Volume 72, Number 2, March-April 2020
Siriraj Medical Journal
SMJ
ISSN 2629-995XE-ISSN 2228-8082
ORIGINAL ARTICLE
95
An Appraisal of Totally Implantable Venous Access Devices
in Pediatric Cancers
Wison Laochareonsuk, et al.
103 Incidental Malignant Lymphoma and Lymphoproliferative
Disorders in Lymph Node Dissection Specimens during
Tumor Removal in Various Organs
Sanya Sukpanichnant, et al.
109 Effectiveness of Back Exercise and Education for Lower
Back Pain Prevention among Nurses at a Tertiary Hospital
in Bangkok, Thailand
Thanapol Chaiprateep, et al.
117 Treatment Outcomes of Advanced Stage Endometrial
Carcinoma (Stage III-IV) and Related Factors
Jesada Wutitammasuk, et al.
125 Pediatric Neuromuscular Diseases Prevalence in Siriraj
Hospital, Thailand's Largest Tertiary ReferralÊHospital
Apirada Thongsing, et al.
132 Long-Term Outcomes of Group-Based Treatment for
Obese Children and Adolescents
Prakasit Wannapaschaiyong, et al.
140 Effect of a Goal Attainment Nursing Program on
Self-management and Blood Pressure Control in High-risk
Hypertensive Patients in a Primary Care Unit
Chontida Ladee, et al.
151 Factors Influencing the Occurrence of Hand Foot and
Mouth Disease Among Children in Day Care Centers in
Northern Thailand
Siriyaporn Khunthason
159 Associated Factors of Subtherapeutic Serum Magnesium
Level for Prevention of Eclampsia in Term Pregnant
Women with Severe Pre-eclampsia
Vitaya Titapant, et al.
167 Increase in Endothelin-1 Expression in Umbilical Cord
Arteries in Preeclampsia
Ghasak G. Faisal, et al.
174 Association of Oxcarbazepine-induced Cutaneous Adverse
Drug Reactions with HLA-B*15:02 Allele
Pramote Euasobhon, et al.
REVIEW ARTICLE
181 The First Robotic Bariatric Surgery Performed in Thailand
- Surgical Techniques and Review of the Literature
Voraboot Taweerutchana, et al.
188 Effectiveness of Herbal Medicine in Renal Lithiasis:
a Review
Alejandro Felipe González, et al.
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International Association of Surgeons
Gastroenterologists & Oncologists
Thailand Chapter
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By Voraboot Taweerutchana, et al.
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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)
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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)
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95
Original Article
SMJ
Wison Laochareonsuk, M.D.*, Kaimook Boonsanit, M.D.*, irachit Chotsampancharoen, M.D.**, Surasak
Sangkhathat, M.D., Ph.D.*
*Department of Surgery, **Department of Pediatrics, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla 90110, ailand.
An Appraisal of Totally Implantable Venous Access
Devices in Pediatric Cancers
ABSTRACT
Objective: To appraise the experience of a pediatric cancer center in ailand regarding employment of totally
implantable venous access devices (TIVAD).
Methods: e records of consecutive patients aged less than 15 years diagnosed with malignancy and underwent an
implantation from the years 2010 to 2018 were reviewed with the main focus on eective duration and complications
of the device. Changes in our practice in perioperative care were also reviewed.
Results: A total of 150 lines in 144 patients (103 hematologic malignancies and 41 solid tumors) were included
with average age 6.4 years. Neck vein access was used in 62 lines, subclavian vein access in 88 lines. e median
follow-up period was 973 days. Immediate complications occurred in 13 cases (9.4%). Excluding cases with death
from unrelated causes, the overall TIVAD survival was 985.1 days while event-free device survival was 797.6 days.
In cases of hematologic malignancies, which were the main users, 1000-day overall survival and event-free survival
of TIVAD were 83.7% and 78.2%, respectively. Catheter-related infections and mechanical obstruction were the 2
most prevalent problems, occurring in 0.20 and 0.08 events/1,000 catheter days, respectively. Infection occurred
in 23 patients and gram-negative bacilli were most common. Moreover, subclavian access was signicantly related
with infectious complications when compared to the neck vein approach.
Conclusion: A TIVAD can be used for chemotherapy longer than 3 years without serious complications. Renement
of surgical techniques and improving care process may improve the longevity of the line.
Keywords: Totally implantable venous access device; longevity; complications; pediatric cancer (Siriraj Med J 2020;
72: 95-102)
Corresponding author: Surasak Sangkhathat
E-mail: surasak.sa@psu.ac.th
Received 15 October 2019 Revised 6 December 2019 Accepted 23 December 2019
ORCID ID: http://orcid.org/0000-0003-3622-3233
http://dx.doi.org/10.33192/Smj.2020.13
INTRODUCTION
A totally implantable venous access device (TIVAD)
is a type of tunneled central venous catheter that provides
venous system accessibility and prevents extravasation
of hypertonic parenteral uid and vesicant medications.
1
With an aim to improve quality of life (QOL) during
chemotherapy
2
, TIVAD are frequently used in pediatric
cancer patients who require long-term intermittent therapy,
especially those with hematologic malignancies.
3
TIVAD
not only improves QOL, but also improves compliance to
the treatment by reducing complications associated with
dicult venous access.
4
Recent studies have shown that
the preferred technique used in TIVAD implantation is
percutaneous venipuncture, commonly via the subclavian
the internal jugular vein.
5-7
If a venipuncture is not possible,
open venesection is an alternative approach. Although
TIVAD was designed to reduce catheter-related infections
by tunneling the catheter within the subcutaneous plane,
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Laochareonsuk et al.
infectious complications can occur when the line has
been used for a long period.
8,9
Moreover, mechanical
complications, especially luminal obstruction, are common
problems which might compromise TIVAD longevity.
10,11
TIVAD has been practiced in Songklanagarind
Hospital, one of the largest referral centers for pediatric
oncology cases in southern ailand, since 2010. Aer
the procedure was partially subsidized by the Universal
Health Coverage scheme, the number of implantations
increased. e implantation was considered primarily
in hematologic malignancies and in selected cases of
pediatric solid tumor who were expected to receive
chemotherapy for more than one year. e implantation
surgical techniques and continuing post-operative care
by a multidisciplinary team were continuously rened
with an aim to achieve a ‘best practices’ program.
In this study, we appraised the longevity and the
complications of TIVAD implantations in our institute
and also analyzed the factors determining event-free usage
longevity. Problems encountered and improvement of
both surgical techniques and care processes during the
period were also reviewed.
MATERIALS AND METHODS
Patient selection
e Human Research Ethics Committee of the Faculty
of Medicine, Prince of Songkla University approved
the study as a retrospective review (EC-59-371-10-1).
e records of all pediatric patients who underwent a
TIVAD implantation by the pediatric surgical team at
Songklanagarind Hospital from January 2010 to December
2018 and were taken care of by the pediatric oncology
team either at our hospital or another hospital were
reviewed.
Surgical techniques and care processes
Pediatric patients aged less than 15 years with
hematologic malignancies, lymphoma, or other pediatric
solid tumors were considered for TIVAD. Cases with a
solid tumor were selected for implantation when they were
expected to receive intermittent intravenous chemotherapy
for longer than 1 year. Percutaneous venipuncture using the
‘catheter under the sheath’ method (Seldinger technique)
was attempted rst when feasible.
12,13
Puncture sites were
either the right subclavian or right internal jugular vein.
During the initial years of implantation in our institute,
the pediatric surgeons generally preferred an approach
through the right subclavian vein without ultrasonographic
guidance. Around 2016, as our service quality review
and other studies showed that immediate complications
were lower when the internal jugular vein was used as
an access point, the team revised our protocol to begin
with percutaneous venipuncture through the internal
jugular vein under real-time ultrasonography. In cases
where a percutaneous venipuncture was not successful or
not suitable, open venesection was the main alternative
choice. On the open venotomy, the right external jugular
or the right internal jugular was the most preferred
access sites. e tip of the catheter was passed though
the superior vena cava (SVC) to be located around the
junction between the SVC and the right ventricle, and the
location was conrmed by intraoperative uoroscopy.
(To reduce catheter misplacement as an immediate
complication, strict positioning under uoroscopy has
been implemented as a quality check point since 2017.)
Together with the positioning regimen, all implanted
catheters were checked for their functions using ‘push
and pause’ infusion test before xation. e catheter was
tunneled along the subcutaneous plane and the port was
placed at the right chest wall cranial to the ipsilateral nipple
and xed to the pectoral fascia using 4-0 polypropylene.
e skin incision was closed by a subcuticular mattress
using 5-0 polydioxanone. In general, the implanted
TIVAD wass le 7-10 days before the rst puncture
test was performed by the surgical team. e catheters
thereaer were taken care of by a multidisciplinary team.
14,15
e bundles of care process were divided into 3 steps:
(1) needle insertion and chemotherapy administration,
(2) monthly NSS ushing to prevent mechanical obstruction,
and (3) needle removal and supervised home care for
the patients and their parents. e care team provided a
logbook and a pamphlet to each patient’s caregivers, in
which events and complications were recorded. When
the patients nished their intravenous chemotherapy and
had no relapse of disease for at least 1 year, the device
was removed by the pediatric surgical team.
As the study aimed to apprise the longevity and
complications in our TIVAD practice, we also focused
on the learning curve and continuous adaptation of
the operative techniques through a quality assurance
process of the care team. Apart from the major change
in the preferential puncture site, the TIVAD clinical
practice guideline has been modied several times, and
the current one reects our best practice.
Data collection
Data were retrieved from our electronic medical
records including age at implantation, gender, diagnosis
of malignancy, anthropometry (weight and height) at
implantation, site and techniques of central venous
access, size of catheter, immediate complications, type
of long-term complications (catheter-related infections,
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mechanical obstruction), onset of complications. Diagnosis
of catheter-related blood stream infections (CRBSI) was
considered when there were positive microbiological
reports of hemoculture collected from both peripheral
blood and catheter blood drawn at dierent times more
than 2 hours apart
16
. Neutropenia was diagnosed when
the patient had an absolute neutrophil count less than
500 cells/cm
3
. Date and reasons for catheter removal were
also recorded. An immediate complication was dened as
an event occurring within 7 days aer implantation.
17,18
Statistical analysis
Demographic data were described by crude value
and representative percentage. Categorical data were
stratied by various factors and compared by chi-square
test, while continuous data were compared with t-test.
e log-rank test was used to calculate time to event
with regard to event-free usage and overall implantation.
Events per catheter day was calculated as the number of
events (i.e. CRBSI, obstruction) per 1,000 overall catheter
days. Statistical signicance was considered at a p-value
of <0.05.
RESULTS
A total of 150 devices in 144 patients (103 hematologic
malignancies and 41 solid tumors) were included in the
analysis. e average age of the patients was 6.4 years
with 66 cases (45.8%) aged less than 5 years and 38 cases
(26.4%) less than 3 years. ere was an increasing trend
of TIVAD use in those with hematologic malignancy
when use in solid tumors gradually decreased with time
(Fig 1).
Considering the access sites, neck veins were used
in 62 lines and subclavian veins in 88 lines. The 26
neck-accessed lines (41.9%) were approached by an
open venesection. ere was a trend toward changing
from subclavian access to neck vein access over the
study time period (Fig 2), especially during the last
years 2017-2018. Immediate complications including
obstruction, displacement, arterial puncture, hydrothorax
and intraoperative bleeding occurred in 13 cases (8.7%),
6 of which (46.1%) required a surgical revision (Fig 3).
e median follow-up period was 973 days (interquartile
range 501-1,732 days).
TABLE 1. Demographic characteristics of the patients comparing between hematologic malignancy cases and solid
tumor cases.
Hematologic malignancy Solid tumors Total
Patients (cases) 103 41 144
Sex
Male 64 (62.1%) 26 (63.4%) 90 (62.5%)
Female 39 (37.9%) 15 (36.6%) 54 (37.5%)
Age (years)
(mean ± S.D.) 6.7±3.6 5.6±5.0 6.4±4.1
Age
> 5 years 60 (58.3%) 18 (43.9%) 78 (54.2%)
3-5 years 27 (26.2%) 1 (2.4%) 28 (19.4%)
< 3 years 16 (15.5%) 22 (53.7%) 38 (26.4%)
Weight (kg.)
(mean ± S.D.) 23.1±12.6 21.0±19.5 22.5±14.9
Weight percentile
<P10 17 (16.5%) 13 (31.7%) 30 (20.8%)
P10-P50 38 (36.9%) 19 (46.3%) 57 (39.6%)
P50-P90 32 (31.1%) 3 (7.3%) 35 (24.3%)
>P90 16 (15.5%) 6 (14.7%) 22 (15.3%)
Abbreviations: S.D.= standard deviation, kg.= kilograms, P= percentile
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Laochareonsuk et al.
TABLE 2. Data of the 150 totally implantable venous access devices (TIVAD) used in this study.
Hematologic malignancy Solid tumors Total
TIVAD (lines) 108 42 150
Insertion site
Neck vein 43 (39.8%) 19 (45.2%) 62 (41.3%)
Subclavian vein 65 (60.2%) 23 (54.8%) 88 (58.7%)
Venous approach
Venipuncture 94 (87.0%) 29 (69.1%) 123 (82.0%)
Venesection 14 (13.0%) 13 (30.9%) 27 (18.0%)
Immediate complications 8 5 13
Intraoperative bleeding - 1 1
Arterial puncture 2 1 3
Displacement 4 1 5
Occlusion 1 2 3
Hydrothorax 1 - 1
Revision 5/8 (62.5%) 1/5 (20.0%) 6/13 (46.1%)
Late complications
Infection 18 (17.5%) 5 (14.3%) 23 (16.7%)
Mechanical obstruction 6 (5.8%) 2 (5.7%) 8 (5.8%)
TABLE 3. Mechanical obstruction and catheter-related blood stream infections of TIVAD by venous access site.
TABLE 4. Infectious complications in the study patients.
Venous access site
Mechanical obstruction Catheter-related blood stream infections
(events/1,000 catheter days) (events/1,000 catheter days)
Neck vein 0.01 0.01
Subclavian vein 0.06 0.24
Cases (n=23) Percentage
Onset of infection
During chemotherapy 12 52.2%
Post-chemotherapy 7 30.4%
Fever prior to admission 4 17.4%
Neutropenia 11 47.8%
Identied organism
Acinetobacter baumannii 4 17.4%
Enterobacter cloacae 4 17.4%
Pseudomonas aeruginosa 4 17.4%
Stenotrophomonas maltophilia 3 13.1%
Staphylococcus aureus 2 8.7%
Candida albicans 2 8.7%
Cryptococcus neoformans 2 8.7%
Escherichia coli 1 4.3%
Rhodococcus equi 1 4.3%
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Excluding cases with death from unrelated causes and
those removed because of immediate complications, the
overall TIVAD longevity was 985.1 days while event-free
device longevity was 797.6 days. In cases of hematologic
malignancies, 1000-day overall survival and event-free
survival of TIVAD were 83.7% and 78.2%, respectively
(Fig 4).
Catheter-related infections and mechanical obstruction
were the 2 most common problems occurring with the
device, occurring in 0.2 and 0.08 events/1,000 catheter days,
respectively (Fig 5). Infectious complications occurred
in 23 pediatric patients, usually developing during the
chemotherapy session (52.2%) and commonly found in
neutropenic condition. Gram negative bacilli was the most
common organism in CRBSI (56.7%) and there were 4
cases of fungal infection. Subclavian access was related to
infectious complications at a signicantly higher frequency
when compared to the neck vein approach (25.4% vs 9.1%,
p-value 0.02). Lines with either mechanical complication
or infection had signicantly poorer longevity compared
to uneventful implantations.
Fig 3. Immediate and long-term complications
of TIVAD stratied by year of implantation.
Fig 1. Total TIVAD implantation during
the study period.
Fig 2. Site of TIVAD implantation stratied
by year of implantation.
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Laochareonsuk et al.
Fig 4. Kaplan Meier curves of event-free usage and overall implantation day of TIVAD stratied by type of malignancy.
Fig 5. Kaplan Meier curves of event-free usage and overall implantation day of TIVAD stratied by type of complication.
DISCUSSION
e number of TIVAD implantations in our practice
has been increasing in recent years, partly because of nancial
support from the Universal Health Coverage scheme of
the ailand health care system. e device is used with
an aim to improve compliance with chemotherapeutic
treatment by preventing extravasation and pain caused
by dicult venotomies. Our study found that more
than 80% of TIVAD could be used longer than 3 years.
Considering its high cost, the majority of TIVAD (70%)
were used primarily in hematologic malignancy cases in
which the therapeutic course usually takes longer than
1-2 years. Eventually, complications developed during
the period of utilization at the incidence of 0.3 events per
1,000 catheter days. e majority of complications were
related to mechanical obstruction and catheter-related
blood stream infections (CRBSI). ere were 2-time peaks
of complication occurrence, the rst being immediate
complications that occurred within days of implantation
in which mechanical problems predominated and the
second being infectious complications during the rst
year of catheter use. is high complication occurrence
during the rst year of use might be explained by the
intensity of chemotherapy in that period. Our data also
found that once a complication occurred, the longevity
of the TIVAD was signicantly compromised.
e TIVAD is a catheter of which the whole device
is surgically implanted within the body, one end laid in
the vena cava and the other end placed under the skin.
Although this system has been proven to have less chance
of infection when compared to the exteriorized catheter,
CRBSI remain a concern. During the on-going period
of this study, we found that the neck vein approach
was superior to the subclavian approach in terms of a
signicantly lower incidence of CRBSI
7,19
, and based on
this nding we modied our surgical protocol to perform
internal jugular venous puncture under ultrasonographic
guidance as the rst choice. Now in our institution the
use of uoroscopy and ow check before the end of a
TIVAD procedure are mandatory. With that strategy
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launched in 2017, the immediate complication rate
reduced from 11% to 6% of total implantations and
there were no immediate complications in 2018.
Risk reduction in TIVAD implantation and care
involves not only the surgery and post-surgical care but
also patient preparation and right surgical timing.
20
One
lesson our team has learned in our early experience is
that implantation should be avoided during the period
that a patient remains in blast crisis or the bone marrow
suppression phase. Implantation is scheduled when a
leukemic patient enters a remission phase and his/her
hematologic prole is within the normal range, usually
between the rst and second sessions of chemotherapy.
Even though transfusion therapy might be able to quickly
restore the number of platelet count to the normal limit,
the risk of hemorrhagic complications and so tissue
infection are not substantially alleviated
21
. Concerning
post-operative and long-term care, a multidisciplinary
team approach is the key point
14
. e rst puncture of a
device is usually performed by the pediatric surgical team.
Further maintenance is then in the hands of pediatricians
and chemotherapeutic nurses in the pediatric cancer
ward. Such care includes a log-book record and regular
inspection and irrigation. With renement of surgical
techniques, the complication rate in our institution
gradually decreased from 29.6/100 catheters to 15.6/100
catheters aer the year 2017.
15
Our next aim to improve the eective use of TIVAD
is to reduce infectious complications. Our data showed
that half of the CRBSI occur during the chemotherapeutic
session. During the neutropenic period, even though a
double culture technique was used, it was not easy to
dierentiate between systemic bacteremia and primary
catheter infection. When blood culture is positive with
gram negative bacteria or fungus, removal of the device
is usually inevitable. Active surveillance of bacterial
colonization within the device and avoiding its use during
the neutropenic period may reduce the problems.
CONCLUSION
In conclusion, our study documents the continuous
improvement of our practice in TIVAD implantation and
care in pediatric malignancy cases. Over time, continually
improving surgical techniques and multidisciplinary
care reduced complications and improved longevity of
TIVAD implantation.
Conict of Interest: All authors have no conict of
interest
Ethical approval: All procedures performed in studies
involving human participants were in accordance with the
ethical standards of Human Research Ethics Committee
of the Faculty of Medicine, Prince of Songkla University
and with the 1964 Helsinki declaration and its later
amendments or comparable ethical standards.
Informed consent: Informed consent was obtained
from all individual participants included in the study.
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5. Wu S, Huang J, Jiang Z, Huang Z, Ouyang H, Deng L, et al.
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meta-analysis of comparative studies. BMC Cancer2016;16:747.
6. Lin WY,Lin CP,Hsu CH,Lee YH,Lin YT,Hsu MC,Shao YY.
Right or le? Side selection for a totally implantable vascular access
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932-7.
7. Hsu CC,Kwan GN,Evans-Barns H,Rophael JA,van Driel
ML. Venous cutdown versus the Seldinger technique for
placement of totally implantable venous access ports. Cochrane
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8. Di Carlo I, Pulvirenti E, Mannino M, Toro A. Increased Use
of Percutaneous Technique for Totally Implantable Venous
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Eur J Surg Oncol2009;35:241-6.
10. Pinelli F, Cecero E, Degl’Innocenti D, Selmi V, Giua R, Villa
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15. Piredda M, Biagioli V, Giannarelli D, Incletoli D, Grieco F,
Carassiti M, et al. Improving cancer patients’ knowledge about
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16. Seifert H, Cornely O, Seggewiss K, Decker M, Stefanik D,
Wisplingho H, et al. Bloodstream infection in neutropenic
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Laochareonsuk et al.
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Original Article
SMJ
Sanya Sukpanichnant, M.D.*, Win Myat Oo, M.D.**,
†
*Department of Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, ailand, **Department of Pathology, No (1)
Defence Services General Hospital, Mingalardon 11021, Yangon, Myanmar.
Incidental Malignant Lymphoma and
Lymphoproliferative Disorders in Lymph Node
Dissection Specimens during Tumor Removal in
Various Organs
ABSTRACT
Objective: To nd incidental malignant lymphoma and lymphoproliferative disorders (LPD) in lymph node
dissection specimens during tumor removal in various organs.
Methods: A review was performed separately by two pathologists in two rounds of all H&E-stained slides of lymph
nodes found during the removal of solid tumors at Siriraj Hospital: the rst round concentrating on the detection of
any metastatic tumor cells in lymph node sinuses and the second round concentrating on any incidental lymphoma
or LPD. en, the results were compared to reach consensus. Immunohistochemical studies were performed to
help conrm the diagnosis of lymphoma or LPD.
Results: In total, 309 cases were reviewed. Lymph nodes were taken out during surgical tumor removal of the
breast (110 cases), colon and rectum (57 cases), female genital organs (41 cases), lung (20 cases), thyroid (20 cases),
oral cavity (16 cases), prostate (14 cases), and others (31 cases). Only 1 case (0.3%) was found to have follicular
lymphoma, while 4 cases (1.3%) were found to have LPD, including in situ follicular neoplasia (1 case), suspected
follicular lymphoma (1 case), and marginal zone hyperplasia (2 cases). An experienced pathologist was able to
detect incidental lymphoma and LPD.
Conclusion: Incidental lymphoma and LPD can be found in lymph node dissection specimens. Attention should
thus be paid during histologic evaluation to nd any incidental lymphoma or LPD for another round of lymph
node screening aer nishing the search for metastasis in the lymph node dissection or sentinel lymph node biopsy
to avoid “inattentional blindness.”
Keywords: Incidental lymphoma; lymphoproliferative disorders; lymph node dissection; solid tumor; inattentional
blindness (Siriraj Med J 2020; 72: 103-108)
Corresponding author: Sanya Sukpanichnant
E-mail: sanya.suk@mahidol.ac.th
Received 26 August 2019 Revised 24 December 2019 Accepted 26 December 2019
ORCID ID: http://orcid.org/0000-0002-9724-2692
http://dx.doi.org/10.33192/Smj.2020.14
INTRODUCTION
Based on research conducted on malignant lymphoma
at Siriraj Hospital in the past decades, one of the authors
(SS) has been publishing pathologic data regarding
†
en a one-year clinical hematopathology fellow from July 1, 2018 to June 30, 2019 at Department of Pathology, Faculty of Medicine Siriraj Hospital,
Mahidol University
malignant lymphoma in ai people in international
medical journals since 1998.
1
Moreover, the same author
published a report in an international medical journal
in 2004 on malignant lymphoma types in ai people
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104
diagnosed from this single institution in up to 1,983
cases.
2
Further studies have been periodically published
regarding various aspects of malignant lymphoma in
ai people.
3-10
Interestingly, the information from Siriraj
Hospital on malignant lymphoma in ai people is
comparable to the data reported from a later collaborative
study of malignant lymphoma in ai people among
many medical centers in ailand,
11
which is perhaps not
surprising as Siriraj Hospital is the largest government-
based hospital (2,000 in-patient beds) in ailand and is
equipped with its own pathology laboratory, rendering
the institute higher chances of obtaining pathology
specimens and encountering a wider range of malignant
lymphoma than in smaller hospitals. Furthermore, the
existence of a great number of patients with long follow-
up visits allows an appreciation of disease variations
along the clinical course or any related conditions or
emerging morbidities. Also it is possible to note incipient
lesions encountered in previous pathology specimens
taken from the patients before they developed overt
lymphoma. Recently, the same author (SS) has published
the results of the study on “Pathologic ndings prior to
the diagnosis of malignant lymphoma – a retrospective
study in a large medical institute” based on a review of all
previous pathology slides prior to the denite diagnosis
of malignant lymphoma, with an aim to search for any
lymphoma or lymphoproliferative disorder that might
have been missed in the initial diagnosis. Among the
999 lymphoma patients who made at least one visit to
Siriraj Hospital for a denite diagnosis or follow-up,
there were two lymphoma patients who had a previous
history of cancer, one with a lobectomy for lung cancer
and the other with mastectomy for breast cancer. Upon
reviewing the lymph node dissection slides on these
two patients, it was found that both had already had
lymphoma in those lymph nodes but they were missed
by the original pathologists: one a case of diuse large
B-cell lymphoma (DLBCL), where the pathologist had
failed to recognize a small cell lymphoid neoplasm in
the regional lymph nodes in the resection specimen of
pulmonary adenocarcinoma 1 year earlier, and another
case of follicular lymphoma (FL) in the sentinel lymph
node in a patient with CA breast 4 years earlier.
12
ese
missed diagnoses can be explained by the perceptional
phenomenon described as “inattentional blindness”;
13
whereby the attention of the pathologist at the time was
only on the metastatic tumor cells, mostly conned in
lymph node sinuses, while the other portions of the
lymph node were neglected (overlooked or “blind”). So
the lymphoma was not reported at that time.
12
Aer the aforementioned study, 4 more cases were
found during hematopathology services at Siriraj Hospital
by one of the authors (SS), namely: 1) a newly diagnosed
case of chronic lymphocytic leukemia (CLL) found to
have already had small lymphocytic lymphoma (SLL) in
the lymph node dissection specimen taken for prostatic
adenocarcinoma performed 6 years previously, but missed
by the attending pathologist at that time; 2) a case of
CLL proven to have nasopharyngeal involvement by
tissue biopsy, which also had the involvement of all the
lymph nodes in the lymph node dissection specimen
taken for pulmonary adenocarcinoma in the following
few months, but was missed by the attending pathologist
at the time (the surgeon failed to inform the underlying
CLL to the pathologist); 3) a case of mantle cell lymphoma
(MCL) with the involvement of all the lymph nodes of a
lymph node dissection specimen taken for pulmonary
adenocarcinoma several months later, but was initially
missed by the attending pathologist; and 4) a known
case of rectosigmoid adenocarcinoma that had follow-
up colonoscopy 2 years later and was found to have
multiple polyps. e polypectomy specimen was shown
to have extranodal marginal zone lymphoma of the
mucosa-associated lymphoid tissue (MALT lymphoma).
en, a review of the previous surgical removal of the
rectosigmoid adenocarcinoma revealed that the lymph
nodes involved marginal zone lymphoma but no MALT
lymphoma was detected in any colonic mucosa taken
for histologic evaluation. No polyp was found in the
resection specimen at that time.
ese incidental lymphoma cases prompted the
authors of the present study to review the literature,
which revealed that the frequency of incidental lymphoma
in lymph node dissection ranged from 0.2% to 1.6% of
cancer patients who underwent tumor removal.
14-20
Most
previous studies were conducted in prostatic cancer
patients (0.2–0.4%),
14-17
and only three studies were
conducted in melanoma patients (0.3%),
18
head & neck
cancer patients of the squamous cell carcinoma type
(1.5%),
19
and breast cancer patients (1.6%).
20
Given this
possible incidence reported in the literature, it would
be interesting to know whether lymph node dissection
in cancer patients performed at Siriraj Hospital could
result in any chance of missed incidental lymphoma or
lymphoproliferative disorders (LPD).
MATERIALS AND METHODS
e pathologic diagnosis of lymphoma given in this
study followed the WHO classication based on clinical,
morphologic, immunophenotypic, and genetic ndings.
21
Sukpanichnant et al.
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105
Original Article
SMJ
Nevertheless, due to some limitations, especially in genetic
studies, the diagnoses in this study were given primarily
based on the morphologic and immunophenotypic
ndings. Table 1 shows the list of antibodies for the
lymphoid markers used for immunohistochemistry in
the present study.
Aer receiving a certicate of approval for this study
from the Siriraj Institutional Review Board (Si 289/2018),
a search of the laboratory information system used at
Siriraj Hospital, known as “HCLAB”, was conducted by
one of the authors (SS) only. All the slides available in the
archive room were retrieved. Aer that, both authors (SS
and WMO) independently performed histologic reviews
of the slides without any communication between them.
ey performed their reviews in two rounds: the rst
round concentrated on the detection of any metastatic
tumor cells in lymph node sinuses, while the second
round concentrated on the lymph node changes to detect
any incidental lymphoma or LPD. Aer both authors
had nished their pathology reviews independently,
a comparison of the results was performed to reach
consensus.
