7, p < 0.001).
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However, if we assume an approximate 25% successful
extubation rate in the conventional weaning group (16
subjects out of 65), the result would still be statistically
signicant in favor of protocol weaning, but the eect
would be less pronounced, with an unadjusted OR of
4.0 (95% CI 1.9–8.6, p < 0.001). Also, we used relevant
service charges related to respiratory and cardiovascular
care in each group as proxies for the cost data. However,
for any particular service in our institution, cost is a
primary determinant of its service charge. erefore, a
comparison of service charges would provide a similar
conclusion as the comparison of costs between groups.
Last but not least, this study was conducted in a single
university hospital in patients with elective cardiac surgery;
the results may not be applicable to other care settings
or to other groups of patients.
CONCLUSION
In conclusion, ventilator weaning and extubation
guided by an established weaning protocol in patients
undergoing elective cardiac surgery was found to be
associated with a higher rate of successful extubation
within 6 hours aer surgery and lower cost related to
respiratory and cardiovascular care within 24 hours
aer admission to the postoperative ICU, compared
to conventional practices of ventilator weaning and
extubation. e rates of overall complications from the
initiation of ventilator weaning to 24 hours aer surgery
were not signicantly dierent.
ACKNOWLEDGEMENT
is study was supported by a grant from the Siriraj
Research Development Fund (managed by the Routine to
Research Project), Faculty of Medicine Siriraj Hospital,
Mahidol University.
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4. Amirghofran AA, Rayatpisheh M, Rayatpisheh S, Kaviani M.
A comparative study of immediate and late extubation aer
open heart surgery. Iran Cardiovasc Res J 2007;1:42–7.
5. Cheng DC, Karski J, Peniston C, Raveendran G, Asokumar B,
Carroll J, et al. Early tracheal extubation aer coronary artery bypass
gra surgery reduces costs and improves resource use. a prospective,
randomized, controlled trial. Anesthesiology 1996;85:1300–10.
6. Reis J, Mota JC, Ponce P, Costa-Pereira A, Guerreiro M. Early
extubation does not increase complication rates aer coronary
artery bypass gra surgery with cardiopulmonary bypass. Eur
J Cardiothorac Surg 2002;21:1026–30.
7. Litmathe J, Boeken U, Kurt M, Feindt P, Gams E. CABG-
procedures in patients with advanced age: early extubation
and fast track management as an option? e Cardiol 2008;4:7–10.
8. Camp SL, Stamou SC, Stiegel RM, Reames MK, Skipper ER,
Madjarov J, et al. Quality improvement program increases early
tracheal extubation rate and decreases pulmonary complications
and resource utilization aer cardiac surgery. J Card Surg
2009;24:414–23.
9. Holowachuk S, Zhang W, Gandhi SK, Anis AH, Potts JE, Harris
KC. Cost savings analysis of early extubation following congenital
heart surgery. Pediatr Cardiol 2019;40:138–46.
10. Piotto RF, Maia LN, Machado MN, Orrico SP. Eects of the
use of mechanical ventilation weaning protocol in the Coronary
Care Unit: randomized study. Rev Bras Cir Cardiovasc
2011;26:213–21.
11. Chan JL, Miller JG, Murphy M, Greenberg A, Iraola M, Horvath
KA. A Multidisciplinary protocol-driven approach to improve
extubation times aer cardiac surgery. Ann orac Surg 2018;
105:1684–90.
12. Serena G, Corredor C, Fletcher N, Sanlippo F. Implementation
of a nurse-led protocol for early extubation aer cardiac surgery:
a pilot study. World J Crit Care Med 2019;8:28–35.
13. Chan PK, Fischer S, Stewart TE, Hallett DC, Hynes-Gay P,
Lapinsky SE, et al. Practising evidence-based medicine: the
design and implementation of a multidisciplinary team-driven
extubation protocol. Crit Care 2001;5:349–54.
14. Ward D, Fulbrook P. Nursing strategies for eective weaning
of the critically ill mechanically ventilated patient. Crit Care
Nurs Clin North Am 2016;28:499–512.
15. Danckers M, Grosu H., Jean R, Cruz RB, Fidellaga A, Han Q, et. al.
Nurse-driven, protocol-directed weaning from mechanical
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by intensive care unit physicians. J Crit Care 2013;28:433–41.
16. Society of thoracic surgeons of ailand [Internet]. Bangkok:
e society of thoracic surgeons of ailand; 2021. Stats-2562;
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en/stat-2562/.
Innok et al.
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Original Article
SMJ
Jadesada Lertsirimunkong, (Pharm.D.)*, Wiwat avornwattanayong, (B.Sc. in Pharm., R.Ph., LL.B., M.A.)**,
Yosita Napuk, (Pharm.D. Student)**, Watcharapong Ajcharoen, (Pharm.D. Student)**, Vipavee Chaisitsanguan,
(Pharm.D. Student)**, Supasuta Wachiranukornkul, (Pharm.D. Student)**
*Department of Pharmacy Administration, College of Pharmacy, Rangsit University, Pathum ani 12000, ailand, **Department of Community
Pharmacy, Faculty of Pharmacy, Silpakorn University, Nakhon Pathom 73000, ailand.
Cost-effectiveness Analysis Comparing Vonoprazan-
based Triple Therapy with Proton Pump Inhibitor-
based Therapy in the Treatment of Helicobacter
pylori Infection in Thailand
ABSTRACT
Objective: Helicobacter pylori (H. pylori) infection is one of the leading causes of gastrointestinal diseases such as
dyspepsia, peptic ulcers. ailand has a 45.9% prevalence of the infection and an increasing rate of resistance to
clarithromycin, leading to standard treatments being less successful. Vonoprazan represents a novel drug oering
a new treatment regimen. Although vonoprazan has been available in ailand since 2019, its cost-eectiveness
has not been studied previously.
Materials and Methods: is study analysed the cost-eectiveness of vonoprazan-based triple therapy compared
with PPI-based therapy, in treating clarithromycin resistant H. pylori, by using the markov model from a societal
perspective.
Results: e total cost of vonoprazan-based triple therapy, levooxacin-PPI based triple therapy and concomitant-
PPI therapy were 784,932.08 baht, 783,863.65 baht and 783,874.55 baht respectively. e quality-adjusted life years
(QALYs) of vonoprazan-based triple therapy, levooxacin-PPI based triple therapy and concomitant-PPI therapy
were 25.1118 years, 25.1147 years and 25.1054 years respectively. e cost-eectiveness ratio (CER) of vonoprazan-
based triple therapy, levooxacin-PPI based triple therapy and concomitant-PPI therapy were 31,257.50 baht/
QALYs, 31,211.35 baht/QALYs and 31,223.34 baht per QALYs respectively.
Conclusion: erefore, levooxacin-PPI based triple therapy was found to be the most cost-eective regimen and
the dominant strategy compared with concomitant-PPI or vonoprazan-based triple therapy. It provided higher
QALYs and lower treatment costs. Levooxacin-PPI based triple therapy should be the rst choice of an alternative
strategy in treating clarithromycin-resistant H. pylori. e results of this study can be used by policymakers to help
inform their decisions.
Keywords: Cost-eectiveness; Vonoprazan; Proton pump inhibitors; Levooxacin; Concomitant; Helicobacter
pylori infection (Siriraj Med J 2021; 73: 823-831)
Corresponding author: Jadesada Lertsirimunkong
E-mail: jadesada.l@rsu.ac.th
Received 7 July 2021 Revised 21 September 2021 Accepted 1 October 2021
ORCID ID: https://orcid.org/0000-0003-2930-8810
http://dx.doi.org/10.33192/Smj.2021.107
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INTRODUCTION
Helicobactor pylori (H. pylori) is one of the leading
causes of gastrointestinal diseases such as peptic ulcers
and peptic cancer. is bacterium was found in the
gastrointestinal tract of more than 90% of peptic ulcer
patients. e worldwide prevalence of H. pylori infection
is about 66%. e prevalence in developing countries
is signicantly higher than in developed countries. At
present, ailand has a 45.9% prevalence of infection.
1
e incidence of infection in the Bangkok metropolitan
region is 74%, of which 50-80% are infections in adults.
2
For the treatment of H. pylori infection, the ailand
Consensus on Helicobacter pylori Management 2015
recommended using standard PPI-based triple therapy
for the rst regimen, including a proton pump inhibitor
and 2 antibiotics for 7-14 days. However, the eradication
rate of this regimen has since decreased below 80% due
to clarithromycin resistance.
3,4
In the Southeast Asia region, the country with the
highest rate of clarithromycin resistance has a resistance
rate of 43%, while ailand’s rate is about 14%.
5
In
2017, there was a conference to nd new guidelines
for H. pylori management in Asia called “Helicobacter
pylori management in ASEAN: e Bangkok consensus
report”. e conclusion of the report recommended that
any countries which have a clarithromycin resistance
rate of more than 10% should not use the standard
regimen and should switch to other non-clarithromycin
regimens instead.
6,7
is was in contrast to the 2015
ailand Consensus on Helicobacter pylori Management’s
recommendation of only using alternative rst-line
regimens (sequential therapy and concomitant-PPI
therapy) in patients whose rst-line regimen therapy
had been unsuccessful. Furthermore, the 2017 Bangkok
consensus report also recommended using concomitant-
PPI therapy over sequential therapy, due to the concern
that sequential therapy will have a lower ecacy if H. pylori
becomes resistant to clarithromycin and metronidazole at
the same time. e recommended second-line regimens
are levooxacin-PPI based triple therapy and bismuth
quadruple therapy, neither of which use clarithromycin.
However, following with the recommendation, bismuth
quadruple therapy has limitations of salt form of bismuth
and dosage. erefore, concomitant-PPI therapy and
levooxacin-PPI based triple therapy are more suitable
regimens for H. pylori infected patients in ailand.
It is not only drug resistance that aects the treatment
of H. pylori, but also pH levels in the stomach. Using an
anti-gastric acid secretion drug is essential for maintaining
stomach pH at 5 and for inhibiting H. pylori growth.
8,9
e novel drug Vonoprazan was rst used in a new
treatment regimen in ailand in 2019. e mechanism
is reversible H
+
,K
+
-
ATPase inhibitor.