RESULTS
e project had to be completed within a one-year
training period to t in with a hematopathology fellowship
program followed by one of the authors (WMO) under
the tutelage of the other author (SS). Due to the time
constraint, only 309 cases in total could be reviewed. e
demographic data are summarized as follows: female to
male ratio, 2.5 (221 to 88); ages of the patients, 21 to 91
years old (median, 60 years old; mean, 59.7 years old);
organs with tumor removal: the breast (110 cases), colon
and rectum (57 cases), female genital organs (41 cases,
including the uterus in 25 cases, ovary in 11 cases, and
uterine cervix in 5 cases), lung (20 cases), thyroid (20
cases), oral cavity (16 cases), prostate (14 cases), larynx
(8 cases), skin (5 cases), stomach (5 cases), liver (4 cases),
pancreas (3 cases), kidney (3 cases), tonsil (1 case), small
intestine (1 case), and eyeball (1 case).
ere were 5 cases found of incidental lymphoma and
lymphoproliferative disorders in lymph node dissection
specimens during tumor removal. e results are presented
in Table 2. ere was 1 case of follicular lymphoma (FL)
at the time of rst diagnosis of endometrial carcinoma
by the original pathologist. Here, the reviews by the
two authors concurred with the diagnosis of crowded
neoplastic lymphoid follicles with the BCL2+, CD10+,
and CD20+ phenotypes typically seen in FL. is patient
was a 55-year-old female, who was lost to follow-up
following discharge aer surgical tumor removal, so
the hematologic work-up for a complete clinical staging
was lacking. en there were 4 cases recognized to be
abnormal by the experienced hematopathologist (SS)
only: 2 suspicious of FL and 2 suspicious of small cell
lymphoid neoplasm (SCLN) with a mantle/marginal
zone conguration. Immunostaining showed that 1
of the 2 suspected cases of FL turned out to be in situ
TABLE 1. List of antibodies for lymphoid markers used for immunohistochemistry in the present study.
Antibody to Marker for Remarks
CD3 T-cells Common T-cell marker
CD5 T-cells Aberrant expression in B-cell neoplasms
CD10 B-cells & T-cells Germinal center B-cell & T follicular helper
CD20 B-cells Common B-cell marker
CD23 B-cells & FDC FDC meshwork in reactive germinal center
Cyclin D1 Cell cycle protein Expressed in neoplastic mantle cells
BCL2 Anti-apoptotic protein Expressed in neoplastic germinal center cells
and various types of lymphomas
Kappa light chain Ig, light chain Expressed in some plasma cells
Lambda light chain Ig, light chain Expressed in some plasma cells
IgD Ig, delta heavy chain Expressed by naive B-cells in mantle layer
Abbreviations: FDC: follicular dendritic cells; Ig: Immunoglobulin
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106
TABLE 2. Incidental lymphoma and lymphoproliferative disorders in lymph node dissection specimens during
tumor removal (total of 5 cases).
Case (age/sex) Tumor removal Incidental lymphoma/LPD Recognized by
#1 (55/F) Endometrial carcinoma Follicular lymphoma, low grade Original pathologist,
SS, WMO
#2 (74/F) invasive ductal carcinoma of breast In situ follicular neoplasia SS only
#3 (68/M) CA rectum Suspected follicular lymphoma SS only
#4 (67/F) Endometrial carcinoma Marginal zone hyperplasia SS only
#5 (80/F) Endometrial carcinoma Marginal zone hyperplasia SS only
Note: ere was no metastatic carcinoma in any of the lymph nodes in these 5 cases.
Abbreviations: SS: Sanya Sukpanichnant; WMO: Win Myat Oo
follicular neoplasia (but this was still queried as low
grade FL) as shown by the few BCL2+, CD10+, and
CD20+ neoplastic lymphoid follicles located close to one
another, but not typically as crowded as those found in FL.
is patient was a 74-year-old female who had invasive
ductal carcinoma of the breast. e other suspected
case of FL failed to show any BCL2 protein expression,
even when using 2 clones of antibodies for BCL2 (clone
124 and clone E17) in the crowded lymphoid follicles.
e 2 suspected cases of SCLN with a mantle/marginal
zone conguration were pelvic lymph nodes that had
hyalinized vessels. ey turned out to be marginal zone
hyperplasia (MZH) aer immunostaining with the help
of IgD to separate the lymphoid cells in the mantle layer
from the lymphoid cells in the MZH. Both patients,
aged 67 and 80 years old, respectively, were diagnosed
as endometrial carcinoma. All of these 4 abnormal cases
did not have any further submission of a pathological
sample aer surgical tumor removal up to the time of
the manuscript preparation on August 23, 2019. In all
these 5 cases in Table 2, there was no evidence detected
of metastatic carcinoma in the lymph node.
In summary, only 1 out of 309 cases was proven to
have low grade FL (0.3%). e other 2 cases of suspected
FL were proven to be in situ follicular neoplasia (1 case)
and a still questionable case of FL (1 case). e other 2
cases of suspected SCLN were proven to be MZH. If
these 4 cases are considered as LPD, then the incidence
of incidental LPD was 1.3%.
DISCUSSION
Incidental lymphoma and LPD can be found in
lymph node dissection specimens during tumor removal
in various organs, as shown in the results above. From
the present study, incidental lymphoma was found in
0.3% of the 309 cases evaluated, which is an incidence
not dierent from those reported in the literature.
14-20
However, its early recognition is important, leading
either to hematologic work-up for a complete clinical
staging when the incidental lymphoma is established or
to searching for a denite lymphoma diagnosis when
incidental LPD is found. Most of the incidental lymphoma
cases reported in the literature and in this study have been
indolent lymphomas without any systemic symptoms,
such as SLL/CLL, follicular lymphoma, or marginal zone
lymphoma.
14-20
Since the conventional management in
asymptomatic indolent lymphoma is usually to adopt
a “watch and wait” policy,
22
it seems that incidental
lymphoma found in lymph node dissection specimens
during tumor removal in various organs may not be an
issue of concern in terms of clinical signicance. But,
in fact, it does matter, as large cell transformations can
occur in a number of indolent lymphoma patients.
23
In our experience and as already published, one case
of DLBCL involved a failure to recognize small cell
lymphoid neoplasm (SCLN) in the regional lymph nodes
in the resection specimen of a patient with pulmonary
adenocarcinoma 1 year earlier.
12
It would have been much
better if the indolent lymphoma (SCLN) was recognized
at the time of CA lung resection and the patient had
undergone hematologic work-up for a complete clinical
staging and proper management, including follow-up.
e problem found in these patients aer surgical tumor
removal is a loss of adequate follow-up as the patients
may believe that they are cured; for instance, all 5 patients
in the study shown in Table 2 did not have any further
Sukpanichnant et al.
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107
Original Article
SMJ
submission of a pathological sample aer surgical tumor
removal.
According to the WHO classication (revised 4
th
edition,
2017),
21
“in situ follicular neoplasia (ISFN)” is dened as
partial or total colonization of germinal centers by clonal
B-cells carrying the BCL2 translocation characteristic of
follicular lymphoma (FL) in an otherwise reactive lymph
node. For patients with incidentally diagnosed ISFN and
no other evidence of FL upon clinical evaluation, the risk
of subsequent FL is very low (≤ 5%). By morphology
alone, it is dicult to recognize ISFN, and the aected
follicles composed almost exclusively of centrocytes
(closely packed centrocytes) may be the only histologic
clue for ISFN. Certainly, immunohistochemistry for
BCL2 and CD10 will show BCL2+ centrocytes exclusively
in the aected follicles, with a higher intensity than in
adjacent T-cells or cells in the mantle layer. ese BCL2+
centrocytes will also show an increased expression of
CD10. us, according to the aforementioned ndings,
ISFN could be diagnosed without the need for genetic
studies to conrm the diagnosis. But, if any genetic
proles are needed, ISFN cells are positive for t(14;18)
or mutations in EZH2.
For the other case of “suspected follicular lymphoma
(FL),” the morphology was quite typical for FL, but
in this particular case, the lymphoma cells lacked the
expression of the BCL2 protein, even when using the 2
clones of antibodies for BCL2 (clone 124 and clone E17).
is phenomenon is at times seen in daily practice and
it can happen when secondary events lead to mutations
in BCL2, resulting in a negative staining of FL with the
commonly used clone 124 antibody to BCL2. According
to the WHO classication,
21
the absence of BCL2 protein
does not exclude the diagnosis of FL. Other germinal
center markers, including LMO2, GCET1, and HGAL,
will be positive in these cases. Determination of surface
immunoglobulin (sIg) by ow cytometry can be helpful
to establish evidence of neoplastic follicular center cells.
However, in this study, this particular case of “suspected
FL” did not have conrmation done by using any other
germinal center markers or the determination of sIg by
ow cytometry because the morphology and the CD10+
and BCL6+ phenotypes in the lymphoma cells seemed
to be sucient to designate this case as “suspected FL.”
Regarding the 2 cases of marginal zone hyperplasia
(MZH) in the study, the literature emphasizes excluding
MZH before making a diagnosis of nodal marginal zone
lymphoma (NMZL). e identication of three separate
zones, namely the innermost pale zone of the reactive
germinal center, the dark staining mid zone of the mantle
layer, and the outermost pale zone of the marginal zone,
without distortion of other lymph node compartments
or pericapsular inltration should lead to a concern of
MZH. e B-cells in MZH are frequently negative for
BCL2 and CD43. Plasma cells should be polyclonal in
MZH. In case of doubt, ow cytometry or a molecular
study for the clonal rearrangement of the immunoglobulin
heavy chain gene would be helpful to distinguish MZH
from NMZL. MZH should lack monoclonal evidence.
24,25
Since MZH of the lymph node is rare, it is quite dicult
to nd the causes. However, the following causes have
been described in the literature: Haemophilus inuenzae
infection (6 cases),
26
EBV infection (1 case),
27
and systemic
bacterial infection (1 case).
28
In addition, associated
conditions found at the time of lymph node swelling were
chronic tonsillitis (1 case) and hepatocellular carcinoma
(1 case).
24
e present study does support the “inattentional
blindness” phenomenon
13
as attention was only on the
metastatic tumor cells, mostly conned in lymph node
sinuses, while the other portions of the lymph node were
neglected (overlooked or “blind”) as proposed by one of
the authors (SS).
12
Also it was observed in the study that
recognition of the histologic ndings of various types of
lymphoma and LPD plays an important role in enabling
pathologists to suspect incidental lymphoma or LPD in
lymph node dissection specimens during tumor removal
in various organs. In order to overcome the “inattentional
blindness” phenomenon during histologic evaluation of
lymph node dissection specimens during tumor removal
in various organs, it is recommended that pathologists
look at all histologic sections of the lymph nodes in a
second round for any incidental lymphoma or LPD
aer searching for metastatic tumor in the rst round.
Certainly, improving the recognition of the histologic
ndings of various types of lymphoma and LPD by an
individual pathologist may be dicult to achieve as it
is personal capability, but continuing education may
enhance this capability.
CONCLUSION
Despite the low incidence of incidental lymphoma,
it is more benecial for patients if pathologists can detect
lymphoma in the lymph node dissection during the
surgical removal of solid tumors. e ndings from the
present study raise some suggestions on ways to enhance
the detection of incidental lymphoma, including: 1)
paying specic attention to be able to nd any incidental
lymphoma in a second round of lymph node screening
aer nishing the search for metastasis in the lymph
node dissection or sentinel lymph node biopsy in a rst
round, in order to avoid “inattentional blindness;
13
and
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108
2) having a greater awareness of the morphology features
in lymphoma and LPD. e latter requires more interest
in hematopathology among general pathologists, as
experienced hematopathologists may already be aware of
more varieties in lymphoma and LPD during screening.
ACKNOWLEDGMENTS
e author Sanya Sukpanichnant is thankful for
support provided by a Chalermphrakiat Grant from the
Faculty of Medicine Siriraj Hospital, Mahidol University.
e author Win Myat Oo is thankful for receiving support
from the Faculty of Medicine Siriraj Hospital, Mahidol
University for a one-year clinical hematopathology
fellowship training (July 1, 2018, to June 30, 2019) at
the Department of Pathology, Faculty of Medicine Siriraj
Hospital, Mahidol University.
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17. Chu PG,Huang Q,Weiss LM. Incidental and concurrent
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18. Verwer N,Murali R,Winstanley J,Cooper WA,Stretch JR,
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anapol Chaiprateep, M.Sc.*, Teera Kolladarungkri, M.D.*, Witsanu Kumthornthip, M.D.**, Saowalak
Hunnangkul, Ph.D.***
*Department of Preventive and Social Medicine, **Department of Rehabilitation Medicine, ***Clinical Epidemiology Unit, Faculty of Medicine Siriraj
Hospital, Mahidol University, Bangkok 10700, ailand.
Effectiveness of Back Exercise and Education
for Lower Back Pain Prevention among Nurses at
a Tertiary Hospital in Bangkok, Thailand
ABSTRACT
Objective: To examine the eectiveness of back exercise and education to promote lower back pain relief among
nurses at a tertiary hospital.
Methods: is quasi-experimental study was conducted using a sample of sixty nurses working at Siriraj Hospital.
Eligible criteria included full-time registered or practical nurses who had undergone direct contacted with patients
for at least six months and suered from chronic lower back pain. e subjects were randomly divided into a training
group and a control group. e training group followed a back exercise program including pelvic tilting, back
extension, and knee to chest at least 3 days a week for 12 weeks while the control group performed daily activities
as normal. Data were collected using a questionnaire at baseline, 4
th
, 8
th
, and 12
th
weeks.
Results: Signicant dierences of pain score and the ai version of the Oswestry questionnaire were scored between
the training and control groups (P-value < 0.001), while benecial eects improved signicantly during the time
points of exercise (P-value < 0.001).
Conclusion: Back exercises and education can eectively relieve lower back pain and improve disabilities among
nursing sta. Following our recommended procedures will improve the safety aspect for nurses working in tertiary
hospitals.
Keywords: Lower back pain; back exercise; nurse (Siriraj Med J 2020; 72: 109-116)
Corresponding author: Witsanu Kumthornthip
E-mail: wkumthornthip@yahoo.com
Received 7 August 2018 Revised 18 June 2019 Accepted 2 July 2019
ORCID ID: http://orcid.org/0000-0002-1738-6769
http://dx.doi.org/10.33192/Smj.2020.15
INTRODUCTION
Lower back pain (LBP) is considered to be a major
health problem among occupational diseases
1
and is
usually found in musculoskeletal disorders (MSDs).
2
LBP is the leading cause of disability in daily life.
People with chronic LBP (CLBP) show muscle
weakness and atrophy predominantly in the lumbar
exors and extensors due to deterioration of the multidus
muscle. Advanced symptoms are associated with reduced
muscle size presenting a smaller cross-sectional area,
leading to a decrease in muscle endurance, exibility
and back motion.
Trunk muscle strength protects the spine during
activities.
3-5
Many previous studies indicated that exercise
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Chaiprateep et al.
improved the strength, endurance, and exibility of
back muscles with also a positive impact on pain levels.
Results demonstrated that healthy participants had more
muscular strength and endurance than those with LBP.
6
However, some evidence suggested that only exercise or
exercise together with education were eective for LBP
prevention, while education alone was unlikely to result
in any improvement in LBP.
7-9
Incidence of LBP was 26.4% for people over 45
years of age as the top health problem in the USA.
10
In
ailand, the Division of Occupational Health, Ministry
of Public Health found that approximately 79% of the
study population had MSDs related to occupation and
LBP was found in 52.4% of the subjects.
1
Nursing is an occupation with a high risk of LBP
related to the working environment. In ailand, 65-84%
of nurses suer from LBP as a result of liing or moving
patients incorrectly, prolonged standing or sitting while
working, improper working posture, lack of exercise and
wearing high-heeled shoes.
1,11,12
us, nursing personnel
require protection by reducing spinal health hazards.
Siriraj Hospital is one of the tertiary hospitals in Bangkok
where many nurses are working at risk. Policymaking
should involve hospital assurance, risk management and
health promotion and prevention schemes to address
how to prevent employees from incurring serious and
long-term injuries related to daily working operations.
Education and back exercises are routinely included in
musculoskeletal clinics for LBP management; however,
the outcomes are equivocal with no evidence suggesting
that one particular type of exercise therapy is clearly more
eective than others.
13-16
Moreover, various exercises are
prescribed randomly and no single standard of care is
recommended. Clinical and biomechanical approaches
for the prevention of LBP tend to follow the favorite
exercises and beliefs of individual therapists. In this
study, a simple and common back exercise program
was selected, combined with the education necessary for
members of the nursing sta suering from mechanical
back pain without any specic cause. e objective was
to examine the eectiveness of education and exercise for
LBP relief among nurses. e hypothesis was postulated
that exercise could reverse neuromuscular impairment
of back muscles and improve lower back pain. Education
greatly improves self-awareness and self-protection, while
behavioral change can result from exercise compliance. If
proved eective, implementation of a combined exercise/
education scheme could improve safety for nurses operating
in the workplace.
MATERIALS AND METHODS
is quasi-experimental study was approved by the
Institutional Review Board, Faculty of Medicine Siriraj
Hospital (Si 377/2016). e sample size was calculated
using the mean pain score from a previous study
17
and
adding 25% to allow for missing data. e required
sample size of subjects was sixty. Type I error was set
at 0.05 and the power of the test was set at 0.80.
Nurses working at Siriraj Hospital were recruited
and selected based on eligible criteria. e samples were
randomly divided into training and control groups.
As inclusion criteria, the subjected were required to
be registered or practical nurses, working full time in
the same ward, with direct contact with patients for at
least 6 months and suering from chronic LBP (pain
duration >3 months). Pregnant nurses and those with
chronic LBP with specic pathology e.g. disc herniation,
spondylolisthesis, LBP with red ag signs and symptoms,
concomitant treatments such as other physiotherapy like
TENS, heat modalities, analgesics, acupuncture, spine
surgery, etc. or sta members unwilling to participate
in the exercise were excluded.
Data were collected using a questionnaire comprising
demographic characteristics, occupational information, pain
score, and the ai version of the Oswestry questionnaire
score. Pain score was evaluated as a psychometric response
by a visual analog scale (VAS). A score of 0 corresponded
to no pain and a score of 10 indicated the most pain.
Correlation between the vertical and horizontal orientations
of the VAS was 0.99.
18
e ai version of the Oswestry
questionnaire score was used to evaluate the functional
disability. Cronbach’s alpha coecient of reliability was
0.91.
19
e training group participated in the exercise
program which was led by sports scientists from the
Department of Health Promotion for at least 3 days a
week for 12 weeks, while the control group performed
daily activities as normal. Exercises included pelvic tilting
related to core stabilization, back extension to strengthen
back muscles and possibly benet lumbar disc bulging
or protrusion, and knee to chest to promote lower back
and gluteal muscle stretching and exibility as shown in
Fig 1 (a-c).
20-22
Furthermore, all participants were educated
regarding the denition of LBP, risk factors, and early
warning signs and symptoms to improve their health
behavior by the researcher. Both groups were assessed
at baseline, and results were followed up at the 4
th
, 8
th
,
and 12
th
weeks, respectively.
Each subject was given his/her own logbook to
record dates of practice, duration and frequency of
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(a). Pelvic tilting
(b). Back extension (c). Knee to chest
exercises to better monitor exercise compliance. During
the follow-up visits, the researcher asked each subject
if they had received any concomitant treatment. If the
answer was “YES”, the type, dosage and intensity were
recorded.
Statistical analysis
Data were analyzed using SPSS version 18.0.
23
Demographic and occupational information were presented
as descriptive statistics. Data were reported quantitatively
using mean ± SD and qualitatively as percentage and
frequency. Two-way repeated measures ANOVA with
Bonferroni correction was used to compare pain scores
and the ai version of the Oswestry questionnaire score.
Intention-to-treat was used for missing data. A P-value
< 0.05 was selected as statistically signicant.
RESULTS
Demographic characteristics
Demographic data are presented in Table 1. Females
strikingly outnumbered males in the specic nursing
occupation; however, there was no signicant dierence
between the study and control group. Mean age in the
control group was higher than in the study group. Other
characteristics such as body mass index (BMI), educational
level, personal habits like smoking, alcohol consumption
and level of activities were similar between the two
groups. Two participants dropped out during the study
period as a result of accidental injury and unwillingness
to continue.
Occupational information
Occupational factors showed no dierence between
the training and control groups, except for the duration
of working which was signicantly longer for the control
group than for the training group (P-value = 0.024)
(Table 2). Likewise, mean age of the control group was
higher than the training group, although it did not reach
statistical signicance (Table 1). One possibility for this
could result from selection bias.
Pain score
e pain score showed interaction between both
groups (P-value < 0.001). At each time point, signicant
dierences were found between both groups. At the
4
th
week, the P-value = 0.009, 8
th
week P-value = 0.001,
and 12
th
week P-value < 0.001. ere were signicant
dierences in the training group (P-value < 0.001) but
no dierences in the control group (P-value = 0.658)
(Fig 2).
Fig 1. Back exercise positions.
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Chaiprateep et al.
TABLE 1. Demographic characteristics of participants (Total n=58).
Characteristic Total Training group Control group P-value
(n=58) (n
1
=28) (n
2
=30)
Sex
Male 8 3 (10.7%) 5 (16.7%) 0.707
Female 50 25 (89.3%) 25 (83.3%)
Age (years) 36.54 ± 8.89 41.67 ± 10.70 0.053
Body Mass Index (kg/m
2
) 23.58 ± 4.29 23.56 ± 2.50 0.979
< 18.5 (Underweight) 4 3 (10.7%) 1 (3.3%) 0.414
18.5-22.9 (Normal range) 19 9 (32.1%) 10 (33.3%)
23.0-24.9 (Overweight) 18 7 (25.0%) 11 (36.7%)
25.0-29.9 (Obese class I) 15 7(25.0%) 8 (26.7%)
≥30.0(ObeseclassII) 2 2(7.1%) 0(0.0%)
Education level
Vocationalcerticate 19 10(35.7%) 9(30.0%) 0.445
Bachelor degree 29 15 (53.6%) 14 (46.7%)
Higher than master degree 10 3 (10.7%) 7 (23.3%)
Smoking habits
Non-smoker 54 28 (100.0%) 26 (86.7%) 0.135
Ex-smoker 3 0 (0.0%) 3 (10.0%)
Regular smoker 1 0 (0.0%) 1 (3.3%)
Alcohol consumption
Non-drinker 37 20 (71.4%) 17 (56.7%) 0.486
Ex-drinker 6 2 (7.1%) 4 (13.3%)
Occasional drinker 15 6 (21.4%) 9 (30.0%)
Leisure time physical activities
Never 15 10 (35.7%) 5 (16.7%) 0.159
Sometimes 37 17 (60.7%) 20 (66.7%)
Usually 3 0 (0.0%) 3 (10.0%)
Always 3 1 (3.6%) 2 (6.7%)
Congenital disease
No 39 17 (60.7%) 22 (73.3%) 0.306
Yes 19 11 (39.3%) 8 (26.7%)
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TABLE 2. Occupational information of participants (Total n=58).
Characteristic Total Training group Control group P-value
(n=58) (n
1
=28) (n
2
=30)
Nursing position
Registered nurse 27 11 (39.3%) 16 (53.3%) 0.284
Practical nurse 31 17 (60.7%) 14 (46.7%)
Ward
Medical 23 12 (42.9%) 11 (36.7%) 0.630
Surgical 35 16 (57.1%) 19 (63.3%)
Duration of working in ward (years) 13.66 ± 7.33 19.19 ± 10.42 0.024*
Overtime work
Never 39 16 (57.1%) 23 (76.7%) 0.196
2-3 times per month 8 4 (14.3%) 4 (13.3%)
2-3 times per week 8 5 (17.9%) 3 (10.0%)
Almost everyday/Everyday 3 3 (10.7%) 0 (0.0%)
Lifestyle outside the workplace
Sitting >20 minutes
No 18 11 (39.3%) 7 (23.3%) 0.189
Yes 40 17 (60.7%) 23 (76.7%)
Standing >20 minutes
No 14 6 (21.4%) 8 (26.7%) 0.641
Yes 44 22 (78.6%) 22 (73.3%)
Walking >20 minutes
No 6 2 (7.1%) 4 (13.3%) 0.671
Yes 52 26 (92.9%) 26 (86.7%)
Use hand or arm repeatedly
No 21 9 (32.1%) 12 (40.0%) 0.534
Yes 37 19 (67.9%) 18 (60.0%)
Fig 2. Comparison of pain score between training and control groups.
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114
Chaiprateep et al.
For the training group, LBP relief was signicant
at the 4
th
, 8
th
, and 12
th
weeks compared with pain at the
baseline (P-value < 0.001). Pain score at the 12
th
week
was signicantly lower than at the 4
th
(P-value < 0.001)
and 8
th
weeks (P-value = 0.001), while pain score at the
8
th
week was signicantly lower than at the 4
th
week
(P-value = 0.004). Pain scores remained the same in the
control group at all time points.
ai version of the Oswestry questionnaire score
Disabilities related to LBP using the Oswestry
questionnaire score (ai version) gave similar interactions
between the training and control groups (P-value < 0.001).
ere were signicant dierences between both groups
at the 8
th
week (P-value = 0.001) and 12
th
week (P-value
< 0.001), while for each group, there were signicant
dierences in the training group (P-value < 0.001) but
no dierences in the control group (P-value = 0.323)
(Fig 3).
For the training group, disability scores at the 4
th
,
8
th
, and 12
th
weeks were signicantly lower than the
baseline (P-value < 0.001). e score at the 12
th
week
was signicantly lower than at the 4
th
(P-value < 0.001)
and 8
th
weeks (P-value = 0.026), while the score at the
8
th
week was signicantly lower than at the 4
th
week
(P-value = 0.001) but no dierences were observed in
the control group at all time points.
Compliance with exercise was 85.7%. Four participants
in the training group and ve participants in the control
group had concomitant treatment during the study;
however, their scores were replaced with the last observation
carried forward (LOCF) to maximize data reliability.
For statistical analysis, a two-way repeated measures
ANOVA, including post hoc testing with Bonferroni
correction, was used for comparisons between the training
group and control group. Furthermore, intention-to-treat
(ITT) was also used for data analysis. All participants,
including those who withdrew, were included. However,
participants who withdrew during the study had no data to
analyze; if they followed the back exercise program, their
pain score and ai version of the Oswestry questionnaire
score should be less than the baseline. erefore, the
last observation carried forward (LOCF) was used to
replace the missing data. is technique ensured that
the estimated result was similar to the actual data.
24
DISCUSSION
e causes of lower back pain are complex and
associated with abdominal and back muscle weakness,
atrophy and loss of muscular endurance and exibility.
Back exercise forms part of the comprehensive treatment
of LBP, emphasizing more active participation of patients
particularly in chronic cases. Our results indicated that
back exercise and education reduced pain and disability
by following an exercise program for at least 3 days a week
for 12 weeks. e back exercise program was designed
for strength, endurance and exibility training of the
commonly involved muscles. Strengthening exercises
were performed at least 2 days a week with at least 2-3
days a week for the exibility exercises. Performing the
exercise program for 12 weeks was necessary because
no neuromuscular adaptation occurs within the rst few
weeks and exercise and muscle hypertrophy is typically
experienced aer 6 to 7 weeks of exercise.
25
erefore,
Fig 3. Comparison of the ai version of the Oswestry questionnaire score between training and control groups.
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a 12-week duration was selected as suitable for this
study to prove the benet of both biomechanical and
physiological eects. Our results were consistent with other
studies indicating that strengthening exercises reduced
pain and disability associated with LBP aer 6 weeks to
12 months of the exercise program.
26-31
Likewise, core
muscle strengthening for at least 3 months was benecial
in aspects of pain relief and functional improvement.
Nevertheless, no signicant dierence was demonstrated
in exercise groups up to 12 months compared with the
exercise group of over 12 months for participants with
chronic LBP.
32
Furthermore, outcomes of core stability
combined with general exercise were similar.
33
In addition, our exercise program was combined
with education to facilitate behavioral change, modify
health beliefs and attitudes, and motivate the participants
to follow the exercise program. Some studies suggested
that education alone did not appear to prevent LBP but
exercise combined with education showed a positive
result.
16,34
Compliance with the exercise routine is a key
success factor to combat chronic LBP. In this study,
logbooks were given to participants for more accurate
monitoring during the follow-up visits, with compliance
of 85.7%.
Dealing with chronic LBP is a sophisticated process
which involves not only pain relief but also functional
restoration. CLBP is oen heredity and not episodic like
acute LBP; therefore, prevention is sometimes better than
treatment. Strategies to prevent chronic pain involve early
diagnosis and early treatment of acute pain conditions.
At present, the concept of treatment is more aggressive
for acute pain control. Some may argue that our study
design was not consistent with the hypothesis. Unlike
acute LBP, the study design for prevention is to reduce
the recurrence of pain and prolong the duration of the
new episode of pain which would be impossible and
incompatible with the natural course. A prevention
scheme in the context of chronic LBP in the workplace
would involve limiting the progression of pain severity,
disability and suering. Here, we recruited CLBP subjects
with mild to moderate pain severity that had minimal
disability following the ai version of the Oswestry
questionnaire score. If CLBP progressed or more injuries
took place, then pain and disability would be expected to
are up. However, both pain amelioration and functional
improvement were shown at all time points compared
with the control group. As mentioned above, our results
supported the research hypothesis.