10
A meta-analysis
study showed that vonoprazan-based triple therapy has an
era dication rate almost two-times higher than PPI-based
Triple erapy, especially in clarithromycin resistant
H. pylori infected patients.
11
us, vonoprazan-based triple
therapy represents an interesting alternative regimen to
eradicate clarithromycin resistant H. pylori. Until now
there has been no cost-eectiveness study carried out
comparing concomitant-PPI therapy, levooxacin-PPI
based triple therapy and vonoprazan-based triple therapy
in ailand. Consequently, the purpose of this study was
to assess the cost-eectiveness of vonoprazan-based triple
therapy compared with concomitant-PPI therapy and
levooxacin-PPI based triple therapy in the treatment
of clarithromycin resistant H. pylori infection.
MATERIALS AND METHODS
Study design
is study was a health economic evaluation using
a model-based structure and presented humanistic
outcomes in quality-adjusted life years (QALYs). e
analysis was assessed using cost-eectiveness ratio (CER)
and incremental cost-eectiveness ratio (ICER). e
perspective of this study was societal. Future costs and
utilities were discounted at 3% per year.
12
Intervention
is study compared three regimes of clarithromycin
resistant Helicobacter pylori infection treatment, approved
for use by the ailand Consensus of Helicobacter pylori
Management in 2015. e treatment included vonoprazan-
based triple therapy
13
(vonoprazan 20 mg, amoxicillin 750
mg and clarithromycin 250 mg, twice a day for 7 days) ,
levooxacin-PPI based triple therapy (levooxacin 500
mg once daily, amoxicillin 1 g twice daily, and standard
dose PPI twice daily for 14 days) and concomitant-PPI
therapy (standard dose PPI, amoxicillin 1 g, clarithromycin
500 mg and metronidazole 500 mg, twice a day for 10
days).
3
Decision model
is study used a Markov model to perform decision
analysis through Microsoft Excel 2016. The model
was developed from the 2015 ailand Consensus on
Helicobacter pylori Management
3
and the Helicobacter
pylori management in ASEAN: e Bangkok consensus
report.
7
is model was validated by two clinical experts in
gastrointestinal diseases, to ensure its appropriateness for
the treatment of H. pylori infection in ailand. Initially,
all patients were in a health status of H. pylori infection.
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Aer treatment, patients who returned a negative urea
breath test would have their health status recorded as
‘successful eradication’. If a positive urea breath test
result was returned, the health status was recorded as
‘failure from the rst regimen state’ and the patient
would go on to receive hybrid therapy. If a patient in a
successful eradication health state suered a reinfection,
they would return to the H. pylori infection health state
again. Patients in all health status could be changed to
the health status of death during the study. e model
is demonstrated in Fig 1.
for 7 days, followed by a standard dose PPI, amoxicillin
1 g, clarithromycin 500 mg and metronidazole 500 mg
twice a day for 7 days) because it is an eective therapy
in high clarithromycin resistant areas.
16
6. No treatment of side eects from any of the regimens
(diarrhea and taste disturbance in vonoprazan-based
triple therapy
15,17
, nausea and diarrhea in levooxacin-
PPI based triple therapy
18
, diarrhea and taste disturbance
in concomitant-PPI therapy
19-26
) was required as side
eects were mild.
27
7. All patients treated with hybrid therapy regimen
were assumed that have successful eradication.
8. e mortality rate of H. pylori infection was
determined by the age range according to the ai mortality
rate
28
due to H. pylori is not a signicant risk factor for
death from any cause.
29
Time Horizon
As most previous studies have examined H. pylori
induced dyspepsia or peptic ulcers in patients aged 18-
65 years
19,30
, the Markov model used in this study was
developed to follow the treatment of H. pylori infection
over a lifetime, from age 18 until death. In 2020, the
average life expectancy in ailand was 75.7 years.
31
A
cycle length of 6 weeks was considered appropriate to cover
the period of clinical treatment, adverse drug reactions
and H. pylori eradication, that was evaluated through
the urea breath test at 4-6 weeks aer the completion
of treatment. H. pylori infection could relapse within 1
year.
32
Probability of clinical outcomes
A systematic search up to September 2020 was
conducted in Pubmed, Cochrane library, Science Direct
and Scopus databases. e keywords were “Vonoprazan,
Levooxacin triple therapy, Concomitant-PPI therapy,
H. pylori or Helicobacter pylori” with “And” and ltered
by randomized controlled trial, meta-analysis, full text
and English published literature. Studies were identied
as eligible for inclusion if they met the following criteria
(i) published in English (ii) randomized control trial,
systematic review, or meta-analysis. e studies were
excluded if they met any of the following exclusion criteria
(i) the outcome was not eradication rate (ii) prevalence
of clarithromycin-resistant H. pylori was not similar to
that found in ailand (iii) not one of the treatment
regimens recommended for use in ailand (iv) did not
analyse eradication rate by intention to treat analysis. All
searched literature was evaluated and given a JADAD
quality assessment score. e transitional probabilities
are shown in Table 1.
Fig 1. Markov model structure of treatment for patients with
H. pylori infection
Assumption of the model
1. Patient did not withdraw from any treatment
during the study and remained until the end of the
treatment.
2. Asymptomatic patients or patients with dyspepsia,
who were conrmed to be infected with H. pylori and failed
from the standard rst-line treatment, were recruited.
3. Patients with H. pylori infection health status
who failed the standard rst-line treatment (Amoxicillin,
Clarithromycin and PPI
3
and treated by vonoprazan-based
triple therapy, levooxacin-PPI based triple therapy or
concomitant-PPI therapy.
4. A successful eradication health status was conrmed
by the negative results of a urea breath test conducted
at least 4 weeks aer treatment.
14,15
5. Patients whose vonoprazan-based triple therapy,
levooxacin-PPI based triple therapy or concomitant-
PPI therapy treatment failed, were switched to a hybrid
therapy regimen (standard dose PPI and amoxicillin 1 g
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Parameters Distribution Mean ± SE References
Transitional probabilities
Levooxacin-PPI based triple therapy
Success Beta 0.8481 ± 0.0404 18
Failure Beta 0.1519 ± 0.0404 18
Relapse Beta 0.0061 ± 0.0041 32
Vonoprazan-based triple therapy
Success Beta 0.7809 ± 0.0310 14, 15, 33
Failure Beta 0.2191 ± 0.0310 14, 15, 33
Relapse Beta 0.0061 ± 0.0041 32
Concomitant-PPI therapy
Success Beta 0.8286 ± 0.0083 19-26, 34
Failure Beta 0.1714 ± 0.0083 19-26, 34
Relapse Beta 0.0061 ± 0.0041 32
Probabilities of side effects
Levooxacin-PPI based triple therapy
Nausea Beta 0.0253 ± 0.0177 18
Diarrhea Beta 0.0380 ± 0.0215 18
Vonoprazan-based triple therapy
Diarrhea Beta 0.1172 ± 0.0161 15, 17
Taste disturbance Beta 0.0399 ± 0.0098 15, 17
Concomitant-PPI therapy
Diarrhea Beta 0.1639 ± 0.0089 19-26
Taste disturbance Beta 0.2212 ± 0.0100 19-26
Costs (Baht)
Medicine costs
Omeprazole 20 mg (per tablet) Gamma 0.6245 ± 0.0624 35
Amoxicillin 250 mg (per tablet) Gamma 6.0432± 0.6043 36
Amoxicillin 500 mg (per tablet) Gamma 1.7122 ± 0.1712 35
Clarithromycin 250 mg (per tablet) Gamma 31.0200 ± 3.1020 35
Clarithromycin 500 mg (per tablet) Gamma 13.5368 ± 1.3537 35
Levooxacin 500 mg (per tablet) Gamma 18.1296 ± 1.8130 35
Vonoprazan 20 mg (per tablet) Gamma 112.6251 ± 11.2625 36
Metronidazole 250 mg (per tablet) Gamma 0.3324 ± 0.0332 36
Laboratory cost
Urea Breath Test (per test) Gamma 3,100.00 ± 310.00 37-39
Gastrointestinal Endoscopy (per test) Gamma 1,712.24 ± 171.22 40
Biopsy (per test) Gamma 805.76 ± 80.58 40
Urease (per test) Gamma 40.29 ± 4.03 40
Treatment and additional procedures
OPD service (per visit) Gamma 120.86 ± 12.09 40
OPD prescription (per visit) Gamma 70.50 ± 7.05 40
Direct non-medical cost
Travel (per visit) Gamma 315.49 ± 31.55 41
Food (per visit) Gamma 63.14 ± 6.31 41
Utility
H. pylori Infection Beta 0.9000 ± 0.0006 42
Nausea Beta 0.6000 ± 0.0500 43
Diarrhea Beta 0.8970 ± 0.0157 44
Taste disturbance Beta 0.9410 ± 0.2356 45
TABLE 1. Parameters used in Markov model.
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Costs
All costs were expressed in ai Baht and are shown
in Table 1. Drugs and laboratory costs were obtained
from the drug’s median price in ailand and National
Drug Information and the service charge of public health
services aliated with the Ministry of Public Health,
ailand.
35,40
e costs of metronidazole 250 mg, amoxicillin
250 mg and vonoprazan 20 mg, were obtained from the
Department of Internal Trade, Ministry of Commerce,
ailand.
36
e urea breath test cost was obtained from
3 hospitals and the mean cost calculated.
37-39
Direct
non-medical costs were obtained from the standard
cost lists for health technology assessment.
41
All costs
were adjusted to 2021 values using the consumer price
index from the Bureau of Trade and Economic indices,
e Ministry of Commerce, ailand.
46
Utility values
e health outcomes were measured in utility weights
for dierent health states and adverse drug reactions,
ranging from 0 (death) to 1 (perfect health). Utility
weights were multiplied by life expectancy to generate
quality-adjusted life-years (QALYs).
Utility values of diarrhea and taste disturbance
were estimated based on the disability weights (DW) of
diarrhea and taste disturbance from the previous study
44,45
that using the calculation, utility weight = 1-DW. Utility
values of H. pylori Infection and nausea were obtained
from a previous study.
42,43
All utility values are shown
in Table 1.
Sensitivity analysis
e one-way sensitivity analysis was performed
through Microso Excel 2016. e parameter values
were changed one by one, usually to a low and a high
value. e results are presented in a tornado diagram to
demonstrate how a change in the value of one parameter
impacts the model results shown as the ICER values.