Demographic data and occupational information of
participants showed no signicant dierences between
the training and control groups except for duration of
working. In the control group, duration of working was
signicantly longer than in the training group, possibly
due to the mean age dierences of the subjects as well
as recruitment or setting bias. Mean age of the control
group was higher than the training group although
it did not reach statistical signicance. Whether this
dierence aected pain severity and functional ability
is doubtful. Degenerative change of the spine is more
likely to develop in older people; however, it does not
equate to back pain.
Back exercise programs combined with education
are benecial for nurses with CLBP who suer from
mild to moderate LBP with minimal disability. ese
may prevent clinical progression through pain reduction
and functional improvement as an easy, low risk, self-
managed way to control LBP.
ere were some limitations in this study. Firstly,
the follow-up period was rather short because of time
limitations and maybe not long enough to demonstrate
the are-up of symptoms and recurrence. Secondly,
participants were only subjectively measured by a
questionnaire survey. Objective measurements were
not conducted due to budget limitations.
CONCLUSION
Our results suggested that back exercise and education
eectively relieved LBP and improved muscle function
among nurses. Therefore, our proposed scheme for
LBP prevention should be implemented in all tertiary
hospitals in ailand to improve both safety and working
conditions of the nursing sta.
ACKNOWLEDGMENTS
e authors would like to thank all participants
from Siriraj Hospital and the Department of Health
Promotion, Faculty of Medicine Siriraj Hospital for
supporting the venue and exercise training. We also
gratefully acknowledge the scholarship from the Siriraj
Graduate Scholarship and Graduate Studies of Mahidol
University Alumni Association.
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Chaiprateep et al.
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117
Original Article
SMJ
Jesada Wutitammasuk, M.D., Pattama Chaopotong, M.D.
Department of Obstetrics & Gynecology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, ailand.
Treatment Outcomes of Advanced Stage
Endometrial Carcinoma (Stage III-IV) and Related
Factors
ABSTRACT
Objective: e aim of this study was to determine treatment response, the recurrence rate, 3-year overall survival,
3-year recurrence-free survival, and associated prognostic factors for survival among advanced-stage endometrial
carcinoma patients at Siriraj Hospital.
Methods: is study was conducted at the Division of Gynecologic Oncology, Department of Obstetrics and
Gynecology, Faculty of Medicine Siriraj Hospital, Mahidol University Bangkok, ailand. A total of 415 patients that
were diagnosed with advanced-stage endometrial carcinoma during January 1998 to December 2014 were enrolled.
Data retrieved from medical records included baseline characteristics, surgico-pathological reports, treatment
protocol, follow-up data, treatment response, and recurrence status. ree-year survival and recurrence-free survival
were estimated by Kaplan-Meier method. Various factors were analyzed for signicant association with survival.
Results: Four hundred of 415 cases were included in the nal analysis. ere were 282 (70.5%) and 118 (29.5%)
patients that were diagnosed with stage III and IV disease, respectively. Two hundred and eighty-two patients had
complete response aer primary treatment, and 94 (33.3%) patients had disease recurrence. e median follow-
up and survival times were 24.5 and 42.5 months, respectively. e 3-year survival rate was 50%, and the median
recurrence-free interval was 12.25 months. Multivariate analysis revealed high-grade tumor histology, lymph
node metastasis, Eastern Cooperative Oncology Group (ECOG) performance status, and menopausal status to be
signicant prognostic factors for overall survival.
Conclusion: Median survival among patients with advanced-stage endometrial carcinoma aer primary treatment
was 3 years. e signicant prognostic factors were high grade tumor histology, lymph node metastasis, ECOG
performance status, and menopausal status.
Keywords: Advanced stage; endometrial carcinoma; prognostic factor; recurrence; survival (Siriraj Med J 2020; 72:
117-124)
Corresponding author: Pattama Chaopotong
E-mail: chaopotong@gmail.com, pattama.cha@mahidol.ac.th
Received 15 January 2019 Revised 26 July 2019 Accepted 8 August 2019
ORCID ID: http://orcid.org/0000-0001-7118-3340
http://dx.doi.org/10.33192/Smj.2020.16
INTRODUCTION
Endometrial carcinoma is the most commonly
occurring gynecologic cancer among women in Europe,
America and others developed countries.
1
In ailand,
endometrial cancer is the third most common cancer of
the female reproductive system aer cervical cancer and
ovarian cancer.
2
e incidence of endometrial cancer is
increasing in ailand.
Endometrial carcinoma have two dierent clinico-
pathological subtypes. Type I, which is endometrioid or
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118
estrogen related, is more common than type II which
is non-endometrioid or non-estrogen related.
1
Type I
usually occurs in younger age or perimenopausal women
with a history of exposure to unopposed estrogen and it
is associated with endometrial hyperplasia or endometrial
intraepithelial neoplasia (EIN). Type II occurs in women
without estrogen stimulation, and may arise in a background
of atrophic endometrium. Type II endometrial carcinoma
tends to occur in older, thin, postmenopausal women
and it is associated with a poorer prognosis.
1,3
e stage of cancer depended on surgicopathological
staging according to International Federation of Gynecology
and Obstetrics (FIGO) staging system. Approximately
75-80% of women with endometrial carcinoma were
diagnosed at early stage and had excellent treatment
outcomes.
1
Conversely, advanced-stage patients (stage
III-IV) who were diagnosed with extrauterine diseases
had poor prognosis and worse treatment outcomes.
4
Surgery is the primary treatment for endometrial
carcinoma patients. Many studies in Europe and America
investigated the use of adjuvant chemotherapy and/or
radiation therapy to improve the survival of patients
with advanced-stage diseases. e overall survival time
among advanced-stage patients is about 12-15 months.
4-6
Alvaro, et al. reported histologic subtype, age, myometrial
involvement, lympho-vascular space invasion, lymph
node metastasis and residual tumor aer surgery to
be signicantly associated with treatment outcomes in
endometrial carcinoma.
7
e objective of this study was to determine treatment
response, the disease recurrence rate, 3-year overall survival,
3-year recurrence-free survival, and associated prognostic
factors for survival among advanced-stage endometrial
carcinoma patients at Siriraj Hospital – ailand’s largest
national tertiary referral center regardless of modality
of adjuvant treatment which was generally required in
advanced-stage cancer. is was the database of Division
of Gynecologic Oncology, Siriraj Hospital and use to be
the data for counselling patients in this group.
MATERIALS AND METHODS
is retrospective study was conducted at the Division
of Gynecologic Oncology, Department of Obstetrics &
Gynecology, Faculty of Medicine Siriraj Hospital. e
protocol for this study was approved by Siriraj Institutional
Review Board (Si 439/2017).
Endometrial cancer patients who were treated
during January 1998 to December 2014, and who had
surgically and/or clinically conrmed FIGO stage III-IV
endometrial cancer based on FIGO 2009 system
8
were
included. Patients who were treated before 2009 were
restaged, and patients with previously diagnosed stage
IIIA from positive cancer cells in peritoneal uid alone
were excluded from the study.
At our center, the standard operation included
peritoneal washing for cytology and total hysterectomy
with bilateral salpingo-oophorectomy. Among patients
considered at-risk for extrauterine disease, such as high-
grade tumor, large tumor volume, deep myometrial
invasion or non-endometrioid subtype, pelvic and/or
paraaortic lymphadenectomy or sampling was required.
All of the preceding operative procedures were performed
by gynecologic oncologists.
Response criteria was evaluated by the Response
Evaluation Criteria in Solid Tumors (RECIST) guideline
(version 1.1). Complete Response (CR) means disappearance
of all known lesion(s). Partial Response (PR) means at
least 30% decrease in the sum of diameters of known
lesions, Progressive Disease (PD) means at least 20%
increase in the sum of diameters of known lesions and/
or the appearance of new lesion(s). Stable Disease (SD)
means neither shrinkage nor increase to qualify for
PR nor PD.
9
Patients that were previously evaluated
for treatment response by World Health Organization
(WHO) criteria or RECIST guideline version 1.0 were
reevaluated using the current RECIST guideline version
1.1.
Follow-up data that was collected aer complete
treatment included careful history taking, and pelvic and
physical examinations by gynecologic oncologist every
3 to 4 months for the rst 2 years aer treatment, every
6 months for the next 3 years and every year thereaer.
Imaging study was performed when indicated. Recurrence
of disease was dened as evidence of measurable disease
and/or pathology/cytology conrmation.
9
e sites of
recurrence were classied as local (intra-pelvic region),
distant (extra-pelvic region) or both.
Sample size calculation
e sample size for this study was calculated based
on the previously reported estimated 12 percent rate
of advanced-stage among patients with endometrial
carcinoma.
10
At least 451 patients were required to achieve
95% condence level with a type I error at 0.05. Overall
survival (OS) was dened as the time between the rst
date of primary treatment and the date of death from
any cause or the last follow-up. Recurrence-free survival
(RFS) was dened by the last date of primary treatment
to the date of conrmed disease recurrence. is study
did not separately analyzed the data of patients who
had initially stable or progressive diseases, or the data
of patients that received other alternative or second-
Wutitammasuk et al.
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Original Article
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line treatments. ese should, therefore, be considered
possible confounding factors.
Statistical analysis
Descriptive statistics were used to assess and
summarize patient baseline characteristics, surgical data,
histopathology, treatment details, response status and
recurrence status. Categorical data are shown as number
and percentage, and continuous data are presented
as mean plus/minus standard deviation. Duration of
follow-up was dened as the date of last treatment to the
date of death or last follow-up. OS and RFS were each
estimated using the Kaplan–Meier method. Univariate
and multivariate Cox proportional hazard models were
used to identify any statistically signicant prognostic
factors. Associations are reported as hazard ratios (HRs)
and 95% condence interval (CIs). P-values less than
0.05 were considered statistically signicant. Statistical
analyses were performed using SPSS Statistics version
16 (SPSS, Inc., Chicago, IL, USA).
RESULTS
During January 1998 to December 2014, the incidence
of endometrial cancer at our center was 1,456 cases, and
415 (28.5%) of those were diagnosed with advanced-
stage (stage III/IV) endometrial carcinoma. Fieen of
415 patients that had incomplete data and/or incorrect
staging were excluded. e remaining 400 patients were
included in our nal analysis.
e mean age and body mass index (BMI) of patients
in this study was 58.5 years and 25.4 kg/m
2
, respectively.
ree-quarters of cases were menopause at the time
of diagnosis. Most patients presented with abnormal
vaginal bleeding and had good performance status.
Eighty-seven percent of cases (348/400) underwent
primary surgery. Most (334/348) of those operations were
performed via laparotomic approach. During surgery,
268 and 155 of 334 cases received pelvic and paraaortic
nodal evaluation, respectively. Complete removal of
disease was achieved in 270 of 348 cases that underwent
primary surgery. e most common histologic subtype
was endometrioid carcinoma (246/400, 61.5%). Fiy-
four percent of cases had high-grade (grade 3) tumor
histology. ere were 282 (70.5%) and 118 (29.5%) cases
that were diagnosed with stage III and IV disease at rst
diagnosis, respectively. Demographic, clinical, surgical
and pathological characteristics of patients are shown
in Table 1.
Aer complete primary treatment, complete response,
partial response, stable disease and progression of disease
was observed in 282 (70.5%), 7 (1.8%), 25 (6.2%) and 86
(21.5%) cases, respectively. Details relating to second-
line or alternative treatment were not included in this
study.
The median follow-up time was 24.5 months
(interquartile range [IQR]: 3.3-53.1), and one-third (94/282)
of complete response patients had disease recurrence.
e median recurrence-free interval was 12.25 months
(range: 0.99-80.49). e patterns of recurrence were
intra-pelvis, extra-pelvis and both in 31.9% (30/94),
48.9% (46/94) and 19.2% (18/94) of patients, respectively.
e 3-year recurrence-free survival (RFS) rate was 67%,
the 3-year overall survival (OS) rate was 50%, and the
median survival time was 42.5 months (range: 10.1-75.0).
Fig 1 shows Kaplan-Meier survival analysis compared
between stage III disease with stage IV disease.
Univariate analysis for factors signicantly associated
with OS and RFS is shown in Table 2. e factors signicantly
associated with OS included age, postmenopause status,
performance status, residual tumor aer primary surgery,
non-endometrioid histologic subtype, tumor grading,
FIGO staging, deep myometrial invasion, lymphovascular
space invasion, positive peritoneal cytology, lymph node
metastasis, extra-pelvic metastasis, receiving adjuvant
treatment and initial treatment response. e factors
signicantly associated with RFS were age, postmenopause,
non-endometrioid histologic subtype, tumor grading,
FIGO stage IVB, deep myometrial invasion and extra-
pelvic metastasis.
Multivariate analysis showed grade 3 tumor, lymph
node metastasis, ECOG performance status and
postmenopausal status to be signicant prognostic factors
for OS with adjusted hazard ratios (HRs ) of 17.0 (95%
condence interval [CI]: 3.1-92.1), 8.5 (95% CI: 2.1-
34.4), 7.8 (95% CI: 1.5-40.2), and 6.9 (95% CI: 2.3-20.2),
respectively. Extra-pelvic metastasis, grade 3 tumor and
age were signicant factors for RFS with adjusted HRs
of 10.4 (95% CI: 4.5-26.9), 9.5 (95% CI: 2.0-44.7), and
1.1 (95% CI: 1.0-1.1), respectively (Table 3).
DISCUSSION
e incidence rate of advanced stage (stage III,
IV) endometrial carcinoma in this study was 28.5%,
which is higher than the rates reported from previous
studies. e incidence rate of advanced-stage endometrial
carcinoma was 12% in a Taiwanese study, and 8.7% in a
study by Alvaro, et al.
7,10
is dierence in rates between
our study and the aforementioned two studies can be
explained by the fact that three-quarters of the patients
in our study were menopause with a high proportion
of high-grade tumor histology and non-endometrioid
(non-estrogen-related) subtype, which has an aggressive
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120
TABLE 1. Demographic and clinical characteristics of enrolled patients.
Characteristics
Age (years), mean±SD
Presenting symptom, n (%)
Abnormal vaginal bleeding
Pelvic mass
Pelvic pain
Other
Menopausal status
Premenopause
Postmenopause
ECOG performance status, n (%)
0
1
2
3
Primary surgery, n (%)
No
Yes
Residual tumor, n (%)
None
≤1cm
>1 cm
FIGO stage (2009), n (%)
IIIA
IIIB
IIIC1
IIIC2
IVA
IVB
Histology, n (%)
Endometrioid
Non-endometrioid
Tumor grade, n (%)
Grade 1
Grade 2
Grade 3
Peritoneal cytology, n (%)
Negative for malignancy
Positive for malignancy
Lymph node metastasis, n (%)
Negativity
Only pelvic LN metastasis
Only PAN metastasis
Both pelvic LN and PAN metastases
Adjuvant therapy, n (%)
None
CT alone
RT alone
Combined RT and CT
Abbreviations: SD = standard deviation; ECOG = Eastern Cooperative Oncology Group; FIGO = International Federation of Gynecology
and Obstetrics; pelvic LN = bilateral pelvic lymph node; PAN = paraaortic lymph node; CT = chemotherapy; RT = radiation therapy
n (%)
58.5±9.9
344 (86.0%)
17 (4.2%)
13 (3.2%)
26 (6.5%)
101 (25.2%)
299 (74.8%)
240 (60.0%)
122 (30.5%)
24 (6.0%)
14 (3.5%)
52 (13.0%)
348 (87.0%)
270 (67.5%)
24 (6.0%)
54 (13.5%)
94 (23.5%)
34 (8.5%)
103 (25.8%)
51 (12.8%)
5 (1.2%)
113 (28.2%)
246 (61.5%)
154 (38.5%)
65 (16.2%)
119 (29.8%)
216 (54.0%)
214 (53.5%)
73 (18.2%)
94 (23.5%)
116 (29.0%)
18 (4.5%)
45 (11.2%)
49 (12.2%)
188 (47.0%)
79 (19.8%)
84 (21.0%)
Wutitammasuk et al.
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TABLE 2. Univariate analysis for prognostic factors of overall survival and recurrence-free survival.
Age
Menopausal status
ECOG status
ECOG 0
ECOG 1
ECOG 2
ECOG 3
Residual tumor
None
≤1cm
>1 cm
Histology
Endometrioid
Serous
Clear cell
Mucinous
Poorly-differentiated
Mixed
Adenosquamous
Neuroendocrine
Carcinosarcoma
Tumor grading
Grade 1
Grade 2
Grade 3
FIGO staging
Stage IIIA
Stage IIIB
Stage IIIC1
Stage IIIC2
Stage IVA
Stage IVB
Myometrial invasion
≤1/2
>1/2
LVSI
Peritoneal cytology positive
for malignancy
Lymph node metastasis
Pelvic LN positive alone
PAN positive alone
Both Pelvic and PAN
Extrapelvic metastasis
Adjuvant treatment
Treatment response
Complete response
Partial response
Stable disease
Progressive disease
Factors
Overall survival Recurrence-free survival
HR (95% CI) P-value HR (95% CI) P-value
1.039 (1.022-1.057)
2.595 (1.000-3.962)
1
1.677 (1.169-2.404)
5.312 (3.166-8.913)
9.948 (5.387-18.370)
1
3.565 (2.076-6.121)
3.819 (2.531-5.763)
1
3.542 (2.409-5.206)
2.629 (1.261-5.481)
9.356 (1.279-68.438)
6.902 (3.952-12.053)
2.127 (1.261-3.587)
1.557 (0.215-11.301)
9.550 (2.307-39.535)
10.188 (4.046-25.650)
1
2.038 (1.006-4.127)
6.112 (3.189-11.714)
1
2.821 (1.377-5.777)
1.803 (1.024-3.173)
2.621 (1.427-4.816)
16.762 (4.914-57.174)
6.527 (3.945-10.800)
1
2.261 (1.502-3.405)
2.224 (1.391-3.555)
1.806 (1.104-2.953)
3.834 (2.156-6.818)
0.799 (0.421-1.518)
5.011 (1.678-14.963)
3.498 (1.964-6.227)
3.863 (2.787-5.355)
0.345 (0.208-0.573)
1
3.476 (1.263-9.564)
9.410 (5.287-16.749)
12.326 (8.443-17.994)
<0.001
<0.001
0.005
<0.001
<0.001
<0.001
<0.001
<0.001
0.010
0.028
<0.001
0.005
0.662
0.002
<0.001
0.048
<0.001
0.005
0.041
0.002
<0.001
<0.001
<0.001
0.001
0.018
<0.001
0.494
0.004
<0.001
<0.001
<0.001
0.016
<0.001
<0.001
1.041 (1.019-1.063)
2.160 (1.290-3.618)
1
1.316 (0.846-2.048)
1.287 (0.403-4.111)
NA
1
2.371 (1.141-4.927)
0.793 (0.344-1.824)
1
3.622 (2.191-5.986)
1.535 (0.477-4.942)
NA
6.214 (2.427-15.908)
2.964 (1.623-5.413)
NA
21.216 (2.822-159.502)
19.279 (4.561-81.498)
1
2.636 (0.994-6.992)
8.371 (3.365-20.824)
1
0.357 (0.084-1.513)
1.156 (0.656-2.038)
1.642 (0.872-3.094)
NA
2.606 (1.500-4.525)
1
1.712 (1.009-2.904)
1.228 (0.755-1.997)
1.504 (0.883-2.564)
1.423 (0.867-2.335)
0.510 (0.232-1.120)
1.041 (0.294-3.693)
1.955 (1.007-3.796)
2.365 (1.516-3.688)
1.034 (0.419-2.549)
<0.001
0.003
0.223
0.670
NA
0.021
0.585
<0.001
0.472
NA
<0.001
<0.001
NA
0.003
<0.001
0.051
<0.001
0.162
0.616
0.125
NA
0.001
0.046
0.408
0.133
0.163
0.093
0.950
0.048
<0.001
0.942
A p-value<0.05 indicates statistical signicance
Abbreviations: HR = hazard ratio; CI = condence interval; ECOG = Eastern Cooperative Oncology Group; FIGO = International Federation
of Gynecology and Obstetrics; LVSI = lymphovascular space invasion; pelvic LN = bilateral pelvic lymph node; PAN = paraaortic lymph node
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TABLE 3. Multivariate analysis for prognostic factors of overall survival and recurrence-free survival.
Factors
Overall survival Recurrence-free survival
HR (95% CI) P-value HR (95% CI) P-value
Age
Menopausal status
ECOG status
ECOG 0
ECOG 1
ECOG 2
ECOG 3
Residual tumor
None
≤1cm
>1 cm
Histology
Endometrioid
Serous
Clear cell
Mucinous
Poorly-differentiated
Mixed
Adenosquamous
Neuroendocrine
Carcinosarcoma
Tumor grading
Grade 1
Grade 2
Grade 3
FIGO staging
Stage III
Stage IV
Myometrial invasion
≤1/2
>1/2
LVSI
Peritoneal cytology positive
for malignancy
Lymph node metastasis
PAN positive alone
Both pelvic and PAN
Extrapelvic metastasis
0.962 (0.908-1.020)
6.874 (2.343-20.168)
1
0.405 (0.165-0.998)
7.845 (1.533-40.129)
NA
1
4.054 (0.786-20.909)
2.573 (0.823-8.049)
1
0.711 (0.277-1.829)
1.883 (0.436-8.134)
NA
NA
2.154 (0.685-6.773)
NA
2.904 (0.316-26.662)
0.051 (0.005-0.556)
1
2.765 (0.495-15.453)
17.018 (3.143-92.135)
1
4.866 (0.001-7.439)
1
0.950 (0.372-2.429)
1.467 (0.658-3.272)
0.957 (0.375-2.443)
8.496 (2.100-34.363)
4.561 (1.665-12.499)
4.337 (1.838-10.233)
0.001 (0.000-3.942)
0.195
<0.001
0.050
0.013
NA
0.094
0.104
0.480
0.396
NA
NA
0.189
NA
0.346
0.015
0.247
0.001
0.884
0.915
0.349
0.927
0.003
0.003
0.001
0.912
1.061 (1.008-1.117)
1.049 (0.301-3.652)
1
1.968 (0.365-10.596)
0.467 (0.054-4.045)
1
0.950 (0335-2.693)
0.597 (0.071-5.032)
0.507 (0.005-53.745)
5.010 (1.196-20.993)
1.318 (0.464-3.743)
1.040 (0.018-58.781)
7.477 (0.731-76.501)
0.697 (0.060-8.077)
1
2.492 (0.507-12.250)
9.526 (2.029-44.727)
1
0.415 (0.001-2.127)
1
1.273 (0.583-2.782)
1.273 (0.536-3.024)
10.379 (4.534-26.873)
0.024
0.940
0.431
0.489
0.923
0.597
0.775
0.028
0.604
0.985
0.090
0.773
0.261
0.004
0.840
0.545
0.584
0.004
A p-value<0.05 indicates statistical signicance
Abbreviations: HR = hazard ratio; CI = condence interval; ECOG, Eastern Cooperative Oncology Group; FIGO = International Federation
of Gynecology and Obstetrics; LVSI = lymphovascular space invasion; pelvic LN = bilateral pelvic lymph node; PAN, paraaortic lymph node
Wutitammasuk et al.
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nature. e combination of these factors increased the
number of patients with advanced-stage disease.
e age group that had the most advanced-stage
endometrial cancer from Surveillance, Epidemiology
and End Results (SEER) data was 55-64 years, and this
is similar to the mean age at rst diagnosis of 58.5 years
in our study
11
. Abnormal vaginal bleeding was the most
common presentation. Although they were diagnosed
with advanced stage, most of the patients in our study
had good performance status (ECOG 0-1) at diagnosis,
so we could not predict the severity of disease by patient
performance or clinical symptoms. e most common
histologic subtype was endometrioid subtype, but the
proportions of non-endometrioid subtype and high-
grade tumor dierentiation were both higher when
compared to the proportions previously reported for all
stages of endometrial carcinoma.
7
ese dierences in
ndings may be attributable to dierence among races,
as suggested by Koshiyama, et al. at group found
dierent histologic subtypes of epithelial ovarian cancer
among dierent nationalities.
12
e 3-year OS of advanced-stage endometrial cancer
in this study was 50%. is is similar to the 48.8% rate
reported by Alvaro, et al.
7
, but it is lower than the rate
reported from a Taiwanese study that included only
endometrioid subtype.
10
Our result showed that patient
survival decreased rapidly when they did not achieve
complete response aer primary treatment. Approximately
seventy percent of had evidence of extra-pelvic recurrence,
which is consistent with hematogenous spreading in
advanced-stage cancer. Systemic adjuvant therapy should,
therefore, be considered in advanced-stage endometrial
carcinoma even though the survival benet of adjuvant
treatment is inconclusive and still being debated.
13,14
Univariate analysis showed multiple factors aected
OS and RFS in advanced-stage endometrial carcinoma.
Subsequent multivariate analysis revealed the most
signicant prognostic factors for OS to be grade 3 tumor
(similar to previous studies
14-16
), lymph node metastasis,
ECOG performance status and postmenopausal status.
Extra-pelvic metastasis, tumor grading and age were
signicant prognostic factors for RFS.
Limitations
is study has some mentionable limitations. First,
the total number of enrolled cases in this study was smaller
than the calculated sample size, which means that our study
may have lacked the statistical power needed to identify
all signicant associations and dierences. However, the
incidence rate of advanced-stage endometrial cancer
in this study was higher than the rates reported from
previous studies.
7,10
Moreover, our sample size was larger
than the sample size from any other single-center study
reported from ailand. However, this can be improved
the accuracy and reliability of the results by multicenter
study. Secondly, this study did not separately analyzed
data from patients who had initially stable or progressive
diseases, or from patients received other alternative or
second-line treatment, and both of these factors could
aect patient survival. Lastly, the retrospective, non-
randomized nature of data collection resulted in some
incomplete information.
In conclusion, the results of this study revealed a rate
of advanced-stage endometrial cancer at rst diagnosis of
28.5%. Seventy percent of patients had complete response
aer primary treatment. e 3-year recurrence free
survival (RFS) rate was 67%, and about half of patients
succumbed to their disease within 3 years aer primary
Fig 1. Kaplan-Meier subgroup analysis of overall
survival according to FIGO staging in advanced
stage endometrial carcinoma patients.
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124
treatment. e signicant prognostic factors for overall
survival were grade 3 tumor, lymph node metastasis,
ECOG performance status and postmenopausal status.
ACKNOWLEDGMENTS
e authors gratefully acknowledge Dr.Saowalak
Hunnangkul of the Division of Clinical Epidemiology,
Department of Research and Development, Faculty of
Medicine Siriraj Hospital Mahidol University, Bangkok,
ailand for assistance with data analysis.
Conict of interest declaration: We declare no conicts
of interest, and no nancial support.
Funding disclosure: is study was no funding disclosure.
REFERENCES
1. Murali R, Soslow RA, Weigelt B. Classication of endometrial
carcinoma: more than two types. Lancet Oncol 2014;15:e268-
78.
2. Khuhaprema T, Srivatanakul P, Sriplung H, Wiangnon S,
Sumitsawan Y, Attasara P. Corpus Uteri. Cancer in ailand
2007;4:54-5.
3. Dowdy SC, Maríani A, Lurain JR. Uterine cancer. In: Berek JS,
ed. Berek & Novak’s gynecology. 15
th
ed. Philadelphia: Lippincott,
Williams & Wiikins; 2012. p.1250-93.
4. Randall ME, Filiaci VL, Muss H, Spirtos NM, Mannel RS,
Fowler J, et al. Randomized phase III trial of whole-abdominal
irradiation versus doxorubicin and cisplatin chemotherapy in
advanced endometrial carcinoma: a Gynecologic Oncology
Group Study. J Clin Oncol 2006;24:36-44.
5. Fleming GF,Brunetto VL,Cella D,Look KY,Reid GC,Munkarah
AR,et al. Phase III trial of doxorubicin plus cisplatin with or
without paclitaxel plus lgrastim in advanced endometrial
carcinoma: A Gynecologic Oncology Group Study. J Clin
Oncol 2004;22:2159-66.
6. igpen JT, Brady M, Homesley H, Malfetano J, DuBeshter
B, Burger RA, et al. Phase III trial of doxorubicin with or
without cisplatin in advanced endometrial carcinoma: A
Gynecologic Oncology Group Study (GOG). J Clin Oncol
2004;22:3902-8.
7. Álvaro TG, Jesús SJ, José LM, Sara BS, Laura MM, Gregorio LG,
et al. Overall survival and disease-free survival in endometrial
cancer: prognostic factors in 276 patients. Onco Targets er
2013;6:1305-13.
8. FIGO committee on gynecologic oncology. Revised FIGO
staging for carcinoma of the vulva, cervix, and endometrium.
Int J Gynaecol Obstet 2009;105:103-4.
9. Eisenhauer EA, erasse P, Bogaerts J, Schwartz LH, Sargent
D, Ford R, et al. New response evaluation criteria in solid
tumours: Revised RECIST guideline (version 1.1). Eur J Cancer
2009;45:228-47.
10. Chen JR, Chang TC, Fu HC, Lau HY, Chen IH, Ke YM, et al.
Outcomes of patients with surgically and pathologically staged
IIIA-IVB pure endometrioid-type endometrial cancer. Medicine
2016;95:1-11.
11. Howlader N, Noone A, Krapcho M, Miller D, Bishop K, Kosary
C, et al. SEER Cancer Statistics Review, 1975-2014. National
Cancer Institute 2017; Available from: https://seer.cancer.gov/
statfacts/html/corp.html.