A Monte Carlo Simulation was used for probabilistic
sensitivity analysis in Microso Excel 2016. All variables
were randomized 1,000 times by probability distribution,
and the incremental cost-eectiveness ratio (ICER)
estimated. e net monetary benet (NMB) was used to
assess the cost-eectiveness in probabilistic sensitivity
analyses. e NMB calculation of vonoprazan-based
triple therapy compared with proton pump inhibitor-
based therapy was formulated as follows
12
NMB = ([QALYs
Vonoprazan-based triple therapy
- QALYs
Proton pump
inhibitor-based therapy
] x Willingness to Pay [WTP])-(Costs
Vonoprazan-
based triple therapy
-Costs
Proton pump inhibitor-based therapy
)
e results were presented as a cost-eectiveness
plane between incremental QALYs and incremental cost,
and the cost-eectiveness acceptability curve between
probabilities of vonoprazan-based triple therapy and
proton pump inhibitor-based therapy, and willingness
to pay (WTP).
RESULTS
Cost-eectiveness Analysis
e results in Table 2 show that the total costs
of vonoprazan-based triple therapy, levooxacin-PPI
based triple therapy and concomitant-PPI therapy
were 784,932.08 baht, 783,863.65 baht and 783,874.55
baht respectively while the quality-adjusted life years
(QALYS) were 25.1118 years, 25.1147 years and 25.1054
years respectively. e cost-eectiveness ratio (CER)
of vonoprazan-based triple therapy with levooxacin-
PPI based triple therapy were 31,257.50 baht/QALYs,
31,211.35 baht/QALYs and 31,223.34 baht per QALYs
respectively. When comparing vonoprazan-based triple
therapy with levooxacin-PPI based triple therapy, the
results revealed that levooxacin-PPI based triple therapy
is a dominant strategy because it delivers greater QALYs
and has a lower cost. When comparing vonoprazan-based
triple therapy with concomitant-PPI therapy, the results
revealed that the ICER was 165,239.06 baht per QALYs.
When compared levooxacin-PPI based triple therapy
and concomitant-PPI therapy, the results revealed that
levooxacin-PPI based triple therapy was a dominant
strategy because of greater QALYs and lower cost.
TABLE 2. Results
Treatment regimens Total costs QALYs CER
(Baht) (Years) (Baht/QALY)
Vonoprazan-based triple therapy 784,932.08 25.1118 31,257.50
Levooxacin-PPI based triple therapy 783,863.65 25.1147 31,211.35
Concomitant-PPI therapy 783,874.55 25.1054 31,223.34
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Sensitivity analysis
e one-way sensitivity analysis in Fig 2 is presented
in a tornado diagram. e probability of relapse from
levooxacin-PPI based triple therapy had the most impact
on the ICER. e probabilistic sensitivity analysis in
Fig 3 presents the incremental cost and the QALYs
of vonoprazan-based triple therapy compared with
levooxacin-PPI based therapy as a cost-eectiveness
plane. Each variable was randomized 1,000 times by
Fig 3. Cost-eectiveness plane between vonoprazan-based triple therapy and levooxacin-PPI based triple therapy
the Monte Carlo simulations. e base-case ICER is
represented by a yellow dot in the gure and falls in
quadrant 2 which mean levooxacin-PPI based triple
therapy was a dominant strategy because of greater QALYs
and lower cost. is revealed that levooxacin-PPI based
therapy was more cost-eective than vonoprazan-based
triple therapy. Nevertheless, the widely distributed ICERs
in the cost-eectiveness plane shows uncertain results.
Fig 2. Tornado diagram showing the results of one-way sensitivity analysis
Lertsirimunkong et al.
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Original Article
SMJ
DISCUSSION
is study is the rst economic evaluation of the
use of vonoprazan-based triple therapy and proton
pump inhibitor-based therapy in clarithromycin-resistant
H. pylori eradication. An increasing rate of resistance
to clarithromycin has led to standard treatments being
less successful in Thailand. The results showed that
levooxacin-PPI based triple therapy is the most cost-
eective regimen. Although levooxacin-PPI based triple
therapy has a high eradication rate, it also increases
the chances of levooxacin resistance, which is now a
reserved antibiotic for the treatment of drug-resistant
tuberculosis and other infection diseases. In order to
prevent drug resistance, this drug is not widely used.
3
erefore, vonoprazan-based triple therapy represents
an interesting alternative therapy. Although it is not a
cost-eective regimen at present, vonoprazan-based triple
therapy will become more cost eective if it contributes
to an increased eradication rate. A study by Yamasaki T.
found that if the dosage of clarithromycin was increased
from 400 mg to 800 mg, the eradication rate would be
increased from 86.7% to 97.8%
47
and a randomized
controlled trial phase 3
15
conrmed that the ecacy
of vonoprazan-based triple therapy in clarithromycin
resistant H. pylori was higher than PPI-based triple therapy.
Whereas, a study involving ai people found that the
H. pylori eradication rate of vonoprazan-based triple
therapy was 63.2%
14
, which is lower than that reported
in foreign studies. is could be because vonoprazan
is mainly metabolized via CYP3A4. As the genes of
ai people may include enzyme enhancers, this would
render Vonoprazan-based triple therapy less eective.
48
erefore, a possible area for further study is to compare
the ecacy or the cost-eectiveness of using vonoprazan,
with high dose clarithromycin (greater than 800 mg per
day). e limitation of this study was scope to focusing
on the ecacy of vonoprazan-based triple therapy and
the proton pump inhibitor-based therapy. Other factors
such as compliance
4
and gastrointestinal pH while taking
the drug
49
which could aect the treatment were not
considered.
CONCLUSION
Levooxacin-PPI based triple therapy in clarithromycin-
resistant H. pylori is a more cost-eective and dominant
strategy. It was found to deliver higher QALYs at lower
treatment costs from a societal perspective. Levooxacin-PPI
based triple therapy should be the rst-choice alternative
strategy in treating clarithromycin-resistant H. pylori.
e results of this study could contribute to informed
decision making by policymakers.
is study has been reviewed and approved by
the Human Research Ethics Committee of Silpakorn
University (COE Number: COE 64.0113-003)
ACKNOWLEDGEMENTS
We would also like to thank Assoc. Prof. Dr. Srisombat
Nawanopparatsak and Dr. Kittiyot Yotsombut for their
recommendations in the development of the decision
model, as well as Mr. Paul Mines for proofreading the
article.
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Sathaporn et al.
Katti Sathaporn, M.D., Jarurin Pitanupong, M.D.
Department of Psychiatry, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla 90110, ailand.
The Relationship between Mental Health with
the Level of Empathy Among Medical Students in
Southern Thailand: A University-Based Cross-
Sectional Study
ABSTRACT
Objective: To determine the level of and factors associated with empathy among medical students.
Materials and Methods: is cross-sectional study surveyed all rst- to sixth-year medical students at the Faculty
of Medicines, Prince of Songkla University, at the end of the 2020 academic year. e questionnaires consisted of:
1) e personal and demographic information questionnaire, 2) e Toronto Empathy Questionnaire, and 3) ai
Mental Health Indicator-15. Data were analyzed using descriptive statistics, and factors associated with empathy
level were assessed via chi-square and logistic regression analyses.
Results: ere were 1010 participants with response rate of 94%. Most of them were female (59%). More than half
(54.9%) reported a high level of empathy. ere was a statistically signicant dierence in empathy levels between
pre-clinical and clinical medical students; in regards to empathy subgroups (P-value < 0.001). e assessment of
emotional states in others by demonstrating appropriate sensitivity behavior, altruism, and empathic responding
scores among the pre-clinical group were higher than those of the clinical group. Multivariate analysis indicated
that female gender, pre-clinical training level, and minor specialty preference were factors associated with empathy
level. e protective factor that signicantly improved the level of empathy was having fair to good mental health.
Conclusion: More than half of the surveyed medical students reported a high level of empathy. e protective factor
that improved the level of empathy was good mental health. However, future qualitative methods, longitudinal
surveillance, or long-term follow-up designs are required to ensure the trustworthiness of these ndings.
Keywords: Empathy; factor; mental health; medical student (Siriraj Med J 2021; 73: 832-840)
Corresponding author: Jarurin Pitanupong
E-mail: pjarurin@medicine.psu.ac.th
Received 17 June 2021 Revised 17 August 2021 Accepted 30 August 2021
ORCID: https://orcid.org/0000-0001-9312-9775
http://dx.doi.org/10.33192/Smj.2021.108
INTRODUCTION
Empathy is the ability to feel or understand what
another person is experiencing from within their frame of
reference. It is the capability to place oneself in another’s
view. In the past, empathy was initially thought of as a
unitary ability; thus, it was considered to consist of two
components: a cognitive capacity that simplies the
meaning of the emotions of another person, an emotional
aptitude that interprets the experience of the emotions
of another person,
1
or both concurrently.
2,3
In recent
studies, empathy has been dened as being underpinned
by three components: emotional contagion, emotional
disconnection, and cognitive empathy.
4,5
However, empathy is an emotional experience
between a spectator and a subject in which the spectator,
based on auditory and visual clues, recognizes and
temporarily perceives the subject’s emotional condition.
6
To be acknowledged as empathic, the spectator must
communicate this purport to the subject. During the
beginning aspect of this stage, the spectator must not
only recognize but also comprehend the bottom of the
subject’s emotions. Although, usually confounded with
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each other, sympathy and empathy are dierent. Sympathy
is a position of emotional attentive, while empathy reects
emotional comprehension or the capability to recognize
another person’s emotional condition.
7,8
roughout medical school, the importance of
empathy should be emphasized, because a successful
treatment depends on an eective patient-physician
interaction; of which empathy is a critical component.
e physician who comprehends their patient on a personal
status stands a better chance of perceiving and conducting
empathy as well as healing said patient eciently than the
physician who does not have this level of comprehension.
9
It is considered that physicians should have eective
communication skills that enable them to communicate
their actual feelings or experiences to patients. Physicians
who are poor communicators and cannot manifest their
feelings properly are more prone to being misunderstood
by patients and people around them. Even though some
physicians cannot empathize properly, they may still be
able to create a suitable reaction, because they understand
how they should respond in given situations, and may
possess excellent communication skills.
10,11
Besides this,
the goal of medicine is not to simply cure the disease,
but rather to treat the patient in a holistic sense by
alleviating suering of any kind; therefore, empathy is
a key component of a physician’s clinical skills.
12
When
patients perceive that the physician understands their
conditions, they may feel more content and willing to
conde in the physician. e process of telling one’s
story can be therapeutic
13
and may also simplify the
healing process.
14,15
Finally, empathy is advantageous
to physicians as well; it reects that they can attune to
the psychosocial aspects of their patients.
16
Even though empathy is very important for a good
physician-patient relationship, previous studies have
suggested that the empathy level may decline as medical
students go through clinical training. It has, therefore,
been proposed that the course of medical education or
clinical training may impact empathy among medical
trainees negatively.
17
Furthermore, it is a challenge for
medical educators to ensure that empathy becomes a
prominent component of medical professionalism.
The Division of Medical Education, Faculty of
Medicine, Prince of Songkla University proposes nine core
competencies for medical graduates. According to these
competencies, empathy is one constituent of professional
habits, communication, and interpersonal skills.
18,19
A
prior study identied that most medical students at the
Faculty of Medicine, Prince of Songkla University used
adaptive coping strategies,
20
and when they were medical
doctors, who worked at hospitals either in the restive or
non-restive areas of the Southern ailand insurgency,
most of them were at normal levels of resilience.
21
However,
limited data concerning empathy levels are available.
In ailand, only one study on empathy levels among
medical students has been conducted in the past nine
years (2012). It found that female medical students at the
pre-clinical level had higher empathy scores than their
male counterparts that were undergoing clinical-level
training.
22
erefore, it was deemed both interesting and
helpful to study the level of empathy, and its associating
factors among ai medical students. is study provides
useful information for the establishment of educational
programs in the medical curriculum geared at enhancing
medical professionalism among medical school graduates.
MATERIALS AND METHODS
Aer approval from e Human Research Ethics
Committee of the Faculty of Medicine, Prince of Songkla
University (REC: 63-456-3-4), this cross-sectional study
surveyed all the rst- to sixth-year medical students enrolled
at the Faculty of Medicines, Prince of Songkla University,
including the Hat Yai Hospital Medical Education Center
and the Yala Hospital Medical Education Center, at the
end of the 2020 academic year. ere were 1075 medical
students, who were categorized by academic year as
follows: 192 1
st
-year, 190 2
nd
-year, 184 3
rd
-year, 174 4
th
-
year, 181 5
th
-year, and 154 6
th
-year medical students. To be
included, one had to meet the criteria of being a medical
student, aged no less than 18 years and completing all
the questionnaires in full. Meanwhile, those who were
foreign students, who declined to participate, or decided
to withdraw from the study were excluded.
Data collection
e data were collected as follows. e research assistant
approached all the medical students in class and handed
them an information sheet, which described the rationale
for the study and the allotted time to complete the survey.
ey had at least 10-15 minutes to consider whether to
join in the study or not. If they wished to participate, the
research assistant distributed the questionnaires. Adhering
to the policy of strict condentiality, the signatures of the
participants were not required, and they were informed
that they retained the right to withdraw from the research
at any time without having to provide any explanation
or reason for doing so. All participants were allowed to
nish, and return the questionnaires immediately or at
a later time. ey could submit the questionnaires via
two options drop them in the case at the front of the
classroom, or return and place them in the case located
at the Psychiatry Department, protecting respondent
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Sathaporn et al.
condentiality was retained. Furthermore, the data were
stored securely, and only the researcher could access
them via a password.
Instruments
1) The personal and demographic information
questionnaire consisted of questions related to age,
gender, religion, hometown, income, cumulative GPA,
medical school, history of substance use, physical or
psychiatric illness, and specialty preference.
2) e Toronto Empathy Questionnaire (TEQ),
which was used to evaluate empathy, consisted of 16
questions and employed a 5-point rating scale for each
question. e item responses were scored according to
the following scale for positively worded items: 0 (never),
1 (rarely), 2 (sometimes), 3 (oen), and 4 (always). e
same scale was used to reverse score negatively worded
items. e scores of all 16 questions were summed,
and they ranged from 0 to 64. Higher scores indicated
high levels of self-reported empathy, while total scores
below 45 were indicative of below-average empathy
levels. e Cronbach’s alpha coecient for this tool
was 0.85. Additionally, empathy was divided into six
subgroups; perception of an emotional state in another
that stimulates the same emotion in oneself; assessment
of emotion comprehension in others; assessment of
emotional states in others by indexing the frequency
of behaviors demonstrating appropriate sensitivity;
sympathetic physiological arousal; altruism; behaviors
engaging higher-order empathic responding, such as
pro-social helping behavior.
23
3) e ai Mental Health Indicator-15 (TMHI-15)
consisted of 15 questions. e score of each question
ranged from 1 to 4. e following scale was used to
reverse score negatively worded items. e scores of all
15 questions were summed, and the total scores, which
ranged from 15 to 60, were categorized as follows: less
than 43 (poor mental health), 44-50 (fair mental health),
and 51-60 (good mental health). e Cronbach’s alpha
coecient for this tool was 0.7.
24
Statistical analysis
Descriptive statistics; such as proportion, mean, and
standard deviation (SD), or medians and inter-quartile
ranges (IQR) were calculated. Bivariate and multivariate
analyses using logistic regressions were employed to
identify the association with level of empathy. e analyses
were conducted using R version 3.4.1 (R Foundation
for Statistical Computing). Statistical signicance was
dened as a p-value of less than 0.05.
RESULTS
Demographic characteristics
One thousand and ten rst- to sixth-year medical
students completed the questionnaires, from the total
of 1075 students, who were approached; the response
rate was 94%. e majority of them were female (59%),
Buddhist (79.1%), and the accumulative GPA was 3.4
(3.1-3.6) (Table 1). Overall, the median age (IQR) was
21 years (20-23), and the income per month was 9,000
baht (6,500-10,000). No statistically signicant dierences
in demographic data (gender, religion, and physical
illnesses) between the pre-clinical and clinical groups
of medical students were detected.
Empathy level
Using the Toronto Empathy Questionnaire, 554
participants (54.9%) reported a high level of empathy
(Table 1). e median TEQ score (IQR) of all participants
was 45 (41-49.7). The median TEQ scores (IQR) of
the pre-clinical and clinical student groups were 49
(45.8-52) and 46 (42.2-50), respectively. Of the six TEQ
subgroups, the assessment of emotion comprehension
in others, behaviors engaging higher-order empathic
responding, and altruism had the highest median scores
(IQR) (3 (2-3), 3 (2-3), and 3 (2.7-3.7), respectively),
whereas perception of an emotional state in another
that stimulates the same emotion in oneself exhibited
the lowest score (IQR) [2.5 (2-3)] (Table 2).
A statistically signicant dierence in the level of
empathy, in terms of subgroups between the groups,
was observed (P-value <0.001) (Table 1). Among the
pre-clinical medical students, the empathy subgroups
of assessment of emotional states in others by indexing
the frequency of behaviors demonstrating appropriate
sensitivity, behaviors engaging higher-order empathic
responding, and altruism had higher scores than among
those studying at the clinical level (Table 2).
Mental health
Using the ai Mental Health Indicator-15 (TMHI-
15), most participants reported fair to good mental health
(51.2% and 27.4%, respectively), and only 216 (21.4%)
respondents had poor mental health (Table 1). ere
was a statistically signicant dierence in mental health
between the pre-clinical and clinical groups of medical
students (P-value <0.001).
Concerning perceived stress, 920 (91.1%) participants
reported having experienced stress within the previous
year. e most common stresses were academic course
work and examinations (92%), learning environment
(38.9%), and living with friends (29.7%).
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TABLE 1. Demographic characteristics, mental health, and level of empathy between two groups of medical students.
Group N (%)
Variables
Total
Pre-clinical Clinical
Chi
2
(n=1010)
(n=544) (n=466)
P-value
Gender 0.103
Male 409 (40.5) 207 (38.3) 202 (43.5)
Female 596 (59.0) 334 (61.7) 262 (56.5)
No answer 5 (0.5)
Religion 0.569
Buddhism 799 (79.1) 433 (83.8) 366 (85.3)
Other (Islam, Christianity, other) 147 (14.6) 84 (16.2) 63 (14.7)
No answer 64 (6.3)
GPA: median (IQR) 3.4 (3.1-3.6) 3.6 (3.3-3.8) 3.3 (3.0-3.5) <0.001
a
Home province <0.001
Southern Region 905 (89.6) 471 (87.1) 434 (93.7)
Other 99 (9.8) 70 (12.9) 29 (6.3)
No answer 6 (0.6)
Physical illness 0.322
No 844 (83.6) 448 (82.7) 396 (85.2)
Yes 163 (16.1) 94 (17.3) 69 (14.8)
No answer 3 (0.3)
Psychiatric illness <0.001
No 947 (93.8) 527 (97.1) 420 (91.1)
Yes 57 (5.6) 16 (2.9) 41 (8.9)
No answer 6 (0.6)
Alcohol consumption 0.058
No 703 (69.6) 392 (72.7) 311 (67)
Yes 300 (29.7) 147 (27.3) 153 (33)
No answer 7 (0.7)
Substance use 1
No 999 (98.9) 540 (99.4) 459 (99.4)
Yes 6 (0.6) 3 (0.6) 3 (0.6)
No answer 5 (0.5)
Specialty preference <0.001
General / not specied 270 (26.7) 112 (20.6) 158 (33.9)
Major 491 (48.6) 291 (53.5) 200 (42.9)
Minor 249 (24.7) 141 (25.9) 108 (23.2)
Mental health <0.001
Poor 216 (21.4) 78 (14.3) 138 (29.6)
Fair 517 (51.2) 280 (51.5) 237 (50.9)
Good 277 (27.4) 186 (34.2) 91 (19.5)
Level of empathy <0.001
<45 456 (45.1) 190 (34.9) 266 (57.1)
≥45 554 (54.9) 354 (65.1) 200 (42.9)
Note: a = P-value from rank sum test
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Sathaporn et al.
TABLE 2. Subgroups of empathy.