12. Koshiyama M, Matsumura N, Konishi I. Subtypes of ovarian
cancer and ovarian cancer screening. Diagnostics (Basel)
2017;7:12.
13. Boer SMd, Powell ME, Mileshkin L, Katsaros D, Bessette P,
Haie-Meder C, et al. Adjuvant chemoradiotherapy versus
radiotherapy alone for woman with high risk endometrial
cancer (PORTEC-3): nal results of an international, open-label,
multicentre, randomised phase 3 trial. Lancet Oncol 2018;19:
295-309.
14. Kuku S, Williams M, McCormack M. Adjuvant erapy in
Stage III Endometrial Cancer Treatment Outcomes and Survival.
A Single-Institution Retrospective Study. Int J Gynecol Cancer
2013;23:1056-64.
15. Florescu M-M, Dragomirescu M, Stepan AE, Ciurea RN,
Margaritescu C, Simionescu CE. Histopathological Prognostic
Factors for Endometrial Carcinoma. Curr Health Sci J 2016;42:
139-44.
16. Lan C, Huang X, Huang Y, Xi S, Huang H, Feng Y, et al. e
outcome and efficacy of adjuvant chemotherapy alone in
patients with stage IIIA endometrial carcinoma with solitary
adnexal involvement: A retrospective single-institution study.
Gynecol Oncol 2014;135:446-50.
Wutitammasuk et al.
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Original Article
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Apirada ongsing, M.D., SurachaiLikasitwattanakula, M.D., Tanaporn Netsuwan, BA., Oranee Sanmaneechai, M.D.
Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, ailand.
Pediatric Neuromuscular Diseases Prevalence in
Siriraj Hospital, Thailand’s Largest Tertiary
Referral Hospital
ABSTRACT
Objective: ere are no epidemiological data on childhood neuromuscular diseases in ailand. We aimed to estimate
the proportion of NMDs among pediatric neurology patients in Siriraj Hospital and determine the specic diagnosis.
Methods: A retrospective study was conducted in the pediatric neuromuscular clinic at Siriraj Hospital between
2014 and 2016.
Results: Of 1,994 patients aged < 21 years with neurological diseases, 217 (10.88 %) had received a diagnosis.
Diagnostic clarity can be achieved using clinical tools such as electromyography, serum creatinine kinase, muscle
histo-immunology, and genetic analysis. Of the 217 patients, 143 (65.9 %) had inherited and 74 (34.1%) had acquired
neuromuscular diseases. e most common inherited NMD were the Dystrophinopathies, including Duchenne / Becker
muscular dystrophy (n = 58), while spinal muscular atrophy was the second most common (n = 25). Myasthenia
Gravis was the most common acquired neuromuscular disease (n = 36).
Conclusion: We found 10.88 percent of patients with neurological diseases have NMD. NMD is a chronic disease
with poor quality of life and so multidisciplinary clinical care is crucial for these patients. In order to improve the
standard of care, collaboration with government and other tertiary hospitals is important and will help serve a
growing population of NMD patients.
Keywords: Neuromuscular diseases; neurology; Duchenne Muscular Dystrophy; spinal muscular atrophy (Siriraj
Med J 2020; 72: 125-131)
Corresponding author: Oranee Sanmaneechai
E-mail: oranee141@gmail.com
Received 26 November 2018 Revised 15 August 2019 Accepted 16 October 2019
ORCID ID: http://orcid.org/0000-0002-4557-0387
http://dx.doi.org/10.33192/Smj.2020.17
INTRODUCTION
Neuromuscular diseases (NMD) usually result in
chronic long-term disabilities and pose a signicant burden
to society and the healthcare system. Most NMD patients
will need multi-disciplinary care due to complications
in multiple organ systems including joint contractures,
respiratory failure and cardiomyopathy. NMD can be
either inherited or acquired. It is important to precisely
diagnose patients since most acquired NMD can be
eectively treated. For inherited NMD, genetic counseling
is crucial to prevent inheritance (transmission) to the
next generation.
Neuromuscular disorders (NMD) can be broadly
divided by the location of the pathological lesions into
those aecting anterior horn cell (AHC), peripheral nerve,
neuromuscular junction (NMJ) and muscle bers.
1-3
Epidemiologic research that explores NMD types, frequency
and their associated genotypic distribution among the
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126
population is important to prioritize healthcare resource
allocation. Emery
2
conducted a comprehensive literature
review and estimated the global prevalence of inherited
neuromuscular diseases to be 28.6x10
-5
or 1 in 3,500. Other
studies have reported a higher prevalence. For example,
in Northern Ireland the prevalence of inherited NMD
in patients age 0-84 years was estimated to be 34.5x10
-5
or 1 in 2,900.
4
A study of childhood neuromuscular
diseases (age 0-15 years) in western Sweden
5
reported the
prevalence to be 63.1x10
-5
for all neuromuscular diseases
and 53.1x10
-5
for inherited neuromuscular diseases. is
study also reported that in 227 children with NMDs,
191 (84%) had inherited NMDs. In contrast, a study
of Chinese children with NMDs (age <19 years old) in
Hong Kong
6
reported a prevalence of 21.4x10
-5
or 1 in
4,669. In the Chinese study, the investigators found that
(68%) of 332 children with NMD had inherited disease.
For prevalence of inherited muscle diseases, a study from
Northern England reports 37.0x10
-5
According to these
studies, the most common inherited NMD are muscular
diseases, followed by anterior horn cell and peripheral
nerve diseases.
4-8
Few studies have examined the prevalence and
proportion of inherited NMD in childhood and none
were conducted in ailand. Worldwide, the diagnosis
of inherited NMD is improving, especially for those
involving single genes. For the more complex diseases
involving multiple genes, the diagnosis still largely depends
on the technical capability of each institution. is,
in turn, aects healthcare resource allocation. ere
is currently no cure for inheritable NMD. erefore,
genetic counseling is essential to achieve a disease-free
state in at-risk individuals and their ospring who are
disease carriers.
e Multidisciplinary Neuromuscular Clinic at
Siriraj Hospital is the largest tertiary care referral center
in ailand. Each year, the clinic sees (diagnoses?) over
100 (new?) cases of pediatric NMD. An understanding
of the proportion of inherited NMD can provide insight
into the urgent need for genetic diagnosis, counseling
and intervention in this vulnerable patient population.
Epidemiologic research is important in all ethnic groups
to gain understanding about genetic parameters, inform
healthcare planning, and to enable interethnic group
comparisons. This study will also contribute to the
development of a registry that will prepare our hospital
for future clinical trials of new therapeutic agents. e
data will also support resource management decisions,
policy planning, and the allocation of rehabilitation
and social welfare program funds.
5,6,9,10
It is dicult to
estimate the prevalence of neuromuscular diseases in
ailand since there are multiple academic hospitals
treating these patients. Siriraj Hospital is ailand’s largest
tertiary hospital with more than 2,000 beds. e distinct
dierent from other hospital is that Siriraj has pediatric
neuromuscular clinic which is considered the rst one in
ailand. Our data represents the proportion of NMDs
among other pediatric neurological diseases in Siriraj
Hospital. erefore, we conducted a retrospectivestudy of
the clinical characteristics of NMD children that receive
care at the neuromuscular clinic (NMC) at Siriraj Hospital,
the largest academic medical center in ailand.
MATERIALS AND METHODS
Objective
To report the number and specic diagnosis of
NMD cases referred to Neuromuscular Clinic at Siriraj
Hospital in Bangkok, ailand, with a focus on the
proportion of inherited NMDs found in this population.
Methods
is was a retrospective study of patients aged 0-21
years with pediatric neuromuscular disease and pediatric
neurologic disease at Siriraj Hospital between July 2014
and December 2016. e institutional Review Board at
Faculty of Medicine Siriraj Hospital Mahidol University
approved the study (Si 724/2015). Patients were seen
in the neurology clinic or neuromuscular clinic. e
Neuromuscular clinic is a multi-disciplinary clinic that
oers specialist care in Pediatric Neurology, Rehabilitation,
Orthosis, Physical erapy and social work. We used
Emery’s criteria and the classication of the World
Federation of Neurology Research Committee Group
on Neuromuscular Disease
2,11,12
to make the diagnosis.
A pediatric neurologist specializing in neuromuscular
disease examined all patients. Appropriate investigations
including nerve conduct study (NCS), serum creatinine
kinase (CK), electromyography (EMG), muscle biopsy
and molecular genetic study were performed to establish
the diagnosis. Approximately 90% of all patient received
full investigations, the rest are diagnosed by clinical
diagnosis for partial investigation. Demographic data,
socioeconomic status, clinical manifestations, complications
and treatment of the disease were collected.
Operational denitions: neuromuscular disorders
aect the nerves that control motor or sensory functions
and the muscle itself, other neurological disorders in this
manuscript means that the neurological disorders that
are not neuromuscular disorders, and inherited NMDs
are neuromuscular disorders that cause by a broad group
of genetic conditions.
Thongsing et al.
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RESULTS
ere were 217 children with NMD who followed
up at the Pediatric Neurology Clinic, representing 10.88%
of all patients with neurologic disease who presented to
the clinic during the study period. One hundred forty-
three patients (65.9%) had inherited neuromuscular
diseases. (Table 1). e most common inherited NMD
is Dystrophinopathies (Duchenne Muscular Dystrophy
(DMD)/Becker Muscular Dystrophy (BMD)) (n=58).
(Table 2) e second most common is Spinal Muscular
Atrophy (SMA) (n= 25), followed by Hereditary Motor
Sensory Neuropathy (HMSN) (n= 16). e most common
acquired NMD was Myasthenia Gravis (MG) (n=36),
followed by Brachial Plexus Injury (n=9), and Acute
Inammatory Demyelinating Polyneuropathy (AIDP)
(n=7), respectively. (Table 3) irty-ve of these 143
patients (24%) also had a positive family history of a
similar disorder in a rst or second-degree relative.
(Table 4)
Since the Dystrophinopathies are the most common
inherited neuromuscular disease found in our NMC clinic,
we also collected further clinical information from these
patients (Table 5). Twenty-six (45%) DMD patients were
ambulatory. Of the 58 DMD patients, 55 were sent for
genetic study (54 sent for Multiplex Ligation-dependent
Probe Amplication (MLPA) and 1 sent for Polymerase
chain reaction (PCR). Twenty-nine (50%) were diagnosed
by MLPA, while the test showed no abnormality in the
remaining 26 patients. Seven DMD patients were not
receiving steroids due to side eects including obesity.
SMA was the second most common inherited neuromuscular
disease (Table 6). All SMA patients received genetic
study (PCR or Denaturing High Performance Liquid
Chromatography (DHPLC)), however one patient result
was missing because he was diagnosed at a dierent
hospital. Overall, 76% of the patients had exon 7&8
deletion of the SMN1 gene. 60% of these patients were
SMA type II.
DISCUSSION
e estimated prevalence of neuromuscular disease
among patients with neurological diseases was 10%, similar
to a previous report.
13
e majority of neuromuscular
diseases in our pediatric patients are inherited in nature.
Even with muscle biopsy however, it is sometimes dicult
to conclude if the etiology is acquired or inherited. In these
cases, next generation sequencing is a promising tool for
patient care. Interestingly, with the arrival of detailed
genetic testing and sophisticated histo-immunochemical
staining methods, established diagnoses are sometimes
changed.
We found that inherited NMDs constituted 65.9%
of all NMDs, similar to a report from Hong Kong. at
study also found that Dystrophinopathies followed by
SMA, were the most common NMD.
6
A Swedish study,
5
reported a higher percentage of inherited NMDs (84%)
and the most common diseases were Hereditary Motor
Sensory Neuropathy (HMSN), Dystrophinopathies and
SMA, respectively. However, when the dataset includes
adult patients such as in studies from Northern Ireland
4
and Northern England,
8
the most common neuromuscular
disease becomes Myotonic Dystrophy then followed
by DMD. is may be due to pediatric patients with
Myotonic Dystrophy normally having mild disease
severity compare to other congenital neuromuscular
diseases, so they don’t seek medical attention. Since
the most common inherited neuromuscular diseases in
children are not dierent from previous studies, we can
conclude that ethnicity is not an important etiological
factor. e previous studies done in all age group show
dierently because the age dierent of population. Four
patients were diagnosed with Nonspecic muscle disease,
due to limited diagnostic resources, especially advance
immunochemistry and next generation sequencing. A
collaboration with an international neuro-genetic center
would be helpful for these patients.
Location Inherited Acquired
Anterior horn cell 25 (11.52%) 2 (0.92%)
Peripheral nerve 16 (7.37%) 28 (12.90%)
Neuromuscular junction 3 (1.38%) 36 (16.59%)
Muscle 99 (45.62%) 8 (3.69%)
Total 143 (65.9%) 74 (34.1%)
TABLE 1. A 217 patients with neuromuscular diseases classify by neuroanatomy and etiology.
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TABLE 2. Detail of specic neuromuscular diseases including acquired and inherited, categorize by anatomical origin.
N
Anterior Horn Cell (AHC)
Spinal Muscular Atrophy (SMA) 25
Monomelic Amyotrophy (MMA) 2
Peripheral Nerve (PNS)
Hereditary Motor Sensory Neuropathy (HMSN) 16
Brachial Plexus Injury 9
Peroneal Nerve Injury 4
Sciatic Neuropathy 2
Left L2-4 Plexopathy 1
AcuteInammatoryDemyelinating
Polyneuropathy (AIDP) 7
ChronicInammatoryDemyelinating
Polyneuropathy (CIDP) 3
Diabetic Polyneuropathy 1
Acute Motor Axonal Neuropathy (AMAN) 1
Neuromuscular Junction (NMJ)
Congenital Myasthenic Syndrome (CMS) 3
Myasthenia Gravis 36
Muscle
Muscular Dystrophy* 79
Congenital Myopathy* 10
HyperCKemia 1
Mitochondria/Metabolic Myopathy* 5
Polymyositis 4
Juvenile Dermatomyositis 2
Necrotizing Autoimmune myositis 2
Nonspecicmuscledisease 4
*Please nd more diagnosis detail for inherited muscular dystrophy, congenital myopathy and mitochondria/metabolic myopathy in Table 3.
TABLE 3. Detail of 99 patient with inherited muscular dystrophy, congenital myopathy and mitochondria/metabolic
myopathy.
N
Muscular Dystrophy
Duchenne Muscular Dystrophy (DMD) /Becker
Muscular Dystrophy (BMD) 58
Congenital Muscular Dystrophy (CMD) 6
Emery-Dreifuss Muscular Dystrophy (EDMD) 3
Ullrich Congenital Muscular Dystrophy (UCMD) 2
COL6A1 Congenital Muscular Dystrophy 2
Facioscapulohumeral muscular dystrophy (FSHD) 2
Limb-girdle muscular dystrophy (LGMD) type IIB 1
Non-specicMuscularDystrophy 5
Congenital Myopathy
CongenitalMyopathy(Non-specic) 7
Congenital Myopathy Uniform type 1 1
MyobrillarMyopathy 1
Congenital Myopathy (Titin)
Mitochondria/Metabolic Myopathy 1
Glutaric aciduria type II with myopathy 3
Hypokalemia Periodic Paralysis (PP) 2
Nonspecicmuscledisease 4
Thongsing et al.
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TABLE 4. e detail of 35 inherited neuromuscular disorders cases with positive family history.
TABLE 5. e characteristic of 58 DMD patients.
TABLE 6. e characteristic of SMA patients (n=25).
Inherited neuromuscular disorders Positive Family History Cases Affected Family
DMD 16/58 (28%) 11/53 (21%)
CMT 4/16 (25%) 4/16 (25%)
SMA 1/25 (4%) 1/25 (4%)
Other 14/44 (32%) 9/39 (23%)
Total 35/143 (24%) 25/133 (19%)
Value
Clinical Stage
Early ambulatory 17 (29.3%)*
Late ambulatory 9 (15.5%)*
Early non-ambulatory 19 (32.8%)*
Late non-ambulatory 13 (22.4%)*
CPK level (n=50) 22,182 ± 56,008 (3,517 - 405,418)**
Diagnosis by MLPA 29 (50%)*
Deletion 24 (41.1%)*
Duplication 5 (8.6%)*
Restrictive Lung 10 (17.2%)
Cardiomyopathy 8 (13.8%)
Steroid 51 (87.9%)
*n (%), **mean ± SD
Value
Type
Type I (0-6 mo.) Non-Sitter 2 (8%)*
Type II (7-18 mo.) Sitter 15 (60%)*
Type IIIA (>18 mo.) Walker and age onset < 3 years 4 (16%)*
Type IIIB (>18 mo.) Walker and age onset > 3 years 4 (16%)*
Exon 7&8 deletion 19 (76%)*
Exon 7 deletion 5 (20%)*
*n (%)
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e second most common inherited NMD in our
study was SMA, a disease that is oen reported to be
associated with SNM1 gene deletion in exon 7. In a
separate study, we found deletions in both exon 7 and 8.
14
We also reported that SMA type II was the most common
in our patient population, while another study reported
Type I as most common.
15
is reects our status as a
provider of tertiary care neurologic consultation. ose
with SMA type I whose disease is severe may not have
been referred in time to receive our care. is dierence
could also be due to the fact that the diagnosis of SMA
type I is typically made early in the course of disease
by a geneticist, and these patients may die before being
evaluated by neurologist or geneticist.
Despite representing only 10% of all patients,
management of the pediatric neuromuscular disease
population is challenging. ese diseases are chronic,
progressive and are associated with severe disability from
joint contractures, respiratory failure, cardiomyopathy
and scoliosis, while most patients have intact cognition.
e goal of supportive care is to prevent complications
and provide physical therapy to overcome limitations
and improve quality of life. Hence, multidisciplinary
management in an established neuromuscular clinic is
crucial to improve quality of life for these patients. Prenatal
diagnosis also plays important role since inherited NMDs
oen aect family members in dierent generations.
erefore, intervention to prevent the disease in ospring
can decrease disease prevalence
3
as well as reduce social
and healthcare costs. e limitation of the study also
include that this study is single center study, thus we
can’t provide the information about the prevalence of
neuromuscular disease in ailand.
CONCLUSION
We found 10.88 percent of patients with neurological
diseases have NMD. e majority of children with NMD
who follow up at Siriraj Hospital had Duchenne Muscular
Dystrophy, Hereditary Motor Sensory Neuropathy and
Spinal Muscular Atrophy. Childhood NMD is a chronic
disease with poor quality of life and so multidisciplinary
clinical care is crucial for these patients. In order to improve
the standard of care, collaboration with government
and other tertiary hospitals is important and will help
serve a growing population of NMD patients. Limited
access to advanced diagnostic modalities prevents proper
diagnosis in some patients. A future collaboration with
an international genetics research center would be an
important step forward to help establish a disease registry
and improve genetic counseling in ailand. National
treatment guidelines and uniform implementation in
pediatric neuromuscular disease clinics is needed for
ailand and other developing countries.
ACKNOWLEDGMENTS
e authors would like to deeply thank all parents,
caregivers and patients with neuromuscular diseases for
their kind participation. We gratefully acknowledge the
sta of the Neurogenetic and Neuromuscular Research
Network Faculty of Medicine Siriraj Hospital for their
support of this study and for providing exceptional patient
care. e authors would also like to thank Miss Chanapa
Supachad for research coordination and support, and
Dr. Chulathida Chomchai for assistance with English
editing.
Funding: Faculty of Medicine Siriraj Hospital, Mahidol
University, Bangkok, ailand
Ethical approval: e Siriraj Hospital Institutional Review
Board approved this study.
Competing interest: All authors declare that there is
no conict of interest.
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Prakasit Wannapaschaiyong, M.D., Achra Sumboonnanonda, M.D., Jeerunda Santiprabhob, M.D.
Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, ailand.
Long-Term Outcomes of Group-Based Treatment
for Obese Children and Adolescents
ABSTRACT
Objective: A 1-year, group-based, treatment program with parental involvement was conducted on 115 obese
youths during 2006-2011. e intervention decreased obesity severity. e current study assessed the participants’
long-term weight loss and obesity-related complications.
Methods: Participants were invited for a single visit. eir weights, heights, and waist circumferences were measured
and compared with corresponding gures at group-based treatment program completion. Factors associated with
changed percentage weight-for-height (%W/H) were assessed.
Results: ere were 43 subjects, including 6 participating telephonically. e median follow-up duration was 5.8
years. %W/H, BMI, and waist circumference increased signicantly (p = 0.012, 0.002, and 0.003, respectively).
%W/H rose for 26 participants (60.5%; failed group) but declined or stabilized for 17 (39.5%; successful group).
e successful-group exercise duration and frequency were signicantly higher (p = 0.006 and 0.018, respectively).
ree participants had type 2 diabetes, including 1 known case, all in the failed group. Newly-found obesity-related
disorders were elevated transaminases (6 participants, with 5 from the failed group), elevated blood pressure
(1 failed-group participant), and dyslipidemia (one from each group).
Conclusion: Only 40% of the participants maintained long-term weight reduction. Regular exercise was associated
with successful weight maintenance. Obesity-related complications were common in the failed group.
Keywords: Obese; child; adolescent; group-based treatment; outcome (Siriraj Med J 2020; 72: 132-139)
Corresponding author: Jeerunda Santiprabhob
E-mail: jeerunda.san@mahidol.ac.th
Received 24 April 2019 Revised 26 July 2019 Accepted 8 August 2019
ORCID ID: http://orcid.org/0000-0002-4726-9360
http://dx.doi.org/10.33192/Smj.2020.18
INTRODUCTION
Obesity among children and adolescents is increasing
globally, leading to numerous health problems.
1,2
Complications such as type 2 diabetes (T2DM), metabolic
syndrome, hypertension, and dyslipidemia are as common
among obese children as among obese adults.
1, 2
Adolescent
obesity is associated with increased adulthood mortality
from ischemic heart disease, metabolic diseases, respiratory
diseases, etc.
3
It is therefore imperative to address obesity
early to obviate detrimental health eects in adulthood.
Childhood obesity treatment involves dietary
control, increased physical activity, and lifestyle
changes. Phamarcotherapy should only be considered
for adolescents unable to reduce weight via intensive
lifestyle modications, and bariatric surgery is only
recommended for severely obese adolescents of nal
or near-nal height with extreme complications.
4
e
treatment goals are weight maintenance or gradual
weight loss, depending on age and obesity degree.
5
At our institute, a 1-year, group-based treatment
program with parental involvement was conducted
during 2006-2011.
6
Participants underwent behavioral
modication as inpatients at the start of the program and
via 5, group-based, outpatient sessions in months 1, 2,
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3, 6, and 9. e detail of the intervention was previously
described.
6
Of the 126 participants (mean age 12.3 years),
115 completed the program. By program-end, the percentage
weight-for-height (%W/H) and percentage body fat
had decreased signicantly (181.8 ± 39.1% vs. 169.3 ±
36.3%, p < 0.001; and 48.2 ± 5.1% vs. 45.0 ± 6.8%, p <
0.001, respectively). Moreover, glucose metabolism, lipid
proles, and liver functions had improved.
6
Although our program produced successful weight
management at the end of the 1-year intervention, long-
term weight-maintenance data was lacking. Previous
studies
7-9
that demonstrated long-term successful weight
loss, had more intensive intervention with more frequent
sessions than our program. is study aimed to examine
the long-term impact of our 1-year, group-based treatment
program, consisting of an initial hospitalization and 5
outpatient sessions, on weight maintenance and obesity-
related complications, and factors associated with weight-
control success.
MATERIALS AND METHODS
A cross-sectional study of the participants of the 1-year,
group-based program was conducted at the Department
of Pediatrics, Faculty of Medicine Siriraj Hospital, during
2014-2016. Participants were invited by telephone or mail
to a single visit to obtain anthropometric measurements;
if unable to attend, a phone interview was conducted.
e number of daily meals, frequency and duration
of exercise (all intensity of aerobic exercise, anaerobic
exercise and any physical activity were included), interim
obesity treatment (including follow-up at our Pediatric
Endocrine clinic and/or at other Hospital), and healthy
lifestyle habits (healthy eating and regular exercise) were
collected. Participants with %W/H > 120% were dened
as obese
10
and were advised to test for fasting blood sugar
(FBS), lipid prole, and liver enzymes.
Blood tests were performed aer overnight fasting.
Glucose was measured using an automated analyzer (Integra
800/Cobas 8000; Roche Diagnostics, Manheim, Germany).
Total cholesterol, HDL-cholesterol, LDL-cholesterol,
triglycerides, ALT, and AST were measured using a
biochemical autoanalyzer (Cobas 8000; Roche Diagnostics).
HbA1c was determined using turbidimetric inhibition
immunoassay (Integra 800 CTS, Roche Diagnostics).
Participants whose %W/H had risen since program-
end were categorized as “failed”; those with reduced or
maintained %W/H were deemed “successful”.
Siriraj Ethics Committee, Mahidol University,
approved this study. All participants gave informed
consent (Si 626/2013).
Statistical analysis
To make comparisons between the participants
and the unreachable/non-participating individuals,
and between the failed and successful weight-control
groups, independent t-tests were used for the normally
distributed data, and Mann–Whitney U tests for the non-
normally distributed data. Comparisons of the clinical
and biochemical data at program-end and long-term
follow-up were performed by paired t-test for the normally
distributed data and Wilcoxon signed-rank test for the
non-normally distributed data. Logistic regression analysis
identied the weight-management strategies associated
with successful weight maintenance after program-
end: 1) no treatment nor continued healthy lifestyle;
2) continued follow-up at our clinic; and 3) continued
healthy lifestyle (diet control and regular exercise) for at
least 12 months preceding this study. A chi-square test
was performed to assess the dierence in the numbers
of participants for each treatment strategy in the failed
and successful groups. e normally distributed data
were presented as mean ± standard deviation, and the
non-normally distributed data as median (min, max).
Statistical signicance was p < 0.05. Data were analyzed
using SPSS (version 18.0).
RESULTS
Out of 115 participants who completed the 1-year
group-based program, 37 participants enrolled, and
another 6 were interviewed telephonically (22 males and
21 females). Fourteen declined, and 58 were unreachable
(Fig 1).
Demographic data at the end of the group-based
obesity treatment program of the participants and non-
participants were similar, except the non-participants had
longer durations aer completing their weight-treatment
programs (Table 1).
Overall, obesity severity had worsened since program-
end (Table 2). Twenty-six participants (60.5%), consisting
of 14 males and 12 females, had increased %W/H (failed
group); the remaining 17 participants (39.5%), consisting
of 8 males and 9 females, had a maintained or decreased
%W/H (successful group). e successful group exercised
more frequently than the failed group (4.7 ± 2.0 vs. 2.9 ±
2.7 days/week, p = 0.018), and for longer (240 [80,1890]
vs. 110 [0,900] min/week, p = 0.006; Table 3).
As to treatment following program-end, 25 participants
(58.1%) did not continue healthy lifestyles nor receive
weight-reduction treatment during the preceding year.
Twenty of those (80%) were in the failed group. Of the
14 participants (32.6%) continuing healthy lifestyles
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134
Fig 1. Numbers of participants at the beginning of the 1-year intervention, at the end of the intervention, and at the long-term follow-up.
TABLE 1. Comparison of demographic characteristics at the end of the group-based program of participating and
unreachable/non-participating volunteers.
Participating Unreachable/
Data volunteers non-participating group P-value
(n = 43) (n = 72)
Male
a
, person 22 (51.2) 37 (51.4) 0.981
Age (years) 13.2 ± 2.2 13.4 ± 2.0 0.548
%W/H (%) 167.2 ± 32.8 170.1 ± 37.6 0.670
BMI (kg/m
2
) 31.9 ± 6.5 32.6 ± 7.1 0.570
Waist (cm) 94.0 ± 14.1 95.6 ± 13.8 0.548
Waist-height ratio 0.59 ± 0.1 0.59 ± 0.1 0.892
Years after program-end
b
(years) 5.8 (3.8–8.6) 7.2 (5–8.6) < 0.001
Data presented as mean ± SD,
a
Data presented as number (percentage),
b
Data presented as median (min, max)
Abbreviations: BMI = body mass index; %W/H = percentage weight-for-height
(dietary control and regular exercise) during the year
preceding the long-term follow-up study, 11 (78.6%)
were in the successful group. Four participants (9.3%)
received continuing health follow-ups at our institute;
3 (75%) of those were in the failed group. In the case of
the successful group, more participants continued with
healthy lifestyles than those who did not continue healthy
lifestyles nor receive treatment, or who continued to
receive follow-up at our institute (p = 0.001). A logistic
regression analysis showed that continuing healthy lifestyles
was associated with weight-control success (OR 14.67,
p < 0.001).
Nineteen participants with increased %W/H had
blood tests to evaluate metabolic complications (19 had
HbA1c; 18 had BS, 17 had lipid proles, and 15 had
ALT and AST). Ten successful-group participants also
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TABLE 2. Comparison of clinical characteristics of participants at the end of the group-based program and at long-
term follow-up.
At program-end At long-term follow-up P-value
Age (years) 13.2 ± 2.2 19.2 ± 2.2 < 0.001
Percentage weight-for-height (%) 167.2 ± 32.8 180.9 ± 52.9 0.012
BMI (kg/m
2
) 31.9 ± 6.5 35.2 ± 10.1 0.002
Waist
a
(cm) 95.0 ± 13.8 102.4 ± 21.8 0.003
Waist-height ratio
a
0.59 ± 0.1 0.61 ± 0.1 0.164
Systolic blood pressure
a
(mmHg) 118 ± 12 127 ± 13 < 0.001
Diastolic blood pressure
a
(mmHg) 67 ± 9 78 ± 12 < 0.001
Data presented as mean ± SD,
a
n = 37
Abbreviation: BMI = body mass index
TABLE 3. Comparison of characteristics and factors aecting obesity control of the “failed” and “successful” groups.