Median (IQR)
Domain of empathy Total Pre-clinical Clinical
(n=1010) (n=544) (n=466)
Perception of an emotional state in another that 2.5 (2.0-3.0) 2.5 (2.5-3.0) 2.5 (2.0-3.0)
stimulates the same emotion in oneself
Assessment of emotion comprehension in others 3.0 (2.0-3.0) 3.0 (2.0-3.0) 3.0 (2.0-3.0)
Assessment of emotional states in others by
indexing the frequency of behaviors demonstrating 2.8 (2.4-3.2) 3.0 (2.6-3.2) 2.6 (2.4-3.0)
appropriate sensitivity
Sympathetic physiological arousal 2.7 (2.5-3.0) 2.8 (2.5-3.2) 2.8 (2.5-3.0)
Altruism 3.0 (2.7-3.7) 3.3 (3.0-3.7) 3.0 (2.7-3.3)
Behaviors engaging higher-order empathic responding 3.0 (2.0-3.0) 3.0 (2.0-3.0) 2.0 (2.0-3.0)
such as pro-social helping behavior
e association of demographic characteristics and
mental health with level of empathy
To identify factors associated with the level of
empathy, demographic characteristics, and mental health
were included in the multivariate analysis. Variables
with p-values of less than 0.2 from the bivariate analysis
were included in the initial model of the multivariate
analysis (Table 3). e multivariate analysis indicated
that females and pre-clinical level students had a higher
level of empathy than their male and clinical-level
counterparts [odds ratio 1.8 (1.36, 2.37) and 1.97 (1.49,
2.59), respectively]. Additionally, medical students who
preferred minor specialties had a higher level of empathy
than those who preferred pursuing general medicine,
[odds ratio 1.87 (1.27, 2.74)] (Table 4). e same was
true when comparing them with those who preferred
major specialties [odds ratio 1.48 (1.05, 2.1)]. A protective
factor that signicantly improved the level of empathy
was having fair to good mental health.
DISCUSSION
is study found that more than half of our medical
students (54.9%) reported a high level of empathy.
However, being female, pre-clinical level medical students,
and preferring minor specialties were associated with
having a higher level of empathy than being male, a
clinical-level student, and preferring general medicine
or major specialties. In addition, having fair to good
mental health was found to be a protective factor that
statistically signicantly improved the level of empathy
of our respondents. Comparing the level of empathy
discovered by our study with those reported by previous
studies, ours was similar to those of studies conducted
in ailand and the United States
22,25
as well as to that
of another recent systematic review of studies, which
also suggested that empathy level worsens distinctly
throughout medical school. e explication for this
might point to the clinical practice phase of training,
and the hardship generated by aspects of the “hidden,”
“formal,” and “informal” curricula as the principal causes
for the downfall in empathy level.
26
Since, according to this study’s results, most participants
(91.1%) reported having stress during the previous year and
identied medical courses or examinations (92%) as well as
learning environment (38.9%) as the most common causes
of stress, it might be plausible that medical education or
clinical training impacts empathy negatively.
17
Although
the deterioration in empathy is mainly observed as a
valid research nding,
27-29
previous systematic reviews
of studies on empathy have highlighted the diversity of
measurements available to survey empathy as well as the
point that correlations between self-reported and observed
empathy might be dierent. Hence, disagreements remain
concerning the validity of self-report questionnaires as a
precise measure of empathy results.
30,31
erefore, future
in-depth studies with a qualitative research design are
required in order to ensure the trustworthiness of the
ndings.
Empathy comprises of the cognitive, aective or
emotional domain. e cognitive domain refers to ‘the
capacity to comprehend the patient’s inner experience
and viewpoint, and an ability to communicate this
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TABLE 3. Bivariate analysis of level of empathy.
Level of empathy N (%)
Variables
Total N (%)
<45 ≥45
Chi
2
(n=1010)
(n=456) (n=554)
P-value
Gender <0.001
Male 409 (40.5) 219 (48.2) 190 (34.5)
Female 596 (59.0) 235 (51.8) 361 (65.5)
No answer 5 (0.5)
Medical training level < 0.001
Pre-clinical 544 (53.9) 190 (41.7) 354 (63.9)
Clinical 466 (46.1) 266 (58.3) 200 (36.1)
Religion 1
Buddhism 799 (79.1) 359 (84.5) 440 (84.5)
Others (Islam, Christ, others) 147 (14.6) 66 (15.5) 81 (15.5)
No answer 64 (6.3)
GPA : median (IQR) 3.4 (3.1-3.6) 3.4 (3.0-3.6) 3.4 (3.1-3.7) 0.284
a
Home province 0.09
South 905 (89.6) 415 (92) 490 (88.6)
Others 99 (9.8) 36 (8) 63 (11.4)
No answer 6 (0.6)
Physical illness 0.733
No 844 (83.6) 383 (84.4) 461 (83.4)
Yes 163 (16.1) 71 (15.6) 92 (16.6)
No answer 3 (0.3)
Psychiatric illness 0.574
No 947 (93.8) 427 (94.9) 520 (93.9)
Yes 57 (5.6) 23 (5.1) 34 (6.1)
No answer 6 (0.6)
Alcohol consumption 0.262
No 703 (69.6) 324 (72) 379 (68.5)
Yes 300 (29.7) 126 (28) 174 (31.5)
No answer 7 (0.7)
Substance use 1
No 999 (98.9) 450 (99.3) 549 (99.5)
Yes 6 (0.6) 3 (0.7) 3 (0.5)
No answer 5 (0.5)
Specialty preference <0.001
General / not specied 270 (26.7) 154 (33.8) 116 (20.9)
Major 491 (48.6) 209 (45.8) 282 (50.9)
Minor 249 (24.7) 93 (20.4) 156 (28.2)
Mental health <0.001
Poor 216 (21.4) 151 (33.1) 65 (11.7)
Fair 517 (51.2) 249 (54.6) 268 (48.4)
Good 277 (27.4) 56 (12.3) 221 (39.9)
Note: a = P-value from rank sum test
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Sathaporn et al.
TABLE 4. Factors associated with high level of empathy.
Factors
Crude OR Adjusted OR P-value
(95% CI) (95% CI) LR-test
Gender <0.001
Male Reference Reference
Female 1.77 (1.37, 2.28) 1.8 (1.36, 2.37)
Medical training level <0.001
Clinical Reference Reference
Pre-clinical 2.52 (1.95, 3.26) 1.97 (1.49, 2.59)
Specialty preference 0.005
General/ not specied Reference Reference
Major 1.78 (1.31, 2.4) 1.26 (0.9, 1.75)
Minor 2.20 (1.55, 3.13) 1.87 (1.27, 2.74)
Mental health <0.001
Poor Reference Reference
Fair 2.46 (1.75, 3.45) 2.17 (1.53, 3.09)
Good 9.27 (6.13, 14.04) 7.92 (5.14, 12.2)
comprehension’,
32
whereas, the aective domain refers
to ‘the capacity to conceive the patient’s emotions and
aspects’.
33
Concerning the empathy subgroups, this study
showed that assessment of emotional states in others by
indexing behaviors demonstrating appropriate sensitivity,
behaviors engaging higher-order empathic responding,
e.g., pro-social helping behavior, and altruism declined
when the medical students progressed to clinical-level
training. is might signify that most of our medical
students can comprehend the patient’s inner experience
as well as conceive the patient’s feelings or aspects, but
they might lack the ability to express their empathy
toward others, or that their empathy might decline with
medical training. Moreover, this study identied that
being female was associated with having a higher level
of empathy than being male. erefore, in clinical-level
training, medical students; especially the male group,
should be instructed to express empathy, which builds
patient trust, calmness, and leads to increased patient
gratication. is point should be a signicant concern
to medical educators.
It is widely accepted that eective articulation or good
communication skills on the part of physicians should
enable them to convey their actual feelings or experiences
to patients. Physicians who are poor communicators
and do not express their feelings properly might be
misapprehended by patients and people close to them.
10
erefore, many studies have tried to create a variety
of types of intervention aiming to promote empathy
competency, by employing patient narrative and creative
arts, writing, drama, and communication skills training.
34
e patient narrative and creative arts interventions
were based around the patient narrative and creative
arts; such as imaginative composition, lyric, poem,
fable, novel, and motion picture. Such interventions
t primarily into the aective dimension of empathy.
35
Regarding writing interventions, studies have used
various genres of writing to heighten empathy with
the rationale that agendas that substantiate humanistic
behavior might conduce towards the medical students’
continuance of empathy.
36
Drama interventions, using
drama to teach empathy, have undertaking the task
of training students “how to act-in-role.” e means
employed communication seminars directing the cognitive
dimension, the exercises in such studies concentrated
upon building the participants’ acting skills as a way to
heighten their capacity to impersonate empathy, and were
found to be successful in signicantly increasing their
level of empathy.
37
Finally, concerning communication
skills training interventions, the use of communication
skills training as an intervention reected the authors’
preference for the cognitive dimension of empathy. In
such studies, communication skills training consisted
of role-play and small-group interactive training.
38-40
Moreover, ndings from previous have suggested that
medical curriculums could be successful in heightening
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and keeping up empathy in medical students. Continuing
to achieve such strategies would help to further clarify
best practices, and more precise studies, particularly,
large-scale and suitably controlled longitudinal research,
is required to instruct recommendations for medical
education. Moving forward, medical education academics
and investigators should consider addressing the widely
reported phenomenon of the deterioration in empathy
among medical students by focusing on psychological factors;
such as, exhaustion and stress, the “hidden curriculum”,
uncertain study setting, loss of enthusiasm, and the
perceived need for detachment. Noteworthy, is also the
need to highlight the prominence of role models and the
reciprocal nature of empathy improvement in training;
this suggests that “Indeed, perhaps students need to obtain
more empathy from their faculty, other physicians, and
even their patients before they can comprehend how to
establish empathic connections”.
41
Additionally, mental health includes having
healthy self-esteem, being satised with life, feeling
secure, having the sense of ‘appointment in life,’ being
condent in emotional control, being empathetic and
happy when helping others, and acknowledging or
accepting problems that are dicult to solve.
24
is
study indicated that good mental health was a protective
factor that signicantly improved the level of empathy.
us, medical educators should consider practicing
relationship-centered care, promoting good mental
health, preventing the negative impacts of stress, fatigue,
burnout, poor sleep quality,
42
and identifying the hidden
curricula or mistreatment suered by medical students
43
as the fundamental building blocks medical of education.
is could help foster the creation and powerful expression
of empathy, which builds patient trust, calmness anxiety,
leads to fewer mistakes, increases patient satisfaction,
and improves health outcomes.
Strengths and limitations
is study had a few noteworthy strengths and
limitations. To our knowledge, this is the rst study with
a high response rate (94.0%) that explored the level of
empathy and mental health as well as factors associated
with empathy among ai medical students. However, it
was a cross-sectional survey, lacked baseline measurements
and long-term follow-up, as well as which it utilized self-
administered questionnaires. Some misunderstandings
regarding the intended meaning of the questions might have
occurred. Nevertheless, to minimize this, questionnaires
with good reliability were utilized (good Cronbach’s
alpha coecient values). Other drawbacks were that
our data were quantitative, and the sample size was
limited to medical students enrolled at only one faculty
of medicine. Hence, this dataset may not fairly represent
the situation of all ai medical students in the faculties
of medicine countrywide.
Henceforward, studies are recommended to include
all medical students from all faculties of medicine in
ailand. In other words, a comprehensive multi-center
study should be conducted. Moreover, future research
should concentrate upon the denite attributes that
inspire a student to be more responsive to dierent
interventions, utilize more qualitative designs, employ
longitudinal surveillance or long-term follow-up, and
include control groups.
CONCLUSION
More than half of the surveyed medical students
reported a high level of empathy. ose who were female,
in the pre-clinical level of studies, and preferred a minor
specialty had a higher empathy level than those who were
male, studying at the clinical level, and preferred general
medicine specialties. e protective factor that improved
the level of empathy was good mental health. However,
future qualitative methods, longitudinal surveillance,
or long-term follow-up designs focusing on medical
students’ empathy are to ensure the trustworthiness of
these ndings.
ACKNOWLEDGMENTS
is project was endorsed by the Human Research
Ethics Committee, and fully funded by the Faculty of
Medicine, Prince of Songkla University (REC: 63-456-
3-4). e authors gratefully acknowledge the invaluable
contributions of the Student Aairs Division, Undergraduate
Education Division, and Medical Education Division of
the Faculty of Medicine, Prince of Songkla University
as well as of Ms. Kruewan Jongborwanwiwat and Mrs.
Nisan Werachattawanand regarding the collection of
data and statistical analysis. Moreover, we genuinely
appreciate the Department of International Affairs,
Faculty of Medicine, Prince of Songkla University for
their assistance in editing the manuscript.
Conict of interest: e authors declare no conict of
interest.
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Review Article
SMJ
Mohammad Ahmad Abdalla, Ph.D.
Department of Human Anatomy, Tikrit University College of Medicine, Tikrit, Iraq
Melasma Clinical Features, Diagnosis,
Epidemiology and Etiology: An Update Review
ABSTRACT
Melasma is one of the commonest dermatological challenges that facing dermatologists in the whole world.
Most of the previously published articles regarding melasma usually focused on its management and the newly
discovered drugs; however, the understanding of the suspected etiology and the pathogenesisis very critical to treat
this skin disorder in a correct manner. erefore, this review is an attempt to do a comprehensive updating on
the present understanding of the melasma epidemiology, etiology, its role in pregnant, post-menopausal women,
and in males, besides its clinical features and diagnosis through searching in many scientic databases including
EMBASE, Cochrane Library, PubMed, Pubmed Central (PMC), Medline, Web of Science, and Scopus.
is review approaches recognizing the pathogenesis that can provide ideas to solve the therapeutic problems
which connect to melasma. erefore, this article is entirely established on previously performed studies so that no
new studies on animal or human subjects were conducted by the author.
Keywords: Melanin; melanocortin; melasma (Siriraj Med J 2021; 73: 841-850)
Corresponding author: Mohammad Ahmad Abdalla
E-mail: dr.mohammad68@tu.edu.iq
Received 12 September 2021 Revised 28 September 2021 Accepted 13 October 2021
ORCID ID: https://orcid.org/0000-0001-8122-3692
http://dx.doi.org/10.33192/Smj.2021.109
INTRODUCTION
Melasma is one of the common acquired
hyperpigmentation conditions, mostly aects the face,
with a high prevalence among females and the darker skin
phenotype individuals.
1
Many etiologies, including family
history, hormonal inuence, and sunlight exposure, have
been involved in its pathogenesis.
2
e overall prevalence
reports wide ranges (1-50) %, because the values are
usually determined in a particular ethnic group within
a specic geographical area.
3
Histologically, melasma
may reveal enlarged melanocytes, increased dermal or/
and epidermal pigmentation, increased melanosomes,
dermal blood vessel, solar elastosis, and rarely perivascular
lymphohistiocytic inltrations.
4
Methodology
Melanogenesis
Melanogenesis is a process that occurs inside the
melanosomes. ere are two forms of melanin pigments
are produced within the melanosomes; pheomelanin and
eumelanin. Pheomelanin is a soluble sulfur-containing
bright red-yellowish polymer, while eumelanin is an
insoluble dark brownish-black polymer.
5
Tyrosinase is a
copper-containing enzyme; however, before tyrosinase can
act on tyrosine two cupric atoms present in tyrosinase must
be reduced to cuprous atoms. Tyrosinase is responsible
for the rst 2 stages in the synthesis of melanin; the
L-tyrosine hydroxylation into L-dihydroxyphenylalanine
(L-DOPA) with the following stage of oxidation for this
o-diphenol into the related quinone (L dopaquinone).
6
It
is worth noting that the L-tyrosine concentration required
for melanogenesis is determined by the conversion of
L-phenylalanine which is an essential amino acid through
the action of the intracellular enzyme phenylalanine
hydroxylase (PAH). e L-phenylalanine signicance in
melanogenesis is elucidated in phototypes of the skin I-VI
as the epidermal PAH actions are linearly correlated.
7
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842
Following the dopaquinone synthesis, the melanin
pathway is split into the synthesis of red-yellowish
pheomelanin and brownish-black eumelanin with
spontaneous conversion into dopachrome and
leucodopachrome. In the eumelanin formation pathway,
the dopachrome consider as either spontaneously
transformed into 5, 6-dihydroxyindole or it is enzymatically
transformed into 5, 6-dihydroxyindole-2-carboxylic acid
via dopachrome tautomerase (DCT), besides pointed out
as tyrosine-related protein-2 (TRP-2). e tyrosinase-
related proteins are of two types, TRP-1 and TRP-2 that
are structurally associated with tyrosinase.
8,9
TRP-1 and TRP-2 are melanosomal proteins that
extend to the membrane of the melanosome like tyrosinase.
ere is a suggestion that TRP-1 elevates the eumelanin
to pheomelanin ratio. Also, they may be explaining the
high tyrosinase stability. Ultimately, the quinones and
indoles polymerization results in eumelanin synthesis.
10
e pathway of pheomelanin branches from that of
eumelanin at the step of L-dopaquinone and it depends
upon the cysteine existence that shows active transporting
through the membrane of melanosomes. e L-dopaquinone
interacts with cysteine to produce cysteinyl-dopa, which
is then converted into the quinoleimine and alanine-
hydroxyl dihydrobenzothazine that polymerized to
pheomelanin. Besides, the tyrosinase enzyme may be
indirectly triggered by the tyrosine hydroxylase isoenzyme
1 (TH1) which exists in the melanosomes that catalyze
L-dopa formation. In turn, the latter L-dopa may play
a role as the tyrosinase substrate.
11
Redox (Reduction Oxidation Reaction) status
within melanosomes is important for the equilibrium
between the pheomelanin and eumelanin synthesis.
is pheomelanin or eumelanin synthesis is directly
aected by the glutathione (GSH) level, the low GSH
level related to pheomelanin, and the high related to
eumelanin. erefore, the functional and expressional
activities of the antioxidant enzymes like glutathione
reductase, glutathione peroxidase, thioredoxin reductase,
and catalase are most likely modifying the melanosomes
pathway.
12
Each melanocyte that establishes at the basal layer of
epithelium together with its dendrites reacts with about
thirty-six keratinocyte cells to transmit melanosomes
and cause skin protection from the ultraviolet radiation
and photo-stimulated carcinogenesis. Besides, the type
and amount of melanin synthesized and transferred
into the keratinocyte cells with successive aggregation,
incorporation, and degradation aects the epidermis
coloration.
12
The ratio of eumelanin to pheomelanin varies
dramatically in the various skin phenotypes, found at
the lowest level in type I and II and highest in type V
and VI; and these types are:-
1. Type I :- (score ranges 0-6) never tans, always
burns (pale white; red hair or blond; blue eyes; with
freckles).
2. Type II :- (score ranges 7-13) minimally tans,
usually burns (white; fair; red hair or blond; hazel, green
or blue eyes).
3. Type III :- (score ranges 14-20) uniformly tans,
sometimes mildly burns, (creamy white; fair; with any
eye or hair colour).
4. Type IV :-(score ranges 21-27) always tans,
minimally burns (moderate brown).
5. Type V:- (score ranges 28-34) very easily tans,
very rarely burns (dark brown).
6. Type VI:- (score ranges 35-36) never tans, never
burns (deep pigmented darkish brown to darkest brown).
13
Fig 1. Melanin synthetic pathway
5
Abdalla.
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Review Article
SMJ
Melasma
e term “facial hyperpigmentation” or “melasma”
is obtained from the Greek word “melas”, meaning
“black”. It also refers to “chloasma gravidarum” or “the
pregnancy mask”. Its onset starts commonly during
the 2
nd
half of gestation, and it exists in 40-75% of all
pregnancies. It occurs usually in dark hair, brown eyes,
and dark-epidermis women. e main variations of
melasma prevalence in various studies were accredited to
the proven fact that explaining the pigmentary alterations
are more visible in individuals with fair skin.
14
Melasma commonly inuences the principal photo-
exposed skin regions, particularly the facial and neck
areas. e commonly involved sites include the cheeks,
chin, forehead, nose, upper lip, and temples; while the
rarely involved sites may distress the sternal region and
extensor arms. However; this condition considers as a
benign disorder that usually with aesthetic implications
only, but it can inuence the self-esteem and self-image,
with negative eects on an individual’s life quality.
15
Clinical features of melasma
Melasma is localized at sun-exposed regions, where
symmetrical light or dark brownish conuent macules or
punctate are present, most sharply delimited, particularly
on the cheeks, forehead, chin, and upper lip. ere are three
kinds of melasma lesions; centrofacial type (implicates
cheeks, forehead, nose, chin, and upper lip), mandibular
type (over the mandibular ramus), and symmetrical
malar type (localized to nose and cheeks).
8,12,16
In male
individuals, the malar type is the commonest, while the
centrofacial is the common type revealed in females.
Wood’s lamp may clinically divide the pigmentation
depth; in the epidermal type may be shown highlighting
multiple pigments in (50%) of cases, compared to dermal
type (5%), were not.
17
While the mixed type in (45%) of
all cases just a partial pigmentation highlighting is found.
Clinically, the dermal type becomes mildly visible bluish
because of the Tyndall eect. e disease severity may
be objectied with Melanin Index (MI) estimated by
specic tools, Melanin Area and Severity Index (MASI)
determining the regions and densities of involvements,
with patient self-evaluations.