Failed group Successful group
n = 26 n = 17
P-value
Male, person
a
14 (53.8) 8 (47.1) 0.663
Age (years) 19.6 ± 2.2 18.5 ± 2.1 0.127
Weight (kg) 112.5 ± 29.8 76.1 ± 13.2 < 0.001
Height (cm) 166.7 ± 9.4 166.7 ± 7.0 0.978
BMI (kg/m
2
) 40.2 ± 9.4 27.4 ± 4.9 < 0.001
%W/H (%) 207.5 ± 48.9 140.1 ± 26.6 < 0.001
Difference in %W/H between program-end 36.3 ± 22.9 -20.8 ± 13.2 < 0.001
and the long-term follow-up
Exercise frequency (days/week) 2.9 ± 2.7 4.7 ± 2.0 0.018
Exercise duration
b
(min/week) 110 (0, 900) 240 (80, 1890) 0.006
Sleeping duration (hours/day) 7.7 ± 1.3 7.6 ± 1.1 0.780
Time spent on TV and internet (hours/day) 5.6 ± 3.1 4.2 ± 2.9 0.149
Number of meals daily 2.9 ± 0.4 2.8 ± 0.4 0.849
Data presented as mean ± SD,
a
Data presented as number (percentage),
b
Data presented as median (min, max)
Abbreviations: BMI = body mass index; %W/H = percentage weight-for-height
sought blood testing (10 had BS and lipid prole; and
9 had HbA1c, AST, and ALT). e results, detailed in
Table 4, revealed increased FBS, ALT, total cholesterol,
LDL-cholesterol, and HDL-cholesterol levels (p = 0.002,
0.031, 0.001, 0.041, and 0.003, respectively). e comparison
of biochemical data between the failed-group participants
and successful-group participants was shown in Table 5.
Failed-group participants had higher levels of FBS and
ALT and lower level of HDL-cholesterol (p = 0.005,
p = 0.012, p = 0.002, respectively).
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TABLE 4. Comparison of biochemical data at the end of the group-based program and at long-term follow-up.
TABLE 5. Comparison of biochemical data between the “failed-group participants” and “successful-group participants”
at the long-term follow-up study.
At program-end At long-term follow-up P-value
FBS (mg/dl; n = 28) 85 (71–96) 91 (76–209) 0.002
HbA1c (%; n = 28) 5.6 (4.8–6.2) 5.5 (4.5–8.9) 0.120
Triglyceride (mg/dl; n = 27) 84 (33–315) 93 (37–314) 0.869
Total cholesterol
a
(mg/dl; n = 27) 163.4 ± 28.3 180.3 ± 29.4 0.001
HDL-cholesterol
a
(mg/dl; n = 27) 45.6 ± 7.9 53.8 ± 14.0 0.003
LDL-cholesterol
a
(mg/dl; n = 27) 97.7 ± 24.2 106.2 ± 29.4 0.041
AST (U/L; n = 24) 19 (12–60) 20 (14–58) 0.884
ALT (U/L; n = 24) 17 (8–69) 23 (12–108) 0.031
Data presented as median (min-max),
a
Data presented as mean ± SD
Abbreviations: FBS = fasting blood sugar; AST = aspartate transaminase; ALT = alanine transaminase; HbA1c = hemoglobin A1c; HDL-
cholesterol = high-density lipoprotein cholesterol; LDL-cholesterol = low-density lipoprotein cholesterol
Failed-group Successful-group
participants participants
P-value
FBS (mg/dl) 93 (83–209) [n=18] 83 (76–94) [n=10] 0.005
HbA1c (%) 5.5 (4.7–8.9) [n=19] 5.2 (4.5–5.9) [n=9] 0.236
Triglyceride (mg/dl) 95 (48–314) [n=17] 74 (37–122) [n=10] 0.075
Total cholesterol
a
(mg/dl) 182.3 ± 30.6 [n=17] 182.1 ± 31.0 [n=10] 0.881
HDL-cholesterol
a
(mg/dl) 46.6 ± 11.0 [n=17] 64.4 ± 13.2 [n=10] 0.002
LDL-cholesterol
a
(mg/dl) 111.9 ± 23.2 [n=17] 102.0 ± 39.6 [n=10] 0.415
AST (U/L) 20 (14–58) [n=15] 18 (14–29) [n=9] 0.324
ALT (U/L) 33 (15–108) [n=15] 16 (12–50) [n=9] 0.012
Data presented as median (min-max),
a
Data presented as mean ± SD
Abbreviations: FBS = fasting blood sugar; AST = aspartate transaminase; ALT = alanine transaminase; HbA1c = hemoglobin A1c; HDL-
cholesterol = high-density lipoprotein cholesterol; LDL-cholesterol = low-density lipoprotein cholesterol
At program-end, the 43 participants had these obesity
complications: impaired glucose tolerance, 6 (14.0%);
T2DM, 1 (2.3%); dyslipidemia, 17 (39.5%), comprised of
hypertriglyceridemia, 6 (14%), low HDL-cholesterol, 11
(25.6%), and high LDL-cholesterol, 5 (11.63%); elevated
transaminases, 1 (2.3%); and hypertension, 4 (9.3%).
In this long-term follow-up study, 28 had FBS
performed; 3 (10.7%) had T2DM, comprising 2 new cases
plus 1 case diagnosed during the group-based treatment
program. e three were: 1) a 20-year-old female, with
%W/H of 225.5% and a 48.9-kg weight gain over 7 years
4 months; 2) a 21-year-old female, who had had impaired
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glucose tolerance during the group-based treatment
program, with %W/H of 221.3% and a 21.5-kg weight
gain over 5 years; and 3) a 22-year-old male, diagnosed
with T2DM during the group-based treatment program,
with %W/H of 254.1% and a 38.7-kg weight gain over 5
years 9 months. All three belonged to the failed group,
had family histories of diabetes, and did not consistently
control their diets or exercise before this study.
Four out of the 37 participants (10.8%) had elevated
blood pressure; 3 were from the failed group. One failed-
group participant had newly-found elevated blood pressure.
All four had a family history of hypertension. Out of
27 participants tested for lipid proles, 9 (33.3%) had
dyslipidemia (hypertriglyceridemia, 3; low HDL-cholesterol,
4; and high LDL-cholesterol, 5), with 7 from the failed
group, including 1 new case. Only 1 successful-group
participant had newly-found high LDL-cholesterol. Out
of 24 participants tested for liver function, 7 (29.2%) had
elevated transaminases; 6 from the failed group included
5 new cases. Only 1 successful-group participant had
newly-found elevated transaminases.
DISCUSSION
During 2006-2011, 115 obese children and adolescents
participated in a 1-year, group-based treatment program
focusing on healthy lifestyles and parental involvement.
6
Forty-three (37.4% of the initial subjects) enrolled in this
subsequent, cross-sectional, follow-up study. Overall,
they demonstrated an increased degree of obesity, with
a median of 5.8 years aer the program ended. However,
40% maintained their weight loss.
Weight-reduction programs involving more intensive
therapy were reported to be successful at long-term weight
maintenance.
7-9
An intensive program involving parents
by Reinehr et al. resulted in sustained weight reduction
for most participants 3 years aer program-end.
7
is
“Obeldicks” program comprised a 3-month intensive
phase, with patients attending 6 group sessions and
parents 6 evening sessions; a 6-month establishing phase,
with individual, monthly, psychological family therapy
given; and a late phase, with individual care if necessary.
Moreover, weekly exercise therapy was provided for
12 months.
11,12
Participants were monitored annually
up to 3 years following intervention-end; a BMI-SDS
(BMI-standard deviation score) change during the rst
3 intervention months was related to a BMI-SDS change
3 years aer intervention-end.
7
Following patients for 8 years, another study by Moens
et al. found successful weight-reduction maintenance for
most participants.
8
Focusing on healthy eating habits,
moderate exercise, and cognitive-behavioral techniques,
the intervention comprised 12-16 sessions during 3
phases: screening and motivation (2 sessions, 3 weeks);
intensive treatment (6 biweekly sessions, 12 weeks); and
follow-up (4-8 monthly meetings). At 8-year follow-up,
participants had an 8% adjusted-BMI reduction, and
66% of children maintained weight control. e authors
found long-term weight loss was positively associated with
age, baseline BMI, and child’s self-worth, but negatively
associated with mother’s poor mental health.
8
e Combined DAK erapy, an intensive, 1-year,
weight-reduction intervention utilizing inpatient and
outpatient treatment sessions, demonstrated weight
reductions at 3- and 5-year follow-ups.
9
During the rst 6
weeks, a multidisciplinary team provided inpatient, obese
children and adolescents with structured, behavioral
therapy. Over the subsequent 10.5 months, the participants
had 11, one-hour, outpatient sessions for nutritional and
physical-activity education, and behavioral therapy.
13
Five-year follow-up found a signicant decrease in BMI-
SDS from baseline (-0.15 ± 0.51, p < 0.001). Altogether,
26% saw BMI-SDS reductions (21.3% with successful
weight reduction [a BMI-SDS decrease of ≥ 0.2], and
4.7% with a BMI-SDS reduction < 0.2).
9
e aforementioned programs dier from ours in
several ways. Firstly, our group-session frequency was
much lower. is may partly explain the unsuccessful,
long-term weight reduction displayed by 60% of our
participants. Limited resources meant we could only
provide 5 group-based sessions. However, we admitted
patients for several days at program-commencement
for lifestyle-modication education. e infrequent
sessions may have impeded lifestyle changes in all patients,
resulting in failure to develop long-term weight-control
behaviors. Secondly, while psychological or cognitive
behavioral therapy was provided by 3 other programs,
7-9
our program lacked such sessions. Psychotherapy could
coach patients in positive-behavior development, weight-
loss goal setting, weight-loss maintenance, and problem
coping.
14
In our study, 17 (39.5%) participants decreased or
maintained %W/H (successful group) while 26 (60.5%)
increased %W/H (failed group). e exercise frequency
and duration were higher for the successful than the failed
group. Participants who maintained reduced weight
exercised 4.7 days/week (median: 4 hours/week) versus
the failed group’s 2.9 days/week (duration: 1.8 hours/
week). Furthermore, consistent exercise and food control
were associated with weight-control success: 11 (64.7%)
of successful-group participants maintained healthy
lifestyles through regular exercise and diet control during
the year preceding the long-term follow-up study.
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138
Other studies have found dietary control and physical
activity benet weight-loss maintenance.
15,16
Mirza et al.
reported that intensive dietary control in the form of
both low glycemic loads and low-fat diets resulted in
weight reduction in obese children at 2-year follow-up.
15
In a cluster-randomized controlled trial, Donnelly et al.
studied the eects of physical activity on weight control
over 3 years in elementary school-children.
16
Ten schools
(713 participants) were the control, while 14 schools
(814 participants) were assigned to Physical Activity
Across the Curriculum (PAAC). PAAC promoted 90
minutes/week of moderate-to-vigorous, physically active
academic lessons, plus 60 minutes/week of physical
education. PAAC exposure aected BMI: schools with
≥ 75 minutes of PAAC/week showed signicantly lower
BMI increases at 3 years than schools with < 75 minutes/
week.
16
e results of those studies
15,16
and ours conrm
that exercise and dietary control signicantly impact
long-term weight control.
By completion of our 1-year group-based treatment
program, obesity complications had fallen.
6
At program-
commencement, 23 participants were prediabetic, 2 had
T2DM, and 65 had dyslipidemia. At program-end, there
were 13 prediabetic participants (reduction: 43.5%); no
new T2DM cases; and 48 dyslipidemia cases (reduction:
26.2%).
6
However, at long-term follow-up, 2 patients
with massive weight gain had T2DM (one already had
impaired glucose tolerance at program-end). For patients
at risk (positive family history of T2DM and/or inability
to achieve weight loss), psychotherapy might induce the
motivation and long-term behavioral changes were needed
to establish healthy lifestyles. Evaluation of underlying
psychological disorders or stress should also be performed
for individuals with pronounced weight gain.
Other obesity-related complications were common
in the failed group. Newly-found disorders were high
blood pressure and dyslipidemia (1 participant each),
and elevated liver enzymes suggesting non-alcoholic
steatohepatitis (5 participants). Our ndings highlight the
importance of eective childhood obesity-management
because youth obesity is associated with increased adult
mortality from obesity-related complications.
3,17
e small number of participants in the long-term
follow-up study is a limitation. Although the non-
participants and 43 participants had similar proles (age
at rst presentation and obesity degree), the long-term
weight-control ndings might not represent the whole
group. Moreover, patients unable to attend hospital were
interviewed telephonically.
Overall, this study revealed that the 1-year group-
based treatment program did not achieve long-term
weight reductions for most patients and was less intensive
than more successful interventions. Resource limitations
precluded the provision of psychotherapy, booster education,
and annual follow-ups. However, 40% of participants
maintained weight around 5 years aer program-end.
Continued healthy lifestyles, and frequent and longer-
duration exercise were associated with successful weight
maintenance. To achieve long-term weight maintenance, a
more intensive weight-loss program with frequent sessions,
psychotherapy, and annual follow-ups or continuous
contact and support (e.g., by telephoning or messaging)
might ensure sustained weight loss.
ACKNOWLEDGMENTS
This study was supported by Siriraj Grant for
Research Development (Grant no. R015731005). e
authors thank Pornpimol Kiattisakthavee, Thamita
irathanakamon, erarat Manpayak, and Siripan
Patharat for their assistance.
Conicts of interest: e authors declare no conicts
of interest.
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Chontida Ladee, MNS*, Sunee Lagampan, Ed.D.*, Panan Pichayapinyo, Ph.D.*, Korapat Mayurasakorn, M.D.,
FRCFPT**, Chalita Lagampan, M.D.***
*Department of Public Health Nursing, Faculty of Public Health, Mahidol University, Bangkok 10400, **Department of Health Research and Development,
Siriraj Medical Research Center, Mahidol University, Bangkok 10700, ***Department of Internal Medicine, Chonburi Hospital, ailand.
Effect of a Goal Attainment Nursing Program on
Self-management and Blood Pressure Control in
High-risk Hypertensive Patients in a Primary Care
Unit
ABSTRACT
Objective: To determine the eects of goal attainment in nursing programs among hypertensive patients who are
at high-risk to cardiovascular disease.
Methods: A quasi-experimental study was conducted in a primary care unit setting. Eligible participants included
hypertensive patients aged 35 years and above with poorly controlled blood pressure and accompanying risk factors for
cardiovascular disease. Seventy-eight participants were divided evenly into two groups via simple random sampling.
e experimental group participated in a 10-week program consisting of small group education/demonstration
sessions focused on goal setting and self-management behavior. ese participants also received a follow-up phone
call and text messages that served as reminders/reinforcements. e control group received routine care only, which
included appropriately consultation with health care providers.
Results: e proportion of participants who achieved optimal blood pressure control (SBP < 140 mmHg) in the
experimental group (80.6%) was greater than the control group (44.1%) (p-value < 0.05). In addition, the systolic
blood pressure of the experimental group (x 131.33 mmHg, S.D. 12.09) was signicantly lower than that of the control
group (x 142.96 mmHg, S.D. 15.77) (p-value < 0.05). e mean scores for self-management behavior were signicantly
higher in the experimental group (x 106.14, S.D. 14.43) than the control group (x 83.21, S.D. 8.17) (p-value < 0.05).
Conclusion: e goal attainment nursing program targeting behavior modication through empowerment was
eective in improving self-management behavior among hypertensive patients at high risk for cardiovascular
disease. us, this program can be applied to patients with uncontrolled chronic diseases.
Keywords: Self-management; hypertension; cardiovascular disease; goal attainment; behavior modication (Siriraj
Med J 2020; 72: 140-150)
Corresponding author: Sunee Lagampan
E-mail: sunee.lag@mahidol.ac.th
Received 3 April 2019 Revised 30 May 2019 Accepted 7 June 2019
ORCID ID: http://orcid.org/0000-0002-8056-6754
http://dx.doi.org/10.33192/Smj.2020.19
INTRODUCTION
Cardiovascular disease (CVD) is the world leading
cause of death claiming roughly 17.9 million per annum.
In view of this staggering statistic, the World Health
Organization supports governments worldwide in
preventative eorts.
1
Hypertension is a signicant risk
factor for CVD. ere is broad evidence from longitudinal
observational studies and meta-analyses of RCTs that
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the BP-related risk for CVD is determined by systolic
blood pressure (SBP) of approximately 115 mmHg.
2
In
previous ndings, the majority of CVD events presented
in patients with blood pressure (BP) > 140/90 mmHg.
However, more recent studies have found that most
CVD events occur in patients with BP < 140/90 mmHg.
Similarly, according to a study conducted in the early
2000s, hypertension can lead to CVD events with coronary
heart disease at 63 percent, stroke at 63 percent and heart
failure 60 percent.
3
is illustrates the need for early
detection and management of high-risk hypertensive
patients to avoid CVD complications.
Lifestyle factors that lead to increased risk for CVD
are well-known (poor diet quality, physical inactivity,
tobacco use, increased blood pressure). Prevention
programs oen seek to address these factors through
education and behavior modication. Interventions that
have proven eective in combating hypertension include
education on the aforementioned risk factors, physical
activity with aerobic exercise and implementation of a
DASH diet (limiting sodium consumption to less than
2,300 mg daily).
4-6
Regular blood pressure monitoring
and medication adherence are also important for disease
control.
7-9
Based on RCT evidence, hypertensive patients
with systolic blood pressure of 130-139 mmHg who
are at high risk for CVD should receive both lifestyle
modication and BP-lowering medication.
2
A previous study found that blood pressure (BP) self-
monitoring resulted in lower systolic blood pressure. ere
is promise in interventions promoting self-management
behavior in achieving proper BP control to lower the
incidence of cardiovascular disease.
8
More research
is needed to evaluate the benets of group education
programs with assessment of risk factors and information
on lifestyle modication. Further studies are also required
to determine optimal ways to overcome the barriers to
engagement between patients and providers in these
programs.
10
Home blood pressure (HBP) monitoring
with weekly telephone follow-ups can eectively track
measurements. In addition, telephone consultation is
also useful in tracking HBP related to BP control. In
this way, health providers can easily follow patients’
BP at home.
7,23
us, interventions can also undertake
a technology-mediated approach for ancillary follow-up
with tele-counseling or tele-monitoring.
11
In this study, a 10-week goal attainment nursing
program was designed for hypertensive patients at high-
risk for CVD at a primary care unit in Siriraj Hospital.
Empowerment and self-management of hypertension
were the fundamental elements of the program. e
study aimed to determine the eects of the program on
self-management behavior to prevent cardiovascular
disease and decrease systolic blood pressure.
MATERIALS AND METHODS
Research Design
e present study was a quasi-experimental research
with two groups in a pretest-posttest design conducted
at a primary care unit (Siriraj Hospital) in Bangkok,
ailand, from May to August 2018.
Participants
Hypertensive individuals with follow-up appointments
between May and August 2018 were recruited.
Inclusion Criteria:
1. Diagnosis of hypertension at least six months prior
to the study
2. SBP over 130 mmHg and/or DBP over 85 mmHg
3. Prescription of at least one antihypertensive drug
4. At least one of the following additional cardiovascular
risk factors:
a) Family history of CVD
b) Smoking
c) Diagnosis with DM
d) Hyperlipidemia (any of the following: total
cholesterol > 200 mg/dL, triglycerides > 150 mg/
dL, low-density lipoprotein > 130 mg/dL, high-
density lipoprotein < 40 mg/dL)
e) Overweight (body mass index > 25 kg/m
2
or
waist circumference > 90 cm in males and > 80
cm in females)
12
5. Personal mobile phone; ai language literacy
Exclusion Criteria:
1. Pre-existing cardiovascular complications
2. Referral to special treatment without returning to
the primary care unit
Sample Size Calculation
e researchers used the eect size of a previous
study based on systolic blood pressure outcome.
13
e
calculation showed that d is 1.24, which is higher than 0.8
and a good eect size.
14
e sample size for the present
study was derived through power analysis (alpha =
0.05 with 80% power). e G power program (Version
3.1.9.2)
15
determined that the total sample size should
be 70 people. In this study, the researchers increased the
sample size by 10 percent to account for the drop-out
rate. us, 78 participants were subsequently and evenly
divided into the experimental and control groups by
simple random sampling.
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142
Ethics
is study was approved by the Human Research
Protection Unit, Faculty of Medicine Siriraj Hospital at
Mahidol University, Bangkok, ailand (Si 201/2018). e
protocol number is 079/2561(EC4), and all participants
signed informed consent forms. (TCTR identication
number: TCTR20190402001)
Recruitment
Eligible participants were screened from electronically
recorded data (Medtrack system). The participants
successfully recruited in odd-numbered weeks were
assigned to the experimental group via simple random
sampling; those recruited in even-numbered weeks were
assigned to the control group.
Patients were invited to participate in the study
aer blood pressure measurements had been taken.
en the objectives, duration, and risks involved in the
study were explained. Condentiality issues were also
addressed. e subjects who agreed to participate then
voluntarily completed and signed the consent forms.
(Fig 1)
Intervention
Experimental Group
e researchers developed a 10-week goal attainment
nursing program to prevent cardiovascular diseases in
hypertensive patients. is program emphasized goal
attainment and promotion of self-management behavior.
e initial process began with interactions to identify the
barriers and common health problems with information
about CVD risk factors. e program then created goals
for the patients. Implementation of the aforementioned
goals led to encouraging self-monitoring, recording and
evaluating of goals. e diculties and physical outcomes
were tracked and supported for ten weeks via telephone
follow-ups. At the last session, the patients received
feedback on behavior modication and evaluation of
goal achievement in a discussion group.
All of these processes improved the continued
interactions between nurses and patients. e program
included two education sessions in a small group, two
follow-up text message reminders, and a 10-minute
personal follow-up telephone call. During the group
education sessions, activities were conducted in each
sub-group of 4-6 patients. (Table 1)
Figure 1 - Flow Chart of Research Process
(n=124) Follow up on Patients from May-August 2018
in a Primary Care Unit
(n=78) Assess Patients for Eligibility
(n=39) Experimental Group
(10-week program participation)
(n=39) Control Group
(routine care for 10 weeks)
Week 5 (n=1) Adjusted Antihypertensive
Medications
Week 8 (n=1) Lost Contact
Week 10 (n=1) Drop-Out
(n=3) Adjusted Antihypertensive
Medications
(n=2) Drop-Outs
Analysis (n=36)
Analysis (n=34)
Simple Random Sampling
Simple Random Sampling
Fig 1. Flow Chart of Research Process.
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TABLE 1. Program activities.
Session Purpose Activities
Week 1
Nurse-patient interaction 1. To build rapport and share Sub-group small-talk
process (30 minutes) information on health problems. - Patients reveal individual obstacles to controlling
disease.
Collaborative goal-setting 1. To collaborate on setting goals Sub-Group Education
process(2hours) forbehaviormodication. -LectureonCVDrisks,provisionofadequate
information using the PowerPoint program, video
content and a guidebook developed by the
researchers.
- Patients set short- and long-term goals by
collaborating with the researchers.
- Discussion about appropriate solutions on how to
achieve set goals.
1. To encourage self-management Sub-Group Education
to facilitate patients in achieving - Coaching on self-management skills in various
behaviormodication. aspects
including nutrition, exercise, compliance with
2. To provide essential information
hypertensive
medication, avoidance of CVD risks and
on CVD and how patients can
home-BP monitoring.
improve
completely for behavior - Practicing self-monitoring, evaluation and
modication. reinforcementbyusinghandbookstokeeprecords.
- Researchers guided patients on practical action to
achieve short- and long-term goals.
Week 3
Transaction process 1. To continue communication with Text reminders are sent individually.
patients by promoting constant behavior
modicationthroughtextmessages.
Week 5
Transaction process 1. To follow progress towards
Personal Follow-Up Telephone Calls: (10 minutes
established goals, and to address
per patient) by following a self-recorded handbook.
any potential barriers to change.
- Researchers allow patients to reveal prideful
2. To track home-BP measurement
feelings regarding reach optimal BP (<140/90 mmHg)
and follow monitoring of goal
andimproveself-condenceonBP-control.
achievement.
-Barrierstobehaviormodicationareclariedand
solves with feasible methods to change former habits.
Week 7
Transaction process 1. To continue communication with Text reminders are sent individually.
patients by promoting constant behavior
modicationthroughtextmessages.
Week 10
Evaluatingthegoal 1.Toreectonchangeablebehaviors Sub-Group Small-Talk
achievement process and BP control for the ten-week period. - Patients review goals and their respective
(2 hours) 2. To evaluate goal achievement: accomplishments e.g. physical outcomes,
self-management behavior and alterations of self-management behavior.
physical outcomes. - Weekly self-recording on nutrition, exercise and
3. To discuss health information, blood pressure are reviewed and compared
share obstacles and achievable through participation in the program.
behaviormodication. -Researchersprovideindividualizedfeedbackat
the end of the session.
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144
Control Group
During the 10-week sessions, patients received
routine nursing care at the primary care unit, obtaining
a self-management guidebook to prevent cardiovascular
disease in the rst week for self-study at home. At the end
of the program, the patients received recommendations
and ve to ten minutes of individualized counseling on
behavior modication.
Measurements
Part 1: Demographic Data
Demographic information on gender, age, marital status,
religion, education level, occupation, and monthly income
was obtained from all of the participants. Anthropometric
indices (body weight and waist circumference) were collected
at baseline. e baseline blood pressure (SBP, DBP) was
collected pre- and post-program for comparison. e
researchers also obtained participants’ medical history
for the duration of hypertensive illness, antihypertensive
medications, comorbidities, CVD risks, alcohol consumption,
smoking, and exposure to secondhand smoke.
Part 2: Self-Management Behavior for CVD
Prevention
Lifestyle practices were evaluated by using a
questionnaire on self-management behavior to prevent
CVD with 35 items composed of dietary intake (11 items),
physical activity (7 items), medication (5 items), avoidance
of CVD risks (5 items) and home BP monitoring (7 items)
with both positive and negative questions. e questionnaire
was developed based on the literature review of research
on the following topics: 1) self-management promotion
program for health behavior in hypertensive patients
16
;
2) self-management behavior questionnaires
17
and 3)
medication adherence questionnaires.
18
e responses
were rated on 4-point scales by which the participants
indicated frequency of consumption by choosing only
one category. e frequency was categorized from 1
(never) to 2 (1-2 times/week), 3 (3-4 times/week) and
4 (5-7 times/week). e total scores ranged between 35
- 140 points and Cronbach’s alpha coecient for this
questionnaire was 0.81.
Blood Pressure Measurement
BP was measured with a GE Carescape V100 Vital
Signs Rolling Stand Monitor. e participants were
required to sit and rest for ve minutes prior to BP
measurement. BP was then measured twice over a period
of one minute on the le arm, and the average BP was
calculated.
Statistical Analysis
SPSS statistics software (Version 18) was used
for data analysis. e signicance level was set at .05
by using descriptive statistics (frequency, percentage,
mean and standard deviation) for the presentation of
the demographic data. Subsequently, a Chi-square test
was used for comparison between the experimental and
control groups.
Within-group dierences in the mean systolic blood
pressure and self-management behavior scores were
analyzed both pretest and posttest with paired t-test;
the between-group dierences of these markers were
analyzed with independent t-test. e Kolmogorov-
Smirnov Test was used for normality testing for baseline
data between the two groups.
RESULTS
irty-six subjects remained in the experimental
group at the end of the study (attrition rate = 7.7%).
One subject was not able to participate in the activities,
one patient was prescribed changes in antihypertensive
medications, and contact was lost with one patient. irty-
four subjects remained in the control group (attrition
rate = 12.8%). ree subjects were prescribed to new
antihypertensive medications, and two patients could
not attend the follow-up appointment. Overall, the total
attrition rate was 10.3 percent.
ere were dierences in gender distribution across
both groups; 75 percent of the experimental group was
female versus 50 percent in the control group. Furthermore,
the mean age of the patients in the experimental group
was 61.47 (±6.33) years, and the mean age in the control
group was 65.29 (±8.42) years. e other demographic
characteristics of the experimental and groups showed
no statistically signicant dierences (marital status,
religion, education level, employment status, income
level) (Table 2).
Both groups had similar health characteristics
such as body weight, waist circumference and systolic
and diastolic blood pressure prior to participation in
the study. e antihypertensive agents prescribed for
the participants included diuretics, calcium channel
blockers, angiotensin-converting enzymes, angiotensin
receptor blockers, beta-blockers and vasodilators with
similar prescription among the hypertensive patients
in both groups. e groups had similar prevalence of
CVD risk behaviors (alcohol consumption, smoking,
and secondhand smoke exposure). e majority of the
participants in both groups had a total of three CVD risk
factors (41.7% in the experimental group, 50.0% in the
control group) (Table 3).
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TABLE 2. Demographic data of the experimental and control groups.
Characteristics Experimental Group Control Group P-value
n (%) n (%)
Gender 0.030
a
Male 9 (25.0) 17 (50.0)
Female 27 (75.0) 17 (50.0)
Age 0.035
b
35-59 years 12 (33.3) 9 (26.5)
≥60years 24(66.7) 25(73.5)
(x = 61.47, S.D. = 6.33, Min = 50, Max = 71) (x = 65.29, S.D. = 8.42, Min = 38, Max = 79)
Marital Status 0.782
a
Single/Widowed/ Divorced 16 (44.4) 14 (41.2)
Married 20 (55.6) 20 (58.8)
Buddhism 36 (100.0) 34 (100.0)
Education Level 0.352
a
Lower than secondary school 26 (72.2) 21 (61.8)
Higher than secondary school 10 (27.8) 13 (38.2)
Occupation 0.989
a
Unemployed 19 (52.8) 18 (52.9)
Employed/business owner/ 17 (47.2) 16 (47.1)
Farming/sewing
Monthly income 0.355
b
Less than/as 5,000 Baht 21 (58.3) 22 (64.7)
More than 5,000 Baht 15 (41.7) 12 (35.3)
a
= Chi-square testing;
b
= t-test
Self-Management Behavior for CVD Prevention
e experimental group had signicantly higher
mean self-management behavior scores as compared
to the control group (106.14, S.D. 14.43 VS 83.21, S.D.
8.17) (p-value < 0.05). Dierences were reected in the
mean scores for dietary intake (p-value < 0.05), physical
activity (p-value < 0.05), avoidance of CVD risk factors
(p-value < 0.05), and home blood pressure monitoring
(p-value < 0.05) (Table 4).
Systolic Blood Pressure
Posttest, the mean systolic blood pressure was
131.33 mmHg (S.D. 12.09) in the experimental group and
142.96 mmHg (S.D. 15.77) in the control group. Analysis
with independent t-test revealed the aforementioned
dierences to be signicant (p-value < 0.05). In addition,
the experimental group experienced a greater decrease
in systolic blood pressure than the control group (91.7%
vs. 70.6%) (p-value < 0.05). More participants in the
experimental group achieved optimal systolic blood
pressure control (< 140 mmHg) than the control group
(80.6% VS 44.1%, p-value < 0.05) (Table 5).
Furthermore, aer the participants had taken part in
the goal attainment program for ten weeks, the researchers
compared the patients who were under blood pressure
control in both groups. Optimal or acceptable systolic and
diastolic blood pressure levels were dened to interpret
who was able to achieve blood pressure control. According
to the ndings, the experimental group (50.0%) had
more patients with blood pressure under 130/80 mmHg
than in the control group (20.6%). Moreover, there were
also more patients who had achieved blood pressure
control at posttest (50.0%) than at pretest (2.8%) in the
experimental group (Fig 2).
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TABLE 3. Health information of the experimental group and control groups.
Health Information Experimental Group Control Group P-value
n (%) n (%)
Body Weight 0.879
a
(x = 68.75, S.D. =12.03, min=51.40, max=120.00) (x = 69.22, S.D. =13.79, min=43.00, max=107.00)
Waist Circumference 0.143
b
Normal 3 (8.3) 7 (20.6)
Over (Male> 90 cm, female> 80cm) 33 (91.7) 27 (79.4)
Baseline Systolic Blood Pressure 0.269
a
130 – 140 mmHg 10 (27.8) 11 (32.4)
> 140 mmHg 26 (72.2) 23 (67.6)
(x = 153.15, S.D.=14.47, min=130.00, max=197.00) (x = 149.24, S.D.=14.91, min=130.00, max=196.00)
Baseline Diastolic Blood Pressure 0.415
a
≤80mmHg 32(89.0) 29(85.3)
81 – 90 mmHg 2 (5.5) 4 (11.8)
> 90 mmHg 2 (5.5) 1 (2.9)
(x = 75.07, S.D. = 8.08, min = 62.00, max = 101.50) (x = 73.38, S.D. = 9.13, min = 60.00, max = 94.00)
Duration of Hypertensive Illness 0.376
a
≤10years 26(72.2) 18(52.9)
> 10 years 10 (27.8) 16 (47.1)
(x = 8.69, S.D. = 4.18, min = 2, max = 16) (x = 9.68, S.D. = 5.02, min = 2, max = 20)
Anti-Hypertensive Drugs*
Diuretics 3 (8.3) 7 (20.6)
Calcium channel blockers (CCBs) 24 (66.7) 25 (73.5)
Angiotensin Converting Enzymes 14 (38.9) 18 (52.9)
Inhibitors (ACEIs)
Angiotensin receptor blockers (ARBs) 16 (44.4) 9 (26.5)
Beta-blockers 16 (44.4) 12 (35.3)
Vasodilators 11 (30.6) 11 (32.4)
History of Illness 0.282
b
Only Hypertension 9 (25.0) 5 (14.7)
Hypertension with co-morbidity 27 (75.0) 29 (85.3)
Diabetes Mellitus 6 (22.2) 10 (34.6)
Hyperlipidemia 9 (33.3)1 3 (44.8)
DM with Hyperlipidemia1 2 (44.5) 3 (10.3)
Glaucoma/Gout/Malignant 0 (0.0) 3 (10.3)
Neoplasm of Breast
CVD Risks
2 Factors 6 (16.7) 11 (32.4)
3 Factors 15 (41.7) 17 (50.0)
4 Factors 13 (36.1) 5 (14.7)
5 Factors 2 (5.6) 1 (2.9)
Alcohol Consumption 0.498
b
No 32 (88.9) 30 (88.2)
Yes 4 (11.1) 4 (11.8)
Smoking 0.204
b
No 35 (97.2) 31 (91.2)
Yes 1 (2.8) 3 (8.8)
Secondhand Smoke Exposure 0.932
b
No 32 (88.9) 30 (88.2)
Yes 4 (11.1) 4 (11.8)
a
= t-test,
b
= Chi-square testing
* = Patients may take more than one drug per person
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TABLE 4. e results of self-management behavior for prevention of CVD between the experimental and control
groups at pre- and posttest.
Self-Management Pretest Posttest
Behavior for Prevention Experimental Control P-value Experimental Control P-value
of CVD Group Group Group Group
mean (SD) mean (SD) mean (SD) mean (SD)
Total scores 78.08 (9.43) 79.24 (7.95) 0.583 106.14 (14.43) 83.21 (8.17) <0.001
Dietary 22.31 (5.12) 21.82 (3.22) 0.637 29.83 (5.17) 22.68 (3.34) <0.001
Physical activity 10.72 (3.41) 11.44 (4.33) 0.442 17.89 (5.38) 11.85 (3.38) <0.001
Medication adherence 16.78 (2.03) 17.62 (2.05) 0.089 18.11 (2.86) 17.97 (1.78) 0.805
Avoidance of CVD risks 15.72 (1.81) 15.24 (2.38) 0.337 17.39 (2.20) 16.35 (2.09) 0.047
Home-BP monitoring 12.56 (3.30) 13.12 (2.46) 0.424 22.92 (4.33) 14.35 (2.60) <0.001
Independent t-test
TABLE 5. Results on changes in systolic blood pressure between the experimental and control groups at the pre-
and posttest.
Achievement of SBP Control Experimental Group Control Group P-value
n (%) n (%)
Pretest 0.114
Controlled (130-139 mmHg) 5 (13.9) 10 (29.4)
Uncontrolled(≥140mmHg) 31(86.1) 24(70.6)
Posttest
Controlled (<140 mmHg) 29 (80.6) 15 (44.1) 0.002
uncontrolled(≥140mmHg) 7(19.4) 19(55.9)
Chi-square testing
Fig 2. Bar charts illustrating blood
pressure control at (a) pretest and
(b) posttest in the experimental
and control groups.
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DISCUSSION
e mean score for the self-management behavior
of the participants who took part in the 10-week goal
attainment nursing program was signicantly higher
than that of the control group. A signicant intragroup
dierence in pre-post mean scores was also noted in the
experimental group (p-value < 0.05). Furthermore, the
experimental group had a considerably higher likelihood
to decrease systolic blood pressure than the control
group (p-value < 0.05). ese ndings have positive
implications.
Small-group educational activities that facilitated
provider-patient interactions were particularly conducive to
sharing experiences, perspectives and barriers to engaging
in lifestyle changes. e ndings are consistent with
previous studies on programs for preventing complications
in hypertensive patients through knowledge sharing and
group discussions.
13,19,20
During the goal attainment process, nurses provided
guidance and feedback in group education. Essential
knowledge about dietary intake, physical activity, medication,
avoidance of CVD risks and home-BP monitoring were
the topics of the lectures. Nurses trained patients by
performing demonstrations on self-management: self-
assessment, self-monitoring, and self-reinforcement. e
most important aspect of the goal attainment process
is understanding between nurses and patients. Patients
play a role in assessing personal capability and limits
in behavior modification. At the same time, nurses
repeatedly assess patients. Next, nurses move toward
the negotiation step for setting reachable and practical
goals. In the aforementioned process, when patients
were trying to modify behavior at home, telephone
communication was a virtual method for monitoring.
us, text reminders and follow-up phone calls were
given as reinforcements throughout the ten-week period.
e phone calls helped nurses to inquire about
the obstacles and problems encountered in behavior
modication. If patients were unable to accomplish set
goals, this process allowed the nurses and patients to
continually interact and share information. e nurses
worked as facilitators in guiding patients to adopt more
feasible methods. Furthermore, the nurses helped patients
by suggesting the setting of more exible goals such as
talking to reduce the frequency of eating brown rice if the
practice is not convenient for some meals. e researchers
found the follow-up phone calls to build empowerment
and self-condence in patients. e text reminders and
phone calls were able to prevent patients from giving
up on behavior modication when they were about to
fail. On the other hand, when patients are able to meet
personal goals, the nurses would oer praise to build self-
condence. Eventually, eective communication helped
the patients properly manage behaviors on their own.
is activity can benet healthcare providers in tracking
patients immediately and easily while the patients are
at home.
According to the World Health Organization, blood
pressure should be controlled at less than 130/80 mmHg
2
.
Based on the above standard, the program implemented
in the present study was eective. One of the reasons
for successful achievement over a period of only ten
weeks is that the program not only educated patients on
essential CVD contents, but the researchers also guided
patients on self-management for behavior modication
on their own. From the start of the program, the patients
needed to be able to assess potential for change in areas
such as intention, ability, time and social support. Next,
behavior plans were formed by collaborating with nurses
in the goal-setting process. Additionally, when patients
stayed at home, the nurses would stay in contact with
them during the ten-week period. erefore, teaching
about self-management resulted in patients’ ability to
maintain blood pressure control (blood pressure < 130/80
mmHg).
e ndings of the present study are consistent
with the results of previous programs emphasizing
behavioral goal-setting in combination with the support
of a follow-up system.
21
Furthermore, the process in
studies which applied the goal-setting to a primary care
unit was eective in decreasing blood pressure.
22,24,25
e present study found that encouragement of blood
pressure monitoring at home resulted in more eective
blood pressure control. e above nding was found to
be related to previous studies that trained patients to
monitor blood pressure at home. In addition to taking
blood pressure measurements, patients need to either
record the measurements correctly in a handbook or
send the BP readings to health care providers through
electronic data sorting.
7,8
In conclusion, providing interactions between nurses
and patients during follow-up appointments at clinics
promotes eective communication on goal-setting for
behavior modication. In the beginning, and when goals
are asserted clearly, patients can modify behavior in the
right direction. Moreover, small group education oers
more eective learning for patients by sharing information
with one another, because small focus group discussions
give patients more condence about revealing personal
information in a group setting than having face-to-face
consultations with nurses. Furthermore, demonstrations
of behavioral practices such as restricting sodium and fat
Ladee et al.
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149
Original Article
SMJ
consumption, estimating daily recommended amounts
of vegetables and planning to increase physical activity
facilitate patients’ comprehension of the content. In
particular, BP-monitoring training helps patients learn
about the physical outcomes of behavior modication.
Teaching patients to read blood pressure levels from
a device enables patients to interpret classication by
using a color graph and recording in a handbook. us,
BP-monitoring is benecial for nurses in continuing to
monitor patients’ blood pressure management. In addition,
follow-up phone calls allow health care providers to follow
up on obstacles and blood pressure trends before the
next appointment. Overall, the program implemented in
the present study is eective in achieving blood pressure
management, particularly in out-patient clinics.
Limitations
e ndings of the present study show that the context
of a program can decrease systolic blood pressure for
participants at posttest. According to the demographics of
the primary care unit, a 10-week goal attainment program
is compatible with participants who routinely come for
follow-up appointments every two to three months. is
period can further present changes in lowering blood
pressure as in previous studies. However, to promote
adherence to maintenance of behavior modication, this
program should be extended to interventions lasting at
least six months based on behavior modication theory.
CONCLUSION
e hypertensive patients at high-risk for CVD
who participated in the 10-week goal attainment nursing
program for cardiovascular disease prevention (focused
on self-management behavior) displayed signicant
improvement in achieving BP control. ese results
indicate that the experimental group had a larger decrease
in systolic blood pressure than the control group (91.7%
vs. 70.6%).
e ndings of this study reveal the benets of blood
pressure control in patients by encouraging communication
between nurses and patients on collaborative goal-setting.
In particular, physical health in blood pressure was clearly
stated from the start of the program. e role of the nurse
in this program focuses on guidance regarding appropriate
methods tailored for individual patients. Moreover, all
goals need to be practicable and reachable for patients. is
strategy accordingly leads to patients’ success in behavior
modication and eective blood pressure management.
In addition, in the self-management process, nurses can
promote the self-blood pressure monitoring of patients
and follow up on obstacles during practice. Continuous
blood pressure monitoring obviously presents noticeable
trends and is easy for nurses to follow. us, nurses
can continually promote empowerment through text
and follow-up telephone calls. ese certainly eect on
building condence in blood pressure control.
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Original Article
SMJ
Siriyaporn Khunthason, M.Sc., Pussadee Laor, M.Sc.
School of Health Science and Center of Excellence for the Hill tribe Health Research, Mae Fah Luang University, Chiang Rai 57100, ailand.
Factors Inuencing the Occurrence of Hand Foot
and Mouth Disease Among Children in Day Care
Centers in Northern Thailand
ABSTRACT
Objective: Hand-foot-and-mouth disease (HFMD) is crucial and has a large-scale impact on worldwide healthcare
systems in terms of expenses especially in the population of young children.
Methods: A community-based, case-control study was conducted to identify the factors inuencing the occurrence of
HFMD among children in day care centers (DCC). e study was conducted in three provinces in Northern ailand
including Chiang Rai, Chiang Mai, and Pha Yao. DCC and study samples were selected by a simple random method.
A validated questionnaire was developed and used for collecting data aer an index of item-objective congruence
(IOC) method has been used to improve the quality of the questionnaire and piloted. Logistic regression was used
to detect the associations between variables at the alpha =0.05.
Results: In total, 1,022 subjects were recruited into the analysis. Regarding parents’ characteristics, 77.3% of the
subjects were female, the average age was 33.9 years, 85.3% were married and 92.2% were Buddhist, 30.4% earned
5,001- 10,000 baht a month, and 49.9% had 1-3 family members. 17.9% had a low level of knowledge, 49.3% had a
neutral attitude, and 96.7% had good practice for HFMD prevention and control. 34.2% of the children were aged ≤
2 years, 54.9% were male, 50.4% were overweight and 21.1% had been breastfed. ree associated factors were found
statistically signicant with the occurrence of HFMD; children aged ≤ 2 years (OR=7.05, 95%CI=3.25–15.28), the
number of household members (OR=1.43, 95%CI=1.04–1.97), and parents’ knowledge (OR=2.35, 95C%= 1.47–3.77).
Conclusion: Improving knowledge of HFMD among the parents, particularly those having many household
numbers, is essential in order to reduce the incidence of the disease.
Keywords: Hand foot mouth disease; day care center; associated factors; children (Siriraj Med J 2020; 72: 151-158)
Corresponding author: Siriyaporn Khunthason
E-mail: siriyaporn.sit@mfu.ac.th
Received 27 May 2019 Revised 7 August 2019 Accepted 15 August 2019
ORCID ID: http://orcid.org/0000-0001-6247-5931
http://dx.doi.org/10.33192/Smj.2020.20
INTRODUCTION
Hand foot and mouth disease (HFMD) is a common
infectious disease
1,2
which is oen reported in children
under 6 years old particularly in tropical zones including
ailand.
3
HFMD is known to be a viral disease with
limited specic treatment, but the number of infections
has impacts on a global scale
4,5
and has deantly become
a public health challenge due to the cost of care, prevention,
and control measures.
6,7
Most of HFMD infected patients
come with mild signs and symptoms; however, some of
them are in a severe stage of infection with brain and
nervous systems complications.
2,8
In ailand, 70,077 cases were reported in 2017
(morbidity rate 107.57 per 100,000 pop.), and the three cases
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152
of reported death, were mostly children aged between 0-6
years
9,10
Northern region of ailand had been announced
as the highest epidemic area.
11
Meanwhile, Chiang Rai,
Chiang Mai, and Pha Yao were ranked in top HFMD
epidemic area in 2015.
12
Health promoting hospitals are the peripheral health
care center under the health care system of ailand.
A center is in a sub-district and responsible for more
than 5,000 inhabitants.
3
ese health care centers are
delivering care by 2-3 health care professionals who
are, for example, nurse, public health professional, etc.
ere are a few health care centers that have a medical
doctor.
10
e limitation of the operation is that some of
the centers are located far away from the city and received
limited recourse each year. erefore, the main duty of
these centers is to treat their patients. A small budget is
provided in health promotion and disease prevention
including the control of HFMD outbreaks.
Chiang Rai, Chiang Mai, and Pha Yao are located
in Northern ailand which their typical mountainous
characteristics, with lower average temperatures than
other regions in ailand for a whole year.
13
ere are
some hill tribe populations living in these areas with
low economic status.
14
For this reason, in daytime, most
parents leave their children in a day care center where
care givers take care of the children. Many studies have
shown that HFMD is associated with economic status.
15,16,17
DCC, operated by the local government, is a place
where children under 6 years are taken care of during the
daytime.
11
Many people in rural area of ailand prefer to
leave their children at the DCC before going to the farm
during the daytime. e numbers of children receiving
care in some DCCs are higher than the standard of the
Ministry of Public Health
3
and some DCCs became
overcrowded.
ere are several guidelines for HFMD control and
prevention in ailand and many health implementations
have also been conducted under the supervision of the
Ministry of Public Health of ailand. However, there
were many episodes of outbreaks reported throughout
ailand during the past years especially in Chiang Rai,
Chiang Mai, and Pha Yao provinces. e study aimed to
investigate the factors inuencing HFMD in DCCs. e
information might help develop the proper prevention
and control measures to reduce the number of HFMD
outbreaks in Northern ailand.
MATERIALS AND METHODS
Study design
A community-based, case-control study was conducted
to reveal the factors inuencing HFMD among children
under 6 years old who stayed in day care centers in
Chiang Rai, Chiang Mai, and Pha Yao, ailand.
Study site
e day care centers located in Chiang Rai, Chiang
Mai, and Pha Yao were the study settings. In 2015,
1,345 DCCs in three provinces (Chiang Rai=499 DCCs,
Chiang Mai=645 DCCs, and Pha Yao=199 DCCs) were
examined. Using the median line of three years prior to
2015 (2012-2014) [Ministry of Public Health, 2016], 438
DCCs were marked as the high epidemic area, and 907
DCCs were marked as the low epidemic area.
Study population
e study population was the children aged less
than 6 years and attended any DCC in 2015. However,
the data was collected from their parents.
Study sample and sample size estimation
Case were children who were less than 6 years old
and had been diagnosed with HFMD (ICD- 10: B08.4)
in DCC by a medical doctor in 2015. e conrmation
of the diagnosis was reviewed based on the medical
record aer obtaining the verbal approval from their
parents. e selected samples that did not have the
medical record on their diagnosis were excluded from
the study. Controls were selected by a random method,
from children who were less than 6 years old and had
not been infected by HFMD in 2015 in the low epidemic
DCC with a 1:2 ratio of the cases to controls.
e sample size was calculated using Schlessel man’s
formula
18
at alpha value 0.05, the power of test was set at
80%, and the ratio of cases to controls was 1:2, probability
of exposure in case at 4.5%.
19
e ratio of the cases to
controls was 1:2; therefore, 332 cases and 690 controls
were required aer adding 10% for any possible errors
in the study.
Research instruments
e questionnaire was developed from reviewing
the literature from all relevant sources of information.
It consisted of three sections; general information,
identification of infection risks, and assessment of
knowledge, attitude, and practice (KAP). ere were
eighteen items for the general information section and
23 items for the identication of HFMD infection risks.
In the KAP section, there were 10 items for knowledge,
10 items for attitude, and 10 items for practice.
e questionnaire had been tested for the validity
and reliability by three external experts who had a relevant
knowledge and experience in the eld.
20,21
e quality
Khunthason et al.
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of the questionnaire also had been improved by being
piloted with 20 selected samples from Mae Fah Luang
University Hospital who had similar characteristics
with the subjects in the study. Cronbach’s alphas were
calculated and found at 0.77 and 0.73 for attitude and
practice respectively.
Process of data collection
e lists of DCCs were classied into two dierent
groups; the high epidemic area and the low epidemic area
by using the median of cases reported during 2012-2014.
A list of DCCs were inserted into the same work-sheet
and labeled with numbers.
A simple random method was applied to select
the targeted DCCs for the high and low epidemic areas.
ere were 62 DCCs from the high epidemic area and
47 DCCs from the low epidemic area.
Cases were all the selected children who met the
criteria, and controls, chosen by a simple random method,
were the children from the same DCC where the cases
were found but did not have HFMD.
e parents whose children had been selected as
case or control were invited to the interview. A private
room was prepared and used for the interview. e
participants were given all essential information of the
research including objective, rights, etc. Signed informed
consent forms were obtained from each participant before
the one-to-one interview which lasted 35 minutes.
Data analysis
e analyses were performed by using SPSS version
20, 2014 (SPSS, Chicago, IL), and Epi-Info version 6.04d
(US Centers for Disease Control and Prevention, Atlanta,
GA). Descriptive and inferential statistics were used to
explain the characteristics and to answer the objective of
the study. Logistic regression was employed to identify
the associations between variables at the signicant level
alpha =0.05.
Ethical consideration
All study protocols were reviewed and approved
by Mae Fah Laung University Ethics Committee on
Human Research by No. REH-59024. Permissions to
access the DCCs were granted by the director of the
local administration oce. Prior to the process of data
collection, the written information about the research
project was delivered to the participants along with
verbal information. Aer they agreed to take part in the
study, a written informed consent form was contributed
to each participant for their signature. All participants
were given a small gi as a token of appreciation for
their participation aer nishing the interview.
RESULTS
A) Characteristics of parents
There were 1,022 participants from 109 DCCs
suitable for the analysis. 37.2% were from Chiang Rai,
33.9% were from Phayao and 29.0% were from Chiang
Rai. 77.3% were female, the average age was 33.9 years
old (SD=10.9, min=17, max=75), 85.3% were married,
92.2% were Buddhist, 36.2% had educational attainment
at primary school level, and 30.4 % made 5,001-10,000
baht a month. 46.5% of the mothers were the major care
giver, and 49.9% of the participants had 1-3 members
in their household.
Case group: 12.1% had a low level of knowledge,
48.0 % had a neutral attitude, and 96.2% had good practice
for HFMD prevention and control.
Control group: 38.5% had a high level of knowledge,
52.0% had a positive attitude, and 96.9% had good practice
on HFMD prevention and control.
Simple logistic model revealed that there were three
factors associated with HFMD. Firstly, the children
whose parents were Buddhist had a 1.96 times greater
chance of infection than those with Christian parents
(90%CI=1.23-3.18). Next, the children whose parents
earned bachelor’s degree had a 2.29 times greater chance of
infection than those with illiterate parents (90%CI=1.23-
4.27). Lastly, the children whose parents had a high level
of knowledge on HFMD prevention and control had
a 1.81 times greater chance of infection than those whose
parents had low level of knowledge (90%CI=1.28-2.57)
and 2.01 times greater than those whose parents had
neutral knowledge (90%CI=1.42-2.85) (Table 1).
B) Characteristic of children
54.9% were male, 56.9% were 3-4 years old, 50.4%
were underweight, 15.4% had been admitted to the
hospital, and 21.1% had been breastfed for less than 6
months since their birth.
Case group: 55.3% were aged less than 2 years old
(mean=2.94, SD=1.02), 57.0% were male, 48.3% were
underweight, 18.1% had been admitted to the hospital,
5.6% had a medical condition, and 26.0% had been
breastfed for less than 6 months.
Control group: 62.8% were aged 3-4 years (mean=2.94,
SD=1.02), 53.7% were male, 51.7% were underweight,
14.1% had been admitted to the hospital, and 81.1% had
been breastfed for less than 6 months.
Simple logistic regression model revealed the
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TABLE 1. Parents’ characteristic and HFMD in a simple logistic regression (1,022).
Characteristics
Total Case Control
n (%) n (%) n (%)
OR 90%CI P-value
Total 1022(100.0) 322 (32.4) 690(67.6) NA
Sex
Male 224 (22.7) 73 (22.9) 151 (22.6) 1.00
Female 762 (77.3) 246 (77.1) 516 (77.4) 1.01 0.77 – 1.39 0.931
Parent’s age (years)
<19 20 (2.2) 4 (1.3) 16 (2.6) 1.00
20-59 847 (92.7) 288 (93.8) 559 (92.1) 2.06 0.82 – 5.21 0.200
>60 47 (5.1) 15 (4.9) 32 (5.3) 1.87 0.65 – 5.38 0.326
Marital status
Single 54 (5.4) 16 (5.0) 38 (5.6) 1.00
Married 854 (85.3) 272 (84.5) 582 (85.7) 1.11 0.67 – 1.84 0.734
Divorce 93 (9.3) 34 (10.6) 59 (8.7) 1.37 0.75 – 2.50 0.393
Family member (person)
1-3 220 (49.9) 120 (30.4) 210 (36.1) 0.77 0.59 – 1.01 0.068
≥4 692(50.1) 212(69.6) 480(63.9) 1.00
Number of child <12 years in family (persons)
1 564 (56.7) 206 (63.4) 358 (35.5) 1.00
2-3 404 (40.6) 111 (34.2) 293 (43.8) 0.65 0.52 – 0.83 0.003*
> 3 28 (2.6) 8 (2.5) 18 (2.7) 0.72 0.38 – 1.58 0.552
Religion
Buddhist 933 (92.2) 312 (95.1) 621 (90.8) 1.98 1.23 – 3.18 0.018*
Christian 79 (7.8) 16 (4.9) 63 (9.2) 1.00
Occupation
Unemployed 72 (7.2) 29 (9.0) 43 (6.4) 1.00
Merchant 416 (41.6) 140 (43.5) 276 (40.8) 0.75 0.49 – 1.16 0.276
GovernmentOfcer 42(4.2) 21(6.5) 21(3.1) 1.48 0.78–2.82 0.314
Farmer 324 (32.4) 83 (25.8) 241 (35.6) 0.51 0.33 – 0.80 0.013
Employee 114 (11.4) 39 (12.1) 75 (11.1) 0.77 0.46 – 1.29 0.403
Other 31 (3.1) 10 (3.1) 21 (3.1) 0.71 0.34 – 1.49 0.442
Income (baht/month)
≤5,000 258(29.3) 87(29.4) 171(29.2) 1.09 0.77–1.53 0.681
5,001–10,000 303 (30.4) 111 (37.5) 192 (32.8) 1.24 0.89 – 1.72 0.287
10,001–15,000 101 (11.5) 27 (9.1) 74 (12.6) 0.78 0.50 – 1.23 0.371
15,001–20,000 40 (4.5) 14 (4.7) 26 (4.4) 1.52 0.63 – 2.11 0.700
≥20,001 179(20.3) 57(19.3) 122(20.9) 1.00
Education
Illiterate 48 (4.8) 12 (3.7) 36 (5.3) 1.00
Primary school 365 (36.2) 125 (38.2) 240 (35.3) 1.56 0.88 – 2.78 0.204
Lower secondary 193 (19.2) 154 (16.5) 139 (20.4) 1.16 0.63 – 2.14 0.679
Higher secondary 236 (23.4) 68 (20.8) 168 (24.7) 1.21 0.67 – 2.20 0.593
Vocational 38 (3.8) 13 (4.0) 25 (3.7) 1.56 0.71 – 3.42 0.352
Bachelor 127 (12.6) 55 (16.8) 72 (10.6) 2.29 1.23 – 4.27 0.028*
Care giver
Father 92 (9.3) 21 (6.4) 71 (10.7) 1.00
Mother 462 (46.5) 151 (46.2) 311 (46.8) 1.64 1.06 – 2.55 0.064
Father and Mother 105 (10.6) 35 (10.7) 70 (10.5) 1.69 0.99 – 2.88 0.104
Relatives 333 (33.6) 120 (36.7) 213 (32.0) 1.90 1.21 – 2.99 0.018
Knowledge
Low (0-6) 172 (17.9) 38 (12.1) 134 (20.7) 1.00
Medium (7-8) 398 (41.4) 135 (42.9) 263 (40.7) 2.01 1.42 – 2.85 0.001*
High (9-10) 391 (40.7) 142 (45.1) 249 (38.5) 1.81 1.28 – 2.57 0.005*
Attitude
Neutral (1-3) 476 (49.3) 161 (51.9) 315 (48.0) 1.00
Positive (4-5) 490 (50.7) 149 (48.1) 341 (52.0) 0.86 0.68 – 1.07 0.256
Practice
Neutral (1-3) 32 (3.3) 12 (3.8) 20 (3.1) 1.00
Good (4-5) 936 (96.7) 301 (96.2) 635 (96.9) 0.79 0.43 – 1.46 0.526
*Signicant level at α=0.10
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TABLE 2. Children characteristic and HFMD in simple logistic regression.