18,19
Extra-facial melasma includes many features such
as irregular, hyperchromic, symmetrical discolorations
at the neck, cervical, sternal areas, arms, forearms,
and eventually at the back. It aects the upper limbs
predominantly among old adults, menopausal women,
and those receiving hormonal replacement therapy.
20
Diagnosis of Melasma
1. Melasma examination under normal light
e skin of melasma lesion is inspected by natural
solar radiations, the macular lesions have irregular, quite
sharply demarcated borders with a “stuck on” appearance
e hypermelanosis type can be epidermal (brownish),
a dermal (bluish-gray), or a mixed (brownish-gray).
7,21
2. Wood’s lamp examination
is procedure used to evaluate the melasma
clinical status, depending upon Wood’s light (320-400
nm) and four types of melasma can be recorded:-
A. e epidermal type: has increased melanin
in suprabasal, basal, and stratum corneum layers. e
pigmentary lesions are emphasized with Wood’s light.
B. e dermal type: does not show enhancement
with the Wood’s light. Melanophages exist in the deep
and supercial dermis.
C. The mixed type: the dermal and epidermal
pigment type that shows no or slight enhancement with
the Wood’s light.
D. Wood’s light unapparent is seen in dark individuals.
As the Wood’s lamp was utilized to determine
the melanin pigment situation either in the dermis or
epidermis (i.e. dermal versus epidermal melasma), the
histopathological and confocal microscopy reports
revealed that it is usually a mixture from the two types
in the same patient even they have only epidermal type
by Wood’s light.
8,9,17,22
3. Hormonal assay
e hormonal level assessments can be guaranteed
because of the activity of hormones imbalance in melasma
disease. FSH, LH, MSH, progesterone, thyroid, and prolactin
hormones level must be estimated, just if indicated.
23,24
4. Microscopic histopathology
Melasma may be clinically diagnosed; however,
the histological report may be also helpful. e histological
ndings are the same in both males and females. Furthermore,
the histopathological features of melasma in males are
still unclearly dened. ese features include attening in
the rete ridge, solar elastosis, and mild inltrations of the
inammatory cells.
25
e amount of melanin is raised in
the dermis or epidermis or even in both. In the epidermis,
it presents in the keratinocyte cells of suprabasal and basal
layers. e number of melanocyte cells is not increased
but these cells are larger in size with more dendrites,
greater melanosomal size, and; therefore, more activity
will be produced. Dermal melanin amount increased in
the middle and supercial dermis in macrophage cells,
usually in aggregation at areas nearby the small dilated
blood vessels. The epidermal melanization with the
existence of melanophages at papillary dermis may be
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revealed in Fontana-Masson and Haematoxylin-Eosin
staining.
26
ere is no proof of degeneration in the basal
layer was recorded. Signicantly elevated expressions
for Stem Cell Factor (SCF) allover broblasts in the
dermis with its C-kit receptors at the epidermal basal
layer were present in diseased skin in comparison with
non-diseased.
27
Several special stains are present that facilitate
the light microscopic visualization of melanocytes and
their products including; silver stain, dopa reaction, and
Fontana-Masson. Histologically, two types of pigmentation
had been characterized, dermal and epidermal.
11
Epidermal melasma appeared to be the most
predominant type proceeded by mixed type. While
melasma has classically been classied as epidermal- or
dermal-based on the presence or absence of Wood’s
light enhancement, respectively, most cases show both
epidermal and dermal melanin. Dermal melanophages
are a normal nding in sun-exposed skin.
17,22
Increased melanophages may also recognize
in several melasma individuals by reectance confocal
microscopy (RCM) examination. Interestingly, RCM
examinations revealed that the topographic distribution
of the melanophages is very diverse from one lesional
area to another and also within the same lesional area.
ese ndings supposed that histological classications
(dermal, epidermal, and mixed) regarding the depth of
the pigment utilizing a single specimen of skin biopsy can
be very risky. A reliable classication could be dependent
upon the dermal/epidermal melan in ratio present over
the entire involved skin area. Until nowadays, it is not
clear, if the origin of dermal pigments comes from
the epidermal layer. Besides, it is unclaried if dermal
pigments may be resolved spontaneously when they are
not supplemented from epidermis. In darkly pigmented
individuals (e.g. those with indeterminate melasma), a
skin biopsy is occasionally performed before treatment
is initiated.
6,28-32
5. Electron microscopy
It shows high amounts of melanin within all layers
of the epidermis and also within the dermis, according
to the melasma histological type. Also, the numbers of
melanocyte cells included the high numbers of melanosomes
compared to melanocyte cells of the normal skin is high.
It may reveal the increased melanosomes were associated
with ndings of many organelles in the melanocyte cells
from the diseased lesions. e melasma lesions included
more Golgi apparatus, mitochondria, rough endoplasmic
retinaculum, dendrites, ribosomes, and supposing more
production ability of those cells.
33,34
6. Immunohistochemistry
It may show high expression for stem cell factor
in the dermal layer and for c-kit in epidermal layer with
high expression for vascular endothelial growth factor,
which can be the main factor achieved in the changed
blood vessels occurs in melasma.
27,35-37
7. Dermoscopy may play a principal role in melasma
diagnosis and in demonstrating the melanin pigment
deposition level. e main ndings include pigmented dots,
globules, more prominent vascularity, and telangiectasia.
Also, the accentuation for the pseudo-reticular pigmentary
network and Owl’s eye structures exist. In addition,
dermoscopy can be used in the assessment of melasma
severity.
38,39
Epidemiology of melasma
Although melasma may inuence individuals from any
race, it is usually common among darker skin phototypes
and the commonest in persons with Fitzpatrick IV-VI
skin types.
4
In a random study including self-recording for
melasma among Hispanic female individuals, it reported
that the incidence about 8.8% but the previous incidence
was 4%. A survey among Arab Americans who lived in
the USA mentioned that the h commonest skin disease
was melasma with 14.5% from a surveyed population,
12
while another study screened 200 persons with melasma
found men demonstrated 20.5%.
20
Another published
article reported the results of three studies that estimating
the incidence of melasma among adult males of Latino
laborers with 36.0%, 7.4%, and 14%.
11
e average age in
aected males was 33.5 years and the duration was about
3.5 years; however, it may be present also among older
males and for more periods.
9
It may cause embarrassment
in men due to its awful-looking; and a general community
stigma that classied it as a disorder or disease when aects
pregnant women. It was recorded that its prevalence
up to 75% among pregnant women, but it exists rarely
before puberty and; therefore, it most commonly starts
in the reproductive years of life.
40
Melasma has recognizable psychological inuences
and signicant emotions on aected individuals. e
eect on the life quality of individuals with melasma
may be standardized by the Melasma Quality of Life
Scale (MELASQOL) or/and by the Dermatology Life
Quality Index (DLQI); the individuals who have high
DLQI scores signify poor Quality of Life (QOL).
18
Etiology of melasma
e exact causes of melasma have not been dened,
Abdalla.
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Review Article
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but numerous factors are possible to be suspected
including genetics, pregnancy, cosmetic use, sun exposure,
antiepileptic medications, oral contraceptives, and thyroid
dysfunction.
41
Among these factors, the following are
the most important:-
1. Risk Factors
e precise melasma cause is still undetermined;
even numerous factors may be involved in this lesion’s
pathogenesis. ese factors are implicated as etiologic or
genetic predispositions and inuences, in approximately
40% of melasma individuals there is one relative at least
aected with this lesion.
4
Other factors inuencing the
onset or/and triggering its onset including hormonal
alterations during gestation or hormonal therapy,
exposure to UV radiations, phototoxic drugs, cosmetics,
chemicals, steroids, antiseizure therapy, and darker
skin colorations.
32,42,43
Psychotropics and anxiety traits
may be strongly related to melasma development; so
that melasma is regarded as “the stress mask”. All the
previously mentioned factors are suggested to cause an
increment in both melanocytosis and melanogenesis, the
primary histological disturbances revealed in melasma.
Furthermore, although its pathogenesis is unknown yet,
the above factors are considered to trigger the disease in
a population with genetic predispositions. Study of those
factors may urge physicians to get better improvement
for preventative measures, management of melasma
individuals, expectation treatment result, and disease
recurrence.
20
e lesion onset is usually proved by deteriorated
stratum corneum layer integrity with the overdue barrier
recovery period, while a high amount of different
inammatory cells that exist in the lesional region are
the common ndings distinguished during melasma
development in Asian population skin.
10
2. Endocrine factors
e levels of hormones either because of hormonal
therapy or during pregnancy periods are regarded to be
one of those most inuencing factors or even the most
remarkable factor on the onset and melasma development.
During pregnancy, endocrine, immunologic, vascular,
and metabolic alterations increase the susceptibility of
pregnant women to obvious alterations in the skin with its
related appendages.
44
Progesterone, estrogen, and alpha-
MSH which are commonly elevated during pregnancy
time and especially at third trimester, are supposed to
stimulate the melasma onset by for example through
estrogen tentative pathway III that causing increase
tyrosinase enzyme and melanosome transfer (Fig 2). Even
with the multiple and various cases that found, no high
levels for the mentioned hormones proved. However,
several researchers believed that hormonal changes with
increased Luteinizing Hormone (LH) and decreased
estrogen levels, as a result of ovarian dysfunctions, can
underlie the pathogenesis process in some conditions
of the idiopathic melasma.
16,22,24
Fig 2. Tentative pathway III of the estrogen
25
In addition to pregnancy, women taken contraceptive
pills with progesterone or women at the post-menopausal
period taken progesterone as hormonal therapy, the
extra-facial melasma was usually common among them,
therefore; the progesterone regarded as a principal factor
in this disease. Impressively, the hyperpigmentation
resulted from sequential or combined contraceptive pills
are incompletely regressing aer ceasing, contrary to
melanoderma of pregnant women. Researchers; however,
have mentioned that estrogen receptors and progesterone
receptors expression at melasma-aected regions need
more investigations and clarications, these researches
can cause better development for the topical anti-estrogen
therapy of melasma.
7,19,45
e thyroid autoimmune characteristic is also regarded
as another important element in the melasma onset
because a signicant number of Hashimoto’s diseased
women get melasma and also those women who get
the disease during pregnancy, will or even already have
thyroid autoimmunity.
28
Finally, other factors have been involved having the
main role in melasma development, like melanocytic nevi
and lentigines. Although, the presence of these factors
is not very closely connected to the disease onset and its
development, like the previously mentioned factors; on
the other hand, melasma is usually revealed in women,
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846
some articles have been done on men with melasma. In
those articles, the most remarkable factors indicated for
melasma development are regarded to be the usage of
cosmetics, sunlight exposure, familial hyperpigmentation,
hepatic disorders, and infections.