Characteristics Total Case Control OR 90%CI P-value
n (%) n (%) n (%)
Age
≤2 325(34.2) 147(55.3) 178(26.0) 7.94 4.20-15.04 <0.001*
3-4 541 (56.9) 111 (41.7) 430 (62.8) 2.48 1.32-4.69 0.019*
>4 85 (8.9) 8 (3.0) 77 (11.2) 1.00
Sex
Male 403 (54.9) 150 (57.0) 253 (53.7) 1.00
Female 331 (45.1) 113 (43.0) 218 (46.3) 0.87 0.68-1.13 0.386
BMI
Underweight 234 (50.4) 83 (48.3) 151 (51.7) 1.29 0.73-2.29 0.455
Normal 183 (39.4) 75 (43.6) 108 (37.0) 1.63 0.92-2.92 0.162
Overweight 47 (10.1) 14 (8.1) 33 (11.3) 1.00
History of hospital admission
Yes 151(15.4) 57 (18.1) 94 (14.1) 1.34 0.99-1.82 0.110
No 829(84.6) 258 (81.9) 571 (85.9) 1.00
Medical condition
Yes 53 (5.3) 18 (5.6) 35 (5.2) 1.00
No 938 (94.7) 302 (94.4) 636 (94.8) 0.92 0.56-1.50 0.789
Breast feeding (month)
< 6 145 (21.1) 55 (26.0) 90 (18.9) 1.52 1.10-2.10 0.031*
≥6 542(78.9) 155(73.8) 387(81.1) 1.00
* Signicant level at α=0.10
TABLE 3. Factors associated with HFMD in multiple logistic regression.
Factors OR 95%CI P-value
Age (year)
≤2 7.05 3.25–15.28 <0.001*
3-4 2.09 0.97 – 4.51 0.061
>5 1.00
Family member (person)
1-3 1.43 1.04 – 1.97 0.028*
≥4 1.00
Knowledge
Low (0-6) 1.00
Medium (7-8) 2.35 1.47 – 3.77 <0.001*
High (9-10) 1.61 1.00 – 2.59 0.051
* Signicant level at α=0.05
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factors signicantly associated with HFMD. Firstly,
the children aged ≤ 2 years had a 7.94 times greater
chance of acquiring HFMD than those aged more than
4 years (90%CI=4.20-15.04) and 2.48 times greater than
those aged 3-4 years (90%CI=1.32-4.69). Besides, the
children who had been breastfed for less than 6 months
had a 1.52 times greater chance to having HFMD than
those who had been breastfeed for 6 months or more
(90%CI=1.10-2.10).
Aer all possible factors were controlled; it was
found that three factors were associated with HFMD
in the children. e children aged ≤ 2 years old had a
7.05 times greater chance of HFMD infection than those
children aged more than 5 years old (95%CI=3.25-15.28).
Furthermore, the children from the family with 1-3
members had a 1.43 times greater chance of acquiring
HFMD than those from the family with ≤ 4 members.
DISCUSSION
e results from the simple model showed that the
children whose parents were Buddhist had a 1.98 times
greater chance of having HFMD than those with Christian
parents; however, the signicance was not found in the
multiple model. HFMD might not be directly connected
to religions, but some rural areas of ailand have had a
quicker economic growth.
22
e economic growth makes
the parents from those rural areas, where one religion
might be predominate than others leave their children
at a day care center so they can go to work. Day care
centers organized by the local government take care of
preschool children during daytime. However, there was
no previous report on the association between religions
and HFMD.
In this study, the children aged ≤ 2 years old had a
7.05 times greater chance of HFMD infection than those
aged more than 5 years old. According to the report of
HFMD assessment in ailand, the age group with high
morbidity was mainly the children aged 0-2 years old
who were immunosuppressed.
5
is is also consistent
with Liu’s study.
23
In Taiwan, it was found that patients
with HFMD were oen children aged less than 3 years
old, similarly in Vietnam and China, the occurrences
of HFMD were found in children younger than 3 years
old. Another study by Chan et al.
24
also found that most
patients were the children aged from 1 to 2.9 years old.
In terms of household members, the households with
1-3 members had a 1.43 times greater chance of HFMD
infection than those with ≥ 4 members. It could be that the
current population characteristic of Northern ailand
is mostly a single family with few members as most
families in the rural areas oen have only 1-2 children.
e number of family members may contribute to the
prevention of HFMD due to the number of members
who had to keep clean. e results of this study support
the study of YIN and et al.
25
indicating that families with
children who had a history of HFMD infection was one
of the factors contributing to HFMD.
Regarding the knowledge of HFMD, the parents
with moderate level of knowledge had a 2.36 times
greater chance of HFMD infection in their children
than those with low level of knowledge. is study had
been conducted to investigate HFMD infection since the
past few years. Aer that, these groups of parents had
more experience in children’s care and learned more
about HFMD. However, knowledge is important because
the correct knowledge leads to appropriate practice in
HFMD prevention and control.
16,26
Generally parents or care givers at home with
knowledge, good attitude and good practices of personal
and environmental hygiene should have children who
are less susceptible to HFMD. It is necessary to nd out
why children whose parents had moderate knowledge
of HFMD turn to have a higher chance of contracting
HFMD. May be having knowledge alone is not enough
and parent and care givers at home, need knowledge of
good practice and preventive measures of HFMD.
4
Day care center is the place that oen found and
report HFMD cases as it is a crowded place where a lot
of children are living together
11
and the children are
usually under 5 years old with low immune system and
lack of personal healthcare.
22
Moreover, care givers with
decient knowledge might misunderstand how to prevent
and control HFMD.
27
Although the Ministry of Public
Health has released the annual health measure for HFMD
control in children’s care centers, there are still HFMD
outbreaks every year. Although this study did not focus
on care givers at DCC, it is clear from other reports,
that care givers are very crucial in the prevention and
control of HFMD, since they spend more time during
the day with a lot of children in a crowded place. eir
knowledge and practices of safe and simple personal
and environmental hygiene is vital to the prevention
and control of HFMD
2
in their study of the knowledge
and practice in prevention control of HFMD stated
that, care givers at DCC have enough knowledge of
HFMD but their knowledge of prevention of HFMD is
not enough and simple practices such as screening of
children at the entrance of the DCC before admission
every morning may be the most ecient method of
prevention of HFMD. Further studies may be needed
in the HFMD preventive practices knowledge of care
givers.
3
Khunthason et al.
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ere are several factors inuencing HFMD such as
the parents being Buddhist, the duration of breastfeeding,
the parents’ knowledge on prevention and control of
HFMD, and importantly, how to keep day care center’s
environment clean. Interestingly, HFMD prevention in
day care centers involves indoor and outdoor environment
conditions of the centers, for instance, cleaning the
contaminated surfaces with eective disinfection agent.
26
Another interesting issue is the guideline for HFMD
prevention and control. Even though ailand had issued
the measure of HFMD prevention and control in day care
centers, outbreaks are still present. us, it is essential to
develop a proper guideline for HFMD prevention and
control which can eectively and practicably help control
the disease. It is obvious that whichever measures are
adopted, care givers both at home and at DCC should
be educated and well informed of the useful preventive
measures to support each other in the prevention and
control of HFMD.
4
CONCLUSION
is study found that the factors including children
aged less than 2 years old, 2-3 family members per
household, and parents’ knowledge of HFMD prevention
and control are related to HFMD in upper Northern
ailand. erefore, ailand should concentrate on
children at an early age with low immunity and the
number of members in each family and promote the
importance of knowledge and understanding of HFMD
prevention and control among parents and care givers
because these all play crucial roles in HFMD prevention
and control.
ACKNOWLEDGEMENTS
The authors would like to thank the chiefs of
Chiang Mai, Phayao, and Chiang Rai Provincial Public
Health Oce for providing the lists of day care centers
and the epidemic data on HFMD. We would like to thank
all the participants for contributing essential information.
Finally, the authors are grateful to the National Research
Council of ailand (NRCT), Mae Fah Luang University,
ailand, and e Center of Excellence for the Hill tribe
Health Research for providing grant for the research.
Conict of interest declaration: e authors hereby
declare no personal or professional conicts of interest
regarding any aspects of this study.
Funding disclosure: is study was supported by Center
of Excellence for the Hill-tribe Health Research (CEHR).
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Vitaya Titapant, M.D., Kingkaew Mingsuttiporn, M.D.
Department of Obstetrics and Gynecology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, ailand.
Associated Factors of Subtherapeutic Serum
Magnesium Level for Prevention of Eclampsia in
Term Pregnant Women with Severe Pre-eclampsia
ABSTRACT
Objective: To investigate the factors associated with subtherapeutic serum magnesium levels in order to prevent
eclampsia in term pregnant women with severe pre-eclampsia.
Methods: is case-control study included 200 term pregnant women with severe pre-eclampsia who received
magnesium sulfate for eclampsia prophylaxis. ese patients were randomly allocated into case and control groups.
Experimental cases included 100 women whose serum magnesium level did not reach the therapeutic level (<4.8
mg/dL) at 2 hours aer initial administration, whereas the controls were 100 women whose serum magnesium levels
reached therapeutic levels (4.8-8.4 mg/dL). Data from the medical records, including baseline characteristics, sign
and symptoms, laboratory ndings and pregnancy outcomes, were extracted for univariate and multivariate analyses.
Results: Only two factors, pre-pregnancy body mass index (BMI) and serum creatinine level, showed signicant
dierences between the two groups. Pre-pregnancy BMI greater than 25 kg/m
2
increased the risk of subtherapeutic
serum magnesium level by 56% compared with normal pre-pregnancy BMI (adjusted OR 1.56, p=0.019), whereas
pre-pregnancy BMI less than 18 kg/m
2
decreased the risk by 80% (adjusted OR 0.2, p=0.02). Also, serum creatinine
levels greater than 0.9 mg/dl decreased the risk by 98.7% (adjusted OR 0.013, p<0.001). No signicant dierence
in pregnancy outcomes was noted in either group.
Conclusion: Pre-pregnancy BMI greater than 25 kg/m
2
increased the risk, whereas pre-pregnancy BMI less than
18 kg/m
2
decreased the risk of subtherapeutic serum magnesium levels. A serum creatinine level greater than 0.9
mg/dl was another factor that decreased the risk.
Keywords: Pre-eclampsia; magnesium sulfate; therapeutic level; associated factors (Siriraj Med J 2020; 72: 159-166)
Corresponding author: Kingkaew Mingsuttiporn
E-mail: kingkaew.msp@gmail.com
Received 18 April 2018 Revised 6 June 2019 Accepted 13 June 2019
ORCID ID: http://orcid.org/0000-0001-5956-8109
http://dx.doi.org/10.33192/Smj.2020.21
INTRODUCTION
Pre-eclampsia is a common obstetric complication
and one of the main causes of maternal and fetal mortality
worldwide1.e incidence of pre-eclampsia varies between
3-10 percent of pregnant women and is the leading cause
of maternal deaths. e causes of such deaths include
intracerebral hemorrhage, congestive heart failure, acute
kidney injury, and eclampsia.
1
Maternal complications
and neonatal complications, such as preterm labor and
respiratory distress syndrome, are also common.
Given that the etiology of eclampsia is unknown,
but the condition occurs exclusively during pregnancy,
the best treatment of choice is termination of pregnancy.
2
However, other supportive treatments, including prevention
of eclampsia, blood pressure control and patient hydration,
should also be considered.
2-4
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Titapan et al.
For prevention of eclampsia, magnesium sulfate
is the most appropriate treatment of choice.
5
ere are
two major regimens that are currently used.
1. Zuspan regimen: an intravenous regimen of 4 grams
of magnesium sulfate is administered as the loading
dose, followed by a maintenance infusion of magnesium
sulfate solution at 2 grams/hour.
6
2. Pritchard regimen: an intramuscular regimen of
4 grams of magnesium sulfate is administered as
the loading dose, followed by 10 grams intramuscularly.
Subsequently, 5 grams is administered intramuscularly
every 4 hours in alternate buttocks.
7
At Siriraj Hospital, we use the intravenous regimen
because it can be easily adjusted to reach the target
therapeutic level.
8
Surprisingly, even subtherapeutic serum magnesium
levels might cause serious maternal complications such
as intracerebral hemorrhage and multiple organ failure.
However, only one study by Tudela CM
9
reported the
factors associated with subtherapeutic serum magnesium
levels for the prevention of eclampsia in pre-eclamptic
pregnant women. is study reported subtherapeutic serum
magnesium levels in more than half of the participants. In
addition, various factors associated with this condition,
including body mass index (BMI), age and multipara,
were reported.
Until now, no such study has been conducted in
ailand. We seek to determine the factors associated
with subtherapeutic serum magnesium levels and whether
these factors dier between our country and the Western
countries.
e primary aim of this study was to identify the
factors associated with subtherapeutic serum magnesium
levels for the prevention of eclampsia in term pregnant
women with severe pre-eclampsia. e secondary aim
was to compare the pregnancy outcomes, including
delivery outcomes, maternal outcomes and neonatal
outcomes, as well as the use of antihypertensive drugs
in these pregnant women.
MATERIALS AND METHODS
Study design
is was a case-control study with a retrospective
chart review.
Sample size calculation
e test of dierence between two independent
proportions was chosen to calculate the sample size in this
study, based on the study of Tudela CM
9
that reported
associated factors related with subtherapeutic serum
magnesium level in pre-eclampsia pregnant women. From
this study, obesity (BMI >25 kg/m
2
) and multipara were
two factors that were strongly related to subtherapeutic
serum magnesium levels. Obese and multipara pregnant
women accounted for 83% and 59%, respectively, of the
2,698 women in the subtherapeutic serum magnesium
level group and approximately 54% and 41%, respectively,
of the 2,600 women in the therapeutic serum magnesium
level group.
Given that multipara was the factor which accounted
for a small percentage, we chose it as the factor for
calculation of sample size. Using this factor for the
calculations, the sample size would be suciently large
to identify a signicant dierence in our study.
Aer calculation, 200 participants, i.e., 100 participants
in each group were required for this study.
Intervention
Aer approval by the Siriraj Institutional Review
Board, Faculty of Medicine Siriraj Hospital, Mahidol
University (Si 580/2014), all medical records of term
pregnant women with severe pre-eclampsia who delivered
their babies in Siriraj Hospital from January 2006 to
December 2013 were reviewed and extracted for further
study. e exclusion criterion included pregnant women
who developed eclampsia before magnesium sulfate
administration.
Two hundred medical records that met the inclusion
criteria were randomly allocated into two groups as
follows:
1. Case group: 100 pregnant women with subtherapeutic
serum magnesium levels (<4.8 mg/dl).
2. Control group: 100 pregnant women with therapeutic
serum magnesium levels (4.8-8.4 mg/dl).
Measurement of serum magnesium level in Siriraj
Hospital
Serum magnesium levels were assessed using the
standard Roche/Hitachi Cobas c systems.
10-12
All the basic characteristics, signs and symptoms of
pre-eclampsia, laboratory ndings, antihypertensive drug
use and pregnancy outcomes were carefully extracted
from the patients’ medical records and compared between
the case and control groups.
Statistical analysis
Quantitative data, such as age, pre-pregnancy BMI,
and total weight gain, were analyzed with the help of a
two-sample t-test.
Qualitative data, such as pregnancy outcomes and
antihypertensive drug use, were analyzed using the Chi-
square test.
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Original Article
SMJ
A logistic regression model was used for the multivariate
analysis. e outcomes were quantied as percentage
and odds ratio with a 95% condence interval. A P-value
< 0.05 was considered signicant. All analyses were
performed with the SPSS version 20 statistical package.
RESULTS
We started with univariate analysis to compare the
basic characteristics between the case and control groups.
e case group had a signicantly higher number of
pregnant women with a pre-pregnancy BMI greater than
25 kg/m
2
than the control group, whereas the number
of pregnant women with a pre-pregnancy BMI less than
18 kg/m
2
was lower in the case group than in the control
group. All the ndings are presented in Table 1.
e laboratory results, including the renal function
test (creatinine, uric acid), the liver function test (AST,
LDH) and hematology (platelet), exhibited signicant
dierences between groups. e details are provided in
Table 2.
All of the signs and symptoms of pre-eclampsia,
including headache, blurred vision, epigastric pain, leg
edema and pulmonary edema, were not signicantly
dierent as shown in Table 3.
TABLE 1. Basic characteristics of the subjects.
Subtherapeutic level Therapeutic level
n*=100 n*=100
P-value
Age (year) 28.24 ± 6.36
#
28.64 ± 6.61
#
0.633
Prepregnancy BMI (kg/m
2
)
<18.5 6 (6%) 32 (32%) <0.001
18.5-24.9 55 (55%) 61 (61%)
≥25 39(39%) 7(7%)
Total weight gain (kg) <0.001
Underweight gain 23 (23%) 37 (37%)
Normal weight gain 19 (19%) 41 (41%)
Overweight gain 58 (58%) 22 (22%)
Nullipara 59 (59%) 69 (69%) 0.226
Associated condition and diseases
DM 0.688
GDMA1 10 (10%) 8 (8%)
GDMA2 3 (3%) 1 (1%)
Overt DM 3 (3%) 2 (2%)
Chronic HT 19 (19%) 10 (10%) 0.071
Other 7 (7%) 8 (8%) 0.788
Smoking 2 (2%) 2 (2%) 1.00
Alcohol 3 (3%) 1 (1%) 0.621
Drug abuse 3 (3%) 1 (1%) 0.621
*n = number, Data was presented as Mean ± SD or n (%)
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Titapan et al.
The number of pregnant women who used
antihypertensive drugs was signicantly increased in
the case group compared with the control group. e
details of antihypertensive drug use are reported in Table 4.
Overall pregnancy outcome exhibited no signicant
dierences for any of the variables as shown in Table 5.
Aer the univariate analysis was performed, the multivariate
analysis was performed to eliminate the confounding factors
by reanalyzing all of the signicant factors associated with
subtherapeutic serum magnesium levels. e odds ratio
was used for the prediction of subtherapeutic magnesium
levels. e multivariate analysis results identied two factors
that exhibited a signicant association with subtherapeutic
serum magnesium levels, which included pre-pregnancy
BMI and serum creatinine levels. Pregnant women with
a pre-pregnancy BMI greater than 25 kg/m
2
exhibited
a 56% increased risk of having subtherapeutic levels
compared with women with a normal pre-pregnancy
BMI (18-24.9 kg/m
2
). In contrast, pregnant women
with a pre-pregnancy BMI less than 18 kg/m
2
exhibited
an 80% decreased risk. In addition, serum creatinine
levels greater than 0.9 mg/dl also decreased the risk of
subtherapeutic serum magnesium levels by 98.7%. e
details of the multivariate analysis are presented in Table 6.
TABLE 2. Laboratory ndings.
TABLE 3. Signs and symptoms of preeclampsia.
Subtherapeutic level Therapeutic level
n*=100 n*=100 P-value
n (%) n (%)
Renal function test
Creatinine (mg/dl) >0.9 6 (6%) 81 (81%) < 0.001
Uric acid (mg/dl) >8 7 (7%) 36 (36%) < 0.001
Hematology
Platelet (x10
3
/µl) < 100,000 1 (1%) 4 (4%) 0.001
Liver function test
AST (U/L) >70 1 (1%) 9 (9%) 0.009
ALT (U/L) >70 1 (1%) 6 (6%) 0.059
LDH (U/L) >600 5 (5%) 17 (17%) 0.006
*n = number
Subtherapeutic level Therapeutic level
n*=100 n*=100 P-value
n (%) n (%)
Headache 10 (10%) 17 (17%) 0.147
Blur vision 9 (9%) 7 (7%) 0.602
Epigastric pain 8 (8%) 8 (8%) 1.00
Leg edema 61 (61%) 52 (52%) 0.199
Pulmonary edema 1 (1) 0 (0) 1.000
*n = number
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TABLE 4. Antihypertensive drug use aer magnesium administration.
TABLE 5. Pregnancy outcomes.
Subtherapeutic level Therapeutic level
n*=100 n*=100 P-value
n (%) n (%)
Amlodipine 1 (1%) 0 (0%)
Hydralazine 18 (18%) 14 (14%)
Labetalol 20 (20%) 6 (6%)
Total 39 (39%) 20 (20%) 0.003
*n = number
Subtherapeutic level Therapeutic level
n*=100 n*=100 P-value
n (%) n (%)
Delivery outcome
Spontaneous vertex delivery 28 (28%) 37 (37%) 0.235
Vacuum extraction 7 (7%) 10 (10%)
Forceps extraction 0 (0%) 1 (1%)
Cesarean section 64 (64%) 52 (52%)
Others 1 (1%) 0 (0%)
Maternal outcomes
Eclampsia 0 (0%) 0 (0%) -
Post-partum hemorrhage 3 (3%) 5 (5%) 0.498
Intracerebral hemorrhage 0 (0%) 1 (1%) 0.497
Sepsis 1 (1%) 1 (1%) 1.000
Intensive unit care admission 0 (0%) 2 (2%) 0.246
Blood transfusion 1 (1%) 3 (3%) 0.369
Death 0 (0%) 0 (0%) -
Neonatal outcomes
Apgar score <7
At 1 minute 7 (7%) 9 (9%) 0.431
At 5 minutes 4 (4%) 1 (1%) 0.184
*n = number
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Titapan et al.
TABLE 6. Multivariate analysis of associated factors of subtherapeutic serum magnesium level.
Adjusted OR P-value
(95% CI)
BMI (kg/m
2
) 0.002
< 18 0.20 (0.05,0.77) 0.020
18-24.9 1.00
≥25 1.56(1.32,23.41) 0.019
Weight gain (kg) 0.066
Under weight gain 0.79 (0.23,2.77) 0.720
Normal weight gain 1.00
Over weight gain 2.92 (0.88,9.75) 0.081
Creatinine (mg/dl) <0.001
≤0.9 1.00
> 0.9 0.013 (0.004,0.047)
Uric acid (mg/dl) 0.616
≤8 1.00
> 8 1.45 (0.34,6.08)
Platelet count (µl) 0.247
≥100,000 1.00
< 100,000 0.21 (0.01,2.92)
AST (U/L) 0.958
≤70 1.00
> 70 1.07 (0.08,14.54)
LDH (U/L) 0.091
≤600 1.00
> 600 0.24 (0.05,1.26)
DISCUSSION
e association of subtherapeutic serum magnesium
levels with the prevention of eclampsia in pre-eclamptic
pregnant women was rst proposed by Tudela CM.
9
In
that study, more than half of the participants exhibited
subtherapeutic serum magnesium levels. at study also
reported factors associated with subtherapeutic serum
magnesium levels in pre-eclamptic pregnant women,
including BMI, age and multipara status.
According to our multivariate analysis, the only
two factors that exhibited signicant association with
subtherapeutic serum magnesium levels were pre-pregnancy
BMI and serum creatinine level.
Similar to the study of Tudela CM.
9
, the outcome of
pre-pregnancy BMI indicated that pregnant women with
a BMI greater than 25 kg/m
2
exhibited a 56% increased
risk of subtherapeutic serum magnesium levels compared
with pregnant women with a normal BMI (18-24.9 kg/m
2
).
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In addition, those with a BMI less than 18 kg/m
2
exhibited
an 80% decreased risk of subtherapeutic serum magnesium
levels.
Based on the magnesium metabolism theory, the
constant proportions of magnesium distribution in the
human body under normal conditions are as follows: so
tissue, 19.3%; muscle, 27%; bone, 52.9%; serum, 0.3%;
and red blood cell, 0.5%. Obese women have more fat,
bone and muscle mass than women with normal BMI,
potentially explaining the relationship of BMI and serum
magnesium levels. Pregnant women with increased BMI
exhibit an increased distribution of magnesium to fat,
bones and muscle, which would reduce the magnesium
distribution in the serum. In addition, women with an
increased BMI had more blood volume, which might dilute
the serum magnesium level. Based on this mechanism,
women with increased BMI have a tendency to have
subtherapeutic serum magnesium levels.
13-16
e kidneys are the crucial organs for controlling
magnesium homeostasis. A serum creatinine level greater
than 0.9 mg/dl reects the reduced ecacy of the kidney
in magnesium excretion. is physiology supported our
nding that the subtherapeutic serum magnesium level
decreases the risk by up to 98.7%.
The number of pregnant women who needed
antihypertension drugs in our study increased in the
subtherapeutic serum magnesium level group compared
with the therapeutic serum magnesium level group. e
nding can be explained by the eect of magnesium
sulfate, which can also decrease the blood pressure by
modulating vascular tone. erefore, the pregnant women
with lower serum magnesium levels in the subtherapeutic
group might require more antihypertensive drugs.
With regard to the comparison of pregnancy outcomes,
there were no statistically signicant dierences in terms
of delivery outcomes, maternal outcomes and neonatal
outcomes in either group. e explanation for these
ndings is that not only the serum magnesium level,
but also many other confounding factors can inuence
the outcomes.
e use of a case-control study design for this study
is useful for determining the signicant outcomes for
multiple risk factors. e criteria for selecting subjects
were carefully considered to control the heterogeneity
and selection bias aecting the similarity of the basic
characteristics of both groups.
At Siriraj Hospital, we manage pregnant women
with severe pre-eclampsia according to our institutional
guidelines. e same practice of history taking, physical
examination, and laboratory investigation and the
same protocol for intravenous regimens of magnesium
sulfate were used for each patient. erefore, most of
the retrospective data were completely recorded, and
the minimal deviation of data collection increased the
reliability of this study.
However, the retrospective nature of the study
presented some limitations. Patient data from our medical
records were documented by many physicians. Many
subjective data, such as the signs and symptoms of pre-
eclampsia, may vary.
is study found that the factors associated with
subtherapeutic serum magnesium levels included pre-
pregnancy BMI and serum creatinine levels. is result
could be applied to daily medical practice by increasing
the dosage of magnesium sulfate in pregnant women
of the subtherapeutic serum magnesium level group,
including women with a pre-pregnancy BMI greater
than 25 kg/m
2
. In addition, physicians should be cautious
when administering magnesium sulfate to those with
a pre-pregnancy BMI less than 18 kg/m
2
or those with
greater than 0.9 mg/dl serum creatinine.
However, because there are only a few studies available
on this subject, further studies should be performed,
especially prospective studies, and a risk scoring model
for subtherapeutic serum magnesium levels should be
developed. We hope that the future guidelines for the
management of pre-eclamptic women will include more
evidence-based data, which in turn can improve the
outcomes of management for these patients.
CONCLUSION
e factors associated with subtherapeutic serum
magnesium levels were pre-pregnancy BMI and serum
creatinine levels. A pre-pregnancy BMI greater than
25 kg/m
2
increased the risk of subtherapeutic serum
magnesium levels in severe pre-eclamptic women, whereas
pre-pregnancy BMI less than 18 kg/m
2
decreased the
risk. Serum creatinine levels greater than 0.9 mg/dl also
decreased the risk of subtherapeutic magnesium levels
in these women.
REFERENCES
1. Cunningham FG, Leveno KJ, Bloom SL, Hauth JC, Rose DJ,
Spong CY, editor. Williams’s Obstetrics. 23
rd
ed. New York:
McGraw Hill; 2012.p.706.
2. Taweesul P, Tannirandorn Y. Clinical and laboratory parameters
associated with eclampsia in ai Pregnant Women. J Med
Assoc ai 2014;97:139-46.
3. Sibai BM, Lipshitz J, Anderson GD, Dilts PV Jr. Reassessment
of intravenous MgSO4 therapy in preeclampsia-eclampsia.
Obstel Gynecol 1981;57:199-202.
4. Sibai BM. Diagnosis and management of gestational hypertension
and preeclampsia. Obstet Gynecol 2003;102:181-2.
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5. JamiluTukur. e use of magnesium sulphate for the treatment
of severe pre-eclampsia and eclampsia. Ann Afr Med 2009;8:
76-80.
6. Zuspan FP. Problems encountered in the treatment of pregnancy-
induced hypertension. A point of review. Am J Obstet Gynecol
1978;131:591-7.
7. Pritchard JA, Cunningham FG, Pritchard SA. e Parkland
memorial hospital protocol for treatment of eclampsia: evaluation
of 245 cases. Am J Obstet Gynecol 1984;148:951-63.
8. Smith JM, Lowe RF, Fullerton J, Currie SM, Harris L, Felker-
Kantor E. An integrative review of the side eects related
to the use of magnesium sulfate for pre-eclampsia and eclampsia
management. BMC Pregnancy Childbirth 2013;13:34.
9. Tudela CM, McIntire DD, Alexander JM. Eect of maternal
body mass index on serum magnesium levels given for seizure
prophylaxis. Obstet Gynecol 2013;121:314-20.
10. Yu AS. Evolving concepts in epithelial magnesium transport.
Curr Opin Nephrol Hypertens 2001;10:649-53.
11. Mann CK, Yoe JH. Spectrophotometric determination
of magnesium with sodium 1-azo-2-hydroxy-3-(2, 4-dimethyl-
carboxanilido)-napthalene-1’-(2-hydroxybenzene-5-sulfonate)
Anal Chem 1956;28:202-5.
12. Kanagal DV, Rajesh A, Rao K, Devi UH, Shetty H, Kumari
S, et al. Levels of serum calcium and magnesium in pre-eclamptic
and normal pregnancy: a study from coastal India. J Clin Diagn
Res 2014;8:OC01-4.
13. Swaminathan R. Magnesium metabolism and its disorders.
Clin Biochem Rev 2003;24:47-66.