9,11,21,46-48
Even there are
a few studies that suggest the circulating LH is crucially
increased in melasma men, while testosterone is remarkably
decreased in the very same category, information that
assumes that melasma can implicate precise testicular
resistance.
4
3. Genetic factors
e skin phototypes III, IV, and V with the
female gender regarded as the most recognized genetics,
other inheritable characters, probably multi-genetic.
One of the most important international researches in
this scope was carried out in dermatological centers of 9
countries (USA, Germany, France, Mexico, Netherlands,
Singapore, Italy, Hong Kong, and South Korea) and
exhibited that 48% from 324 melasmic females had a
positive familial history of this disease. Also in about 97%
of total cases, another family member from the rst degree
of relativity is aected.
48
Epidemiological information in
this consideration may seriously dier in other countries
individuals: the prevalence of positive familial history
recorded in literature are 70.3% in male individuals and
56% in female individuals in Brazil,
40
54.7% in Iran,
23
33% in India.
49
Although scattered and occasionally not
implicating large patient’s sample, these articles that
reveal important variations even between individuals
living in the same environmental situations, suppose
that the susceptibility to melasma lesion is polygenic and
might be also aected by the epigenetic modulations of
melanogenesis. A study reported that expression of 16
microRNA (miRNA) could dier between the melanocyte
cells managed with (forskolin and solar-stimulated UV
radiation) from untreated melanocyte cells; one of those
miRNAs, known as miR-145, was remarkably down-
regulated and also capable of aecting the expression of
some main pigmentary genes (Tyr, Trp1, Rab27a, Sox9,
Mitf, Myo5a, Fscn1).
50,51
4. Sun exposure
e most principal and obvious environmental
stimulating factor for melasma is sunlight exposure.
Among the various constituents of sunlight, UV radiation
(A and B) has the main role; since they may induce or
increase melanogenesis, migration directly, and melanocyte
proliferations, but even indirectly, through triggering the
formation of endothelin 1, interleukin 1 (IL-1), ACTH,
and α-MSH by keratinocyte cells.
52-54
e major role for the visible and the infrared
radiation in the melanogenesis process is less remarkable,
but not negligible; an association between occupational great
exposure to the heat or the intense articial lighting and
exacerbation of melasma or/and low react to management
was recorded by several researchers.
4
e indirect proof
for the eect of the visible light revealed that the sunscreen
compounds causing absorption for ultraviolet irradiations,
and also the visible light reinforces the depigmentation
eect for hydroquinone further than the sunscreen that
blocks UV radiation only.
32,55
e UV light is regarded as another important
agent or factor that has a specied and proven role by
multiple previous studies and also case reports.
12,13,39
e UV light is not regarded to be capable to develop
melasma without any hormonal changes or genetic
predispositions, but it is supposed to be essential in
stimulating the lesion when the background presents.
Apart from the genetic predispositions, autoimmunity
and systemic disorders are highly associated with the
development and appearance of the lesion. Systemic
disorders like Addison’s disease could almost always be
doubtful and required exclusion in the clinically relative
cases.
22,28
5. Drugs
Melasma-like pigmentation has been noticed in
individuals taking antiepileptic drugs like phenytoin or
mephenytoin. Chlorpromazine and related phenothiazines
may induce pigmentations at sun-exposed parts of
skin especially those who received high doses for long
periods. Other drugs include anti-tumor agents like
cyclophosphamide, bleomycin, and adriamycin.
4,7,56,57
In order to induce skin hyperpigmentation,
sometimes even more than a single mechanism is
involved. The tetracycline especially minocycline,
tricyclic antidepressants particularly imipramine and
desipramine, antimalarials, cytotoxic drugs, phenothiazines
mostly chlorpromazine, amiodarone, anticonvulsants,
sulfonylureas, and clofazimine are all could be listed as
the drugs stimulating hyperpigmentation. Clofazimine
stimulated pigmentations is a brown color, claried in
sun-exposed regions, sometimes unrecognizable from
melasma. In most cases, those lesions are accompanied by nail
involvement. e xed drug eruption considers as a clinical
distinctive kind of drug-stimulated hyperpigmentation
presented by recurrent plaques in the same situations.
It more frequently implicates genitalia, acral areas, and
the lips. Many medications may develop this disease,
but the greatly remarkable are sulfonamides, ibuprofen,
and barbiturates.
8,10,39,41,58,59
Abdalla.
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6. Cosmetic
ese include a wide variety of perfumes, soaps,
creams, powders, shampoos, that contain psoralen, tar
derivatives, or hexachlorophene substance which are
photodynamic that may cause facial pigmentation.
45
However, the pigmented cosmetic dermatitis
consider as a variant of the pigmented contact dermatitis
because the cosmetic ingredients are the primary allergens
where the face is predominantly involved. Clinically, the
patchy or diuse brown hyperpigmentation presents
over forehead and/or cheeks or the entire face making
it hardly dierentiate from melasma.
60
7. Idiopathic
Most cases among males and at least one-third
of all cases among females are idiopathic.
18
Melasma in pregnancy, post-menopausal women, and
oral contraceptives role
During pregnancy, particularly in the third trimester,
females have elevated levels of pituitary, ovarian and placental
hormones, which exhibit a trigger for melanogenesis
that can describe the relations between pregnancy and
melasma.
23
High levels of progesterone, estrogens, and
MSH also cause an increment in the transcription of
dopachrome and tyrosinase tautomerase that can be
implicated in developing pigmentations in this specic
period.
61
ose ndings suggest that melasma lesions in
pregnant women are more possible to be related to the
circulated female hormone than the MSH peptides. In
fact, the high levels of progesterone, which occurs during
pregnancy; and the estrogen formation, which takes
place from the 8
th
till the 31
st
week of gestation mirrors
the perfect progressive patterns of hyperpigmentation.
In melasma, the major role of female hormone onset is
proposed by its increased incidence in women getting
exogenous progesterone or/and estrogen and its association
with the menstrual period.
4,11
e onset of melasma mostly happens during the
2
nd
half of pregnancy and it may be present in 40-75%
of all pregnancies.
23
On contrary, a study done on 324
women who managed melasma disease in nine dierent
clinics worldwide, recorded the melasma onset in 25%
of females aer using the OCP, in 27% of females during
gestation, and in 41% of females aer gestation.
48
Melasma continues aer gestation among less than
10%, though a single study report existence in about 30% of
cases aer ten years. If the melasma continues postpartum,
some females notice a premenstrual hyperpigmentation
are. Regarding that UV exposure triggers up-regulation
of melanocyte cells and their activity in the pathogenesis
of melasma, susceptible females could be recommended
to protect unavoidable heavy sunlight exposures and
guarantee preservation with broad-spectrum (UVB and
UVA) sunscreens and suitable clothing.
32,54
As the female sex hormones that exist within OCP
show to be principal for melasma development, the same
association could be expected in postmenopausal females
on Hormone Replacement Therapy (HRT). Indeed,
there are some case reports for melasma present in the
postmenopausal. Melasma in the forearms appears to
be a comparatively common sign particularly in old age
individuals and postmenopausal females using estrogen
therapy supplementations. As several of those persons
had melasma in the face when young that may explain
the presence of people with estrogen-sensitive melanocyte
cells in forearm skin that show maturation at an older
age.
8,9,12,25
Tamoxifen considers a Selective Estrogen
Receptor Modulator (SERM) and spends mixed estrogenic
with antiestrogenic actions depending upon the tissues
and cell types.
57
Melasma in male
Some articles of melasma developing in men were
available; in 1957, the rst recorded male melasma case
was in a French primary hypogonadism man, presented
with low testosterone level and high FSH and LH.
62
Similarly, another study was done on een Indian men
who had idiopathic melasma, characterized by a low level
of testosterone and high level of LH in comparison with
same age controls; the estrogen level was undetected.
20
In another study, a melasma case aer oral therapies
with triggers for production of testosterone, a compound
containing indole-3-carbinol, androstenedione,
dehydroepiandrosterone (DHEA), and Tribulus Terrestres,
which is a gonadotropic trigger that elevates LH secretions.
39
Melasma and the pituitary gland
e melanocortins produced from intermediate lobe
of the hypophysis gland, they regarded as a group of peptide
hormones important for melanogenesis that activate the
formation and release of melanin by melanocyte cells
situated at skin and hairs. e melanocortins contain three
dierent kinds of MSH (α-MSH, β-MSH, and γ-MSH) with
ACTH; all of them are obtained from a similar precursor,
the proopiomelanocortin prohormone (POMC), which
secretions are stimulated by the Corticotropin-Releasing
Hormone (CRH) created within the hypothalamus.
4,52
In humans, ACTH and α-MSH are also created
regionally in skin (both within keratinocyte and melanocyte
cells) and have main roles in pigmentation, probably
via autocrine or/and paracrine mechanisms. e CRH
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848
expression with CRH receptors found in the normal
human melanocyte, melanoma, and nevus cells. e
plasma immunoreactive β-MSH measured for individuals
with/without melasma getting progesterone alone or
a combination of estrogen-progesterone therapy; the
β-MSH level was indierent from gender and age-matched
control group.
7,12,53
It is essential to recognize melasma that is located
mostly on the face and less considerably on neck or
forearm, from the generalized hyperpigmentation due to
some adrenal or pituitary disorders causing high levels
of MSH and POMC-obtained ACTH with subsequent
universal skin hyperpigmentation. The individuals
inuenced by major adrenal insuciencies, ACTH-
depending Cushing’s and Nelson’s syndromes, diagnosed
by increased POMC-obtained ACTH levels.
4,7,22,56
CONCLUSION
Melasma is a clinical condition caused by multiple
factors and etiopathogenetic mechanisms that are required
in order to understand more eective management. e
discovery of recent pathways and pathogenic mechanisms
is essential in collocation the way for recent more eective
melasma treatment agents or procedures. e pathogenic
melasma mechanisms might be heterogeneous in various
ethnic groups among the population. is review approaches
toward recognizing the pathogenesis that can provide
ideas to solve the therapeutic problems that connect to
melasma. erefore, this article is entirely established
on previously performed studies so that no new studies
on animal or human subjects were conducted by the
author.
ACKNOWLEDGMENTS
e author would like to thank Tikrit University
College of Medicine (TUCOM) for its technical and
editorial assistance.
Conict of interest: None declared.
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