14. Saris NE, Mervaala E, Karppanen H, Khawaja JA, Lewenstam
A. Magnesium.an update on physiological, clinical and analytical
aspects.Clin Chim Acta 2000;294:1-26.
15. Kroll MH, Elin RJ. Relationships between magnesium and
protein concentrations in serum.Clin Chem 1985;31:244-6.
16. Ephraim RK, Osakunor DN, Denkyira SW, Eshun H, Amoah S,
Anto EO. Serum calcium and magnesium levels in women
presenting with pre-eclampsia and pregnancy-induced
hypertension: a case-control study in the Cape Coast metropolis,
Ghana. BMC Pregnancy Childbirth2014;14:390.
Titapan et al.
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Safa A. K. Algobori, M.Sc.*, May F. Alhabib, Ph.D.**, Manal T. Alobaidy, Ph.D.***, Imad M Alani****, Enas I.
Matloup, FIBMS*****, Ghasak G. Faisal, FIBMS******, Mohammad O. Selman, FIBMS*, Azhar M.Suhail, Ph.D.********
*Department of Applied Embryology/ High Institute of Infertility Diagnosis and ART/ Al-Nahrain University, Baghdad, Iraq. **Department of
Histology and Embryology, college of medicine Al-Nahrain University, Baghdad, Iraq. ***Department of reproductive physiology, high institute of
infertility and ART, Al-Nahrain University, Baghdad, Iraq. ****Department of Dentistry, Al-Hikmah University College, Al-Yarmook, Baghdad,
IRAQ. *****Department of Family Medicine, Al-Yarmouk Teaching Hospital, Ministry of Health, Baghdad, Iraq. ******Department of Fundamental
dental and Medical Sciences, Kulliyyah of Dentistry, International Islamic University Malaysia, Kuantan, Pahang, Malaysia. *******Alkarkh Health
Directorate Baghdad, Saydiah, Baghdad, Iraq.
Increase in Endothelin-1 Expression in Umbilical
Cord Arteries in Preeclampsia
ABSTRACT
Objective: Endothelin1 (ET1) is 21- amino acid vasoconstrictor peptide secreted by endotheliumwhich has an
important role in the pathoohysiology of preeclampsia (PE). e objective of this study was to evaluate the binding
sites and quantitative changes in ET1 in umbilical cord vessels of PE patients.
Methods: is study recruited 40 pregnant women between 20-40 years old at 3
rd
trimester. All cases selected for
this study underwent an elective cesarean section, grouped into 2 groups; PE group of 20 pregnant women (at 3
rd
trimester) who proved to have pregnancy induced hypertension and proteinuria. e control group was of 20 healthy
pregnant females at the same average of gestational age and with the same exclusion criteria and no PE, underwent
elective caesarean section. Umbilical cord tissues were taken from the maternal side, xed with formalin, paran,
embedded sections of umbilical cord were treated with Endothelin1 antibody. e immunoreactivity of ET1 was
assessed using Aperio image scope soware. Statistical analysis was done using SPSS program.
Results: e results demonstrated a signicant increase (P = 0.001) of ET1 expression in cord vessels of PE group
with respect to control group (mean 28.5±1.7, 2.6±0.4 respectively).
Conclusion: It is concluded that ET1 is markedly increase in PE and may be the cause behind promoted vascular
smooth muscle cell contraction and blood pressure elevation in PE.
Keywords: Endothelin1; preeclampsia; pregnancy; umbilical cord (Siriraj Med J 2020; 72: 167-173)
Corresponding author: Ghasak G. Faisal
E-mail: drghassak@yahoo.com
Received 2 December 2019 Revised 4 February 2020 Accepted 21 February 2020
ORCID ID: http://orcid.org/0000-0002-4736-7630
http://dx.doi.org/10.33192/Smj.2020.22
INTRODUCTION
e umbilical cord is the fundamental connection
between developing fetus and the placenta. It is made of
three blood vessels; two small arteries, which carry the
deoxygenated blood from the fetus to the placenta and a
one large vein which carries nutrition-rich oxygenated
blood to the fetus; this vein is unlike the regular veins in
that it contains a layer of smooth muscles.
1
ese blood
vessels lie in an embryonic gelatinous connective tissue
known as Wharton’s jelly, all are enclosed in a layer of
amnion.
2
e blood vessels of human umbilical cord are
dissimilar from the main vessels of the same caliber in
the body for many reasons; exudation of uid take place
in these vessels and participate to the formation of the
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Algobori et al.
amniotic uid.
3
Umbilical vessels lack vasa vasorum, thus
rely on their own oxygen supply, making them more
vulnerable to modication in hemodynamic status.
4
Hypertension is a commonly occurs during pregnancy.
Preeclampsia (PE) is disorder that occurs in pregnancy
that damages both the mother’s circulation and the
fetal growth. e risk factors for development of PE
includes obesity, insulin resistance and hyperlipidemia
all these conditions will lead to increase in the release of
inammatory mediators and rise the oxidative stress which
will eventually lead to dysfunction of the endothelium.
5
PE
occurs at 20 weeks gestation and onward, it is characterized
by an elevation in blood pressure higher than “140/90
mm Hg” accompanied by signicant proteinuria “ ≥300
mg/dl in 24-hour urine collection”.
6
PE aects many
pregnancies and is still considered as a dangerous risk
to mother and fetus.
7,8
PE is much higher in association
with intrauterine growth retardation because there might
be a chronic hypoxia which leads to contraction of the
placental vascular bed which eventually increases the
arterial resistance.
4,8
Endothelins are family of 21-amino acid peptides
encoded by 3 genes and produced in several tissues,
mainly by endothelial cells lining blood vessels; they
are group of vasoconstrictor peptides covering three
isoforms, endothelin-1, endothelin-2, and endothelin-3.
“ET1, ET2, and ET3” characterize by the presence of 2
intramolecular disulde bonds.
9
ET1 is the main isoform
made by vascular endothelium. Once formed, ET1 acts
as a paracrine and autocrine mediator rather than an
endocrine hormone, it has strong vasoactive performance
and has been involved in the pathogenesis of a lot of
vascular diseases like hypertension,
10
which can cause
brosis of blood vessels and a state of inammation
due to increase in cytokine production.
11
When ET1 is
released by the endothelium, it performs its action on
ETA and ETB receptors of the neighboring endothelium
or smooth muscle cells by paracrine or autocrine manner.
e genes for ETA and ETB receptors had been cloned.
ETA and ETB receptors on smooth muscle induce many
cellular activities such as contraction, proliferation cell
hypertrophy and apoptosis,
12
studies in animal models
representative of PE, have shown that endothelin receptor
blockers prevent the development of this disease.
13
Large
quantity of Endothelin‐1 was demonstrated in human
umbilical vessels, amniotic membrane ,amniotic uid
and placenta.
14
is research aims to evaluate the binding
sites for Endothelin-1 in the vessels of the umbilical
cord and to quantify the dierences in expression of
Endothelin-1 in these vessels of women with in PE.
MATERIALS AND METHODS
Sample collection
e sample size was determined using Raoso tool
with the condence level set at 95% and the margin of
error is 10% with the resultant sample size required is
20 patients with preeclampsia.
e present study enrolled 40 pregnant women
ageing between 20-40 years old at the third trimester who
attended AL- Imamayn Al-Khademyiayn medical city
hospital in Baghdad who underwent elective cesarean
section. e choice of patients undergoing cesarean
section was because we wanted to standardize the method
of delivery and it is easier to attend to the patient and
harvest the fresh placenta immediately upon delivery.
e exclusion criteria are patients with hypertension
before pregnancy, diabetes mellitus, vascular diseases
and smoking.
e Patients were grouped into two groups of 20.
Group I “PE group” consisted of pregnant women (at
third trimester) who had systolic blood pressure (BP)
≥140 mmHg, diastolic BP ≥90 mmHg and proteinuria of
at least 1+ (≥300 mg/dl). Group II “control” consisted of
normotensive pregnant women at the same average age
(systolic BP <140 mmHg and diastolic BP <90 mmHg).
Written consent was obtained from the patients aer
explaining the procedure to them. e present study was
approved by the Head of the Postgraduate Committee,
Department of Applied Embryology, High Institute of
Infertility Diagnosis and ART, Al-Nahrain University.
Immunohistochemical staining with Endothelin-1
antibody (ET-1)
e placenta and umbilical cord was collected during
the caesarean section procedure. Transvers pieces of the
umbilical cords “one cm in thickness” was taken from the
maternal side (area close to the placenta) of each patient,
xed in 10% buered formal saline, dehydrated by ascending
concentrations of ethanol, cleared in xylene, impregnated
and embedded in paran wax. Paran sections of 4 μm
thickness were placed on positively charged slides then
the sections incubated overnight at room temperature.
e tissue sections were de-paranized and rehydrated,
blocked with peroxidase and serum blocking reagents,
treated with ET-1was purchased from Abcam (a30536)
Primary antibody was diluted in a serum block-to (1/100)
μg/ml as determined by titration and was added in sucient
volume to cover the tissue.and incubated overnight with
biotinylated secondary antibody and HRP-streptavidin
complex respectively, then treated with DAB chromogen,
stained by haematoxylin as counter stain, dehydrated
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by series of ethanol, cleared in xylene and covered with
cover slips. e immunoreactivity of ET1 was assessed
quantitatively by Aperio Image Scope soware. e
computerized analysis of the immunohistochemical
reactivity of ET1 using Aperio image scope program was
done by choosing a determined area from each sample
which had no spaces and then enter the picture to the
program which read the negative, weak positive, positive
and strong positive reaction in the cells. e positive
reading included positive and strong positive cells we
excluded the weak positive. e accuracy of the reading
was ensured by repeating the reading three times and
taking the mean.
Statistical analysis
e IBM Corp. SPSS Statistics for Windows, Version
23 Armonk, NY: IBM Corp. was used to analyze the data.
All data in this study are presented as mean ± SEM. Data
were analyzed by Mann-Whitney U test, the value of
p < 0.05 was considered as statistically signicant.
RESULTS
e umbilical arteries of the control group have
constricted, folded shaped endothelium and their wall
consist of pale staining layer of variable thickening in
the center called ‘tunica intima’ which is surrounded by
muscular layer called ‘tunica media’. e medial layer
is closely attached to the surrounding Wharton’s jelly
which is merged with tunica adventitia in umbilical vessels
(Fig 1) while in PE group this layer is clearly separated from
the jelly due to the presence of strong vasoconstriction
which may lead to narrowing the lumen Fig 1.
In the control group, SMCs of arterial wall are
fusiform shaped concentrically closely arranged with
each other with elongated, large nuclei having wavy like
appearance (Fig 2A). While in PE group, the muscle cells
are irregularly arranged and the nuclei become small
sized losing their longitudinal appearance. Irregular
spaces appear between SMCs lead to accumulation of
these cells in groups due to increase inter cellular uid
which is associated with edema. e presence of these
spaces in the PE cords made it easier to distinguish
between the muscle cells than it is in the control group
(Fig 2B).
e immunoreactivity for ET1 appeared as small
dark brown granules or deposits concomitant with the
structural arrangement of the cord when visualized by
DAB using the haematoxylin as a counter stain. e
reaction mainly occurred in the cytoplasm of smooth
muscle bers and to a lesser extent in the endothelium
lining blood vessels (Fig 3A). e strongest staining
reactivity pattern was observed in the smooth muscle
bers seen as high intense brownish granules especially
in the arteries of PE samples (Fig 3B).
e positivity of the vascular smooth muscle cells
varied between strong positive and positive. In spite
of the dierence in the thickness of vascular smooth
muscle layer in between PE group and control group,
the number of cells that showed strong positive reaction
to ET1 was signicantly high (Fig 4A). In contrast, the
control samples showed large number of weakly stained
smooth muscle cells when treated with ET1 antibody,
tunica adventitia showed no reactivity at all (Fig 4B).
e expression percentage of ET- 1 was signicantly
increased in PE patients compared to the control group
Fig 5.
DISCUSSION
Several theories have been suggested about the
eventual cause of preeclampsia, it is clear that in PE
there is an abnormal vascular remodeling.
15
It has been
demonstrated that the remodeling of spiral arteries is not
complete in these patients.
16
Reduction of utero-placental
perfusion as a consequence of anomalous cytotrophoblast
invasion of the spiral arterioles is a prompting episode
leading to preeclampsia.
17
Ischemia/hypoxia in the placenta
is believed to induce abnormal endothelial function
leading to the release of vasoactive substances such
as “nitric oxide, endothelin, and angiotensin II” that
have intense eects on blood ow and arterial pressure
regulation.
18,19
Due to the fact that human umbilical
cord vessels have a special feature in being decient
of innervation, the action of the vasoactive substances
seemed to be decisive in monitoring the tone of the
umbilical vessels; several studies have demonstrated that
the production of vasoactive substances, such as nitric
oxide and ET1 are changed in PE in comparison with
normotensive pregnancies.
20,21
e choice of patients undergoing cesarean section
was because we wanted to standardize the method of
delivery and it is easier to attend to the patient and
harvest the fresh placenta immediately upon delivery.
We don’t think that the mode of delivery would aect
the rate of expression of ET1.
ET-1 is a strong vasoactive peptide, its concentration is
increased in PE and plays a serious role in the pathophysiology
of PE; there are many investigation on the role of ET1
in the stimulation of hypertension in PE. Indeed, ET1
was observed to prompt vasoconstriction via the ETA
receptor, which had been shown to induce hypertension
in PE.
22,23
e concentration of ET1 was found to be
3 times higher in the plasma umbilical cord than in
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Algobori et al.
DA
WJ
WJ
A
A
B
B
Fig 1. (A) Cross section of umbilical cord of control group shows the general appearance of the umbilical artery where its tunica adventitia
(AD) merged with Wharton’s jelly (WJ) control group, H&E stain, X40. (B) Cord in PE group show the separation of the medial layer of
umbilical artery from the surrounding Wharton’s jelly, H&E, X100.
SM
SM
Fig 2. (A) Cross section of the umbilical artery shows the normal concentrically arranged smooth muscle (SM) in arterial wall of control
group. (B) Irregularity of SM with an increase in the inter-cellular spaces between these cells in PE group. H&E stain, X400
Fig 3. Cross section in umbilical artery with immunohistochemical staining with endothelin 1 antibody showing the positive expression of
endothelin 1 in the cytoplasm of smooth muscle (M) and in endothelial cells (E). Endothelin1 Ab, PE group, magnication (A) x100, (B)
x 40.
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Fig 4. Cross section of umbilical artery showing intense brown pigmentation of ET1 immune-localization in the endothelial cells (E) and
the smooth muscle (M) of the PE group (A) and the very weak reaction to the anti endothelin1 of the control group (B) endothelin1 Ab,
magnication X400.
Fig 5. e expression of endothelin 1 in preeclampsia group with respect to control group presented as mean±SEM, p-value <0.05.
the plasma of maternal side, and was related to the
inuence of low pO2 in fetal blood.
24
In spontaneous
labor, the concentration of ET1 in the umbilical cord and
retroplacental blood plasma was ten times higher than
those in the maternal peripheral blood suggesting that
an elevation of the intrauterine secretion of endothelin-1
at delivery may stimulate the constriction of the blood
vessels in the umbilical cord and placental bed.
25
Endothelin 1 can also have a prolonged eect on
blood pressure regulation e plasma level of ET1 can
have substantial long-term eects on circulation and
arterial pressure regulation. us, oversecretion of ET1
might have a signicant role in mediating renal failure and
hypertension observed in women with PE.
26
e present
investigation might be the rst study that demonstrated
ET1 in umbilical vessels revealing that the strongest
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Algobori et al.
staining pattern was detected in muscle & endothelial
cells particularly in the arteries of PE samples. In PE
the dysfunction of endothelial cells is responsible for
the dierent presentations of PE like hypertension and
proteinuria which results in a disturbance in the balance
between substances that cause vascular dilatation and
constriction.
27
Locally, ET1 a potent vasoconstrictor is
produced by endothelial cells, increases smooth muscle
contractility.
28
It is known that endothelin plays a signicant
role in the development of PE during pregnancy.
29
therefor,
ET1 may stimulated a contractile response in arteries
with damaged endothelium, and the severity of the
damage in PE might potentiate the eect of ET1.
30
A
previous study on pregnancies with intra uterine growth
retardation revealed that ET-1 was localized diusely in
placental specimens from normal and IUGR pregnancies.
e localization of ET-1 immunoreactivity was much
higher in the endothelium of capillaries of villi as well
as in the cells of the basal plate in the placenta of normal
pregnancy than pregnancies with IUGR.
31
ET-1 plays a signicant role in regulating blood
vessel function in all organ systems, ET1 elicited a
presser response in vascular smooth muscle cells chiey
mediated by ETA receptors, and a depressor response
chiey mediated by nitric oxide released from endothelial
cells through ETB receptors.
32
e present study has
demonstrated a strong positivity of the vascular smooth
muscle cells in the arterial wall which can lead to the
dysregulation of vascular function leading to vascular
constriction. Clinically, ET-1 has been implicated for the
deterioration of renal function through loss of nephrin as
Studies with an endothelin-1 (ET-1) receptor antagonist
indicated that ET-1 was the main factor aecting loss of
nephrin.glomerular endothelium was found to produce
ET-1 when incubated with serum from PE patient, and
recombinant ET-1 triggered nephrin shedding from
podocytes.
33
which lead to the renal manifestation of
preeclampsia which are characterized by proteinurea
and hypertension.
ET-1 inhibits cell proliferation and vitality and
triggers oxidative stress in the human placenta by altering
the balance between oxidants and antioxidants forces in
favor of oxidation
34
that’s why we can clearly see changes
in histological appearance of the umbilical cord of PE
patients where the smooth muscle layer looses its uniform
shape and shows cellular swelling which is a sign of cell
injury. erefore, according to this study, further research
can be conducted on the benet of blocking the ET-1
receptor in preventing the progression of preeclampsia
to eclampsiawhich can save many mothers at risk from
developing this disorder that carries high mortality rate.
e main limitation of this study is to get standardized
immunohistochemical staining of the samples obtained
so we need to observe the correct staining site in the
tissue and ignore false positive random staining.and
also to be able to preserve the tissue well to allow good
preservation of the antigens as it is well known that a
good immunohistochemical stain requires fresh tissue
samples and the older the tissue the more loss of antigens.
CONCLUSION
It is concluded that ET1 is markedly increase in PE
and may be the cause behind promoted vascular smooth
muscle cell contraction and blood pressure elevation in
PE.
ACKNOWLEDGMENTS
We would like to thank the International Islamic
University Malaysia for funding this project under
Publication Research Initiative Grant Scheme number
18-030-0030 and sta at AL- Imamayn Al-Khademyiayn
medical city hospital for their help in conducting this
project.
Conict of interest statement
All the authors have contributed in this research,
we have no conict of interest to declare.
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31. Erdem M, Erdem A, Erdem O, Yildirim G, Memis L, Himmetoğlu
O. Immunohistochemical localization of endothelin-1 in
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33. Collino F, Bussolati B, Gerbaudo E, Marozio L, Pelissetto S,
Benedetto C, et al. Preeclamptic sera induce nephrin shedding
from podocytes through endothelin-1 release by endothelial
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Euasobhon et al.
Pramote Euasobhon, M.D.*, Sukunya Jirachaipitak, M.D.*, Suwanna Chanpradub, M.D.**, Pranee Rushatamukayanunt,
M.D.*, Chanin Limwongse, M.D.***, Peter Courtney, MMBS.****,*****
*Department of Anesthesiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, **Department of Anesthesiology, Bangkok
Metropolitan Administration General Hospital, Bangkok, ***Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University,
Bangkok, ailand, ****Department of Anaesthesia, Royal Melbourne Hospital, Australia.
Association of Oxcarbazepine-induced Cutaneous
Adverse Drug Reactions with HLA-B*15:02 Allele
ABSTRACT
Objective: Oxcarbazepine (OXC) has similar structure and ecacy to carbamazepine (CBZ), but with fewer side
eects. However, there have been only a few reports of serious cutaneous adverse reactions to OXC. HLA-B*15:02’s
association with cutaneous adverse drug reactions (cADRs) induced by OXC is still inconsistent. is study investigated
the incidence of cADRs that were induced by OXC and their association with the HLA-B*15:02 allele in ais.
Methods: A retrospective cohort study of 494 patients receiving oxcarbazepine between January 2012 and January
2018 was undertaken. HLA-B*15:02 testing had been carried out on 79 of the 494 patients.
Results: No incidents of serious cutaneous adverse reactions, Stevens-Johnson syndrome (SJS), or toxic epidermal
necrolysis (TEN) were found. A 2.4% (12/494) of OXC-related cADRs was determined. Four out of six patients
with maculopapular eruptions (MPE) were HLA-B*15:02 positive. Patients who had the allele potentially developed
OXC-induced MPE, with an odds ratio of 6.58 (95% CI 1.11-39.15, p=0.040). Only a history of other antiepileptic
drug (AED) allergies demonstrated a signicant risk factor of OXC-induced MPE.
Conclusion: Our research demonstrated that the association between the HLA-B*15:02 allele and MPE induced by
OXC was signicant. Patients with a history of other AED allergies were also at risk of developing OXC-induced MPE.
Keywords: Antiepileptics; association; HLA-B*15:02; cutaneous adverse drug reactions; human leukocyte antigen;
incidence; maculopapular eruption; oxcarbazepine; Stevens-Johnson syndrome (Siriraj Med J 2020; 72: 174-180)
Corresponding author: Sukunya Jirachaipitak
E-mail: sukunya.jir@mahidol.ac.th
Received 22 October 2019 Revised 24 January 2020 Accepted 27 January 2020
ORCID ID: http://orcid.org/0000-0001-5188-3286
http://dx.doi.org/10.33192/Smj.2020.23
INTRODUCTION
Carbamazepine (CBZ) and oxcarbazepine (OXC)
are both aromatic antiepileptic drugs (AEDs). ey are
utilized extensively as treatments for epilepsy, bipolar
disorder, some neuropathic pain conditions, particularly
trigeminal neuralgia.
1
However, severe cutaneous adverse
drug reactions (SCARs), including Stevens-Johnson
syndrome (SJS), toxic epidermal necrolysis (TEN), drug
reaction with eosinophilia and systemic symptoms (DRESS)
and acute generalized exanthematous pustulosis (AGEP)
occasionally occur with these AEDs. e reactions may
lead to long-term sequelae and fatal outcomes. According
to the US Food and Drug Administration (FDA), adverse
events declared to the World Health Organization and
CBZ producers reveal that the rate of SJS and TEN
induced by CBZ can be ten-fold higher in some Asian
countries (4.1-5.9 per 10,000 patient-years of exposure)
than in Europe and the USA (0.2-0.9).
2
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Although many studies have since identified a
similar relationship between HLA-B*15:02 and SJS/
TEN induced by CBZ, the allele does not appear to be
a universal marker for CBZ-induced SJS/TEN, but it
seems to be ethnically specic, for example, Japanese and
Caucasian populations did not have this relationship.
3,4
Also, an association between the allele and CBZ-induced
maculopapular eruptions (MPE) has been inconclusive.
To illustrate, Sukasem et al. calculated an Odds ratio of
7.27 (95% CI 2.04-25.97) in ais
5
while Locharernkul
et al. reported an Odds ratio of 1.21 (95% CI 0.21-6.99)
in ais
6
and Man et al. demonstrated an Odds ratio of
0.84 (95% CI 0.15-4.51) in Han Chinese.
7
e strong correlation between the HLA-B*15:02
allele in Han Chinese patients and SJS induced by CBZ
was rst reported by Chung et al. in 2004.
8
Subsequently,
several case-control studies have since conrmed the
nding in Han Chinese, Malaysians and ais
5,6,9,10
and
suggested that screening of patients for the allele should
be conducted prior to prescribing CBZ.
4,11
If a positive
result was obtained, they should not be treated with
CBZ.
12
Oxcarbazepine (OXC), a member of the aromatic
AEDs, has a similar structure and ecacy to carbamazepine
(CBZ) but fewer side eects. OXC is considered as an
alternative AED, but allergic cross-reactions between
CBZ and OXC occur in approximately 1 in 4 patients.
13
e incidence of OXC-induced cutaneous adverse drug
reactions (cADRs) was 2.0-2.7%.
14,15
However, there have
been only a few reports of serious adverse reactions to
OXC, and the inter-relationship between the allele and
cADRs induced by OXC in ais is still controversial.
Although a recent case-control study reported a signicant
association between the HLA-B*15:02 allele and OXC-
induced SJS, the positive predictive value was only 0.73%.
16
In current practice, however, doctors usually avoid OXC
in HLA-B*15:02 positive patients who may benet from
the AED.
Our study aims were to ascertain the incidence of
cADRs caused by OXC and their association with the
HLA-B*15:02 allele in the ai population.
MATERIALS AND METHODS
Aer protocol approval was obtained from the
Institutional Review Board of Siriraj Hospital (Si 400/2017),
a retrospective cohort study was conducted. We included
494 patients who had received OXC at Siriraj Hospital
between January 2012 and January 2018. e research
team reviewed the patients’ demographic data and the
histories of drug and substance allergies documented in
their electronic medical records.
Diagnosis of oxcarbazepine-induced cutaneous adverse
drug reactions
e diagnoses of OXC-induced cADRs were obtained
from the Adverse Drug Reaction and Counselling Unit
at the hospital and a manual search of the medical
records. is was based on the patients’ histories and
the clinical morphology of their skin reported by the
attending physicians and dermatologists. Diagnoses of
SCARs were reached by consensus by the physicians
and dermatologists; they were based on the presence
of life-threatening skin reactions, as evidenced by full-
thickness epidermal necrosis, extensive erythema, and
bullous epidermal detachment accompanied by mucosal
involvement. SJS was dened as involving a body surface
area detachment of ≤ 10%, while SJS/TEN overlap involved
10-30% of body surface area and TEN involved ≥ 30%.
17
Diagnoses of a drug reaction with eosinophilia and
systemic symptoms (DRESS) were established using
the criteria and scoring system of the European Registry
of Severe Cutaneous Adverse Reactions (RegiSCAR)
group; the reactions included acute rash, fever, enlarged
lymph nodes, systemic involvement of at least 1 internal
organ, blood count abnormalities, eosinophilia, and
lymphadenopathy.
18
MPE were dened as self-limited,
diffuse, erythematous macules and papules without
blistering or pustulation.
14
As the cADRs usually develop
within 3 months aer exposure to OXC, the OXC-induced
cADRs were diagnosed when skin lesions were identied
within 3 months aer the rst prescription of OXC.
HLA-B genotyping
With the cooperation of the Division of Medical
Genetics, Siriraj Hospital, 79 patients who had had a
genomic test for HLA-B*15:02 and received OXC were
identied. Genomic DNA was extracted by QIAGEN
quick DNA prep according to the manufacturer’s protocol.
DNA quality was measured by spectrophotometry. A
modied PCR-SSCP was performed using sequence
specic primers to amplify HLA-B*15:02 locus using
Real-time PCR (PCRmax Eco48, UK) followed by melting
curve analysis.
19
Both negative and positive controls
were run in parallel. A positive melting curve peak at
91.4 degree Celsius was interpreted as the presence of
HLA-B*15:02. A positive melting curve peak at 77 degree
Celsius is used as an internal control of PCR reaction.
is PCR-SSCP cannot distinguish HLA-B*15:02 from
HLA-B*15:13 and HLA-B*15:25, both of which are rarely
present in ai population.
Statistical analysis
Based on a prescription-event monitoring study,
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176
Euasobhon et al.
the sample size of at least 252 patients used in this study
was calculated from a 95% condence interval (CI) of the
OXC-induced cADRs incidence of 2.7% with an allowable
error of 2%.
15
Statistical analyses were conducted on SPSS
for Windows, version 18 (SPSS Inc., Chicago, IL, USA).
Patients’ clinical and demographic data were presented
as number (%) or mean ± SD. e HLA-B*15:02 allele
test results were reported as positive or negative. e
risk factors related to cADRs induced by OXC were
analyzed with Fisher’s exact test of independence and the
unpaired t-test. e association strength was determined
by employing the odds ratio and its 95% condence
intervals (95% CI). A two-sided p-value of < 0.05 was
dened as being statistically signicant.
RESULTS
A total of 494 patients (194 males; 300 females;
mean age = 59.0 ± 18.7 years) who received OXC between
January 2012 and January 2018 were reviewed. Only 79
had a genomic DNA test for HLA-B*15:02.
Table 1 summarizes the 494 patients’ demographic
data (age and gender) and clinical characteristics (body
mass index, indication for OXC usage). Only a history of
other AED allergies (including gabapentin, pregabalin,
carbamazepine, phenytoin and sodium valproate)
demonstrated a signicant association with OXC-induced
MPE (Table 2). One out of nine patients with CBZ allergy
also developed OXC-induced cADRs.
We found that 12 out of the 494 patients had had
OXC-induced cADRs; six patients had had a genomic
test for HLA-B*15:02, while the other 6 had not. ere
were no reports of SCARs. As a result, the incidence of
OXC-induced cADRs in this study was 2.4% (12/494).
Of the 79 patients who underwent genomic testing,
21 (26.6%) were positive for HLA-B*15:02. Four out of the
six patients with OXC-induced cADRs were HLA-B*15:02
positive, with a positive predictive value of 19% and a
negative predictive value of 96.6%. Patients who had
the allele potentially developed OXC-induced cADRs,
having an odds ratio of 6.58 (95% CI 1.11-39.15, p =
0.040; Table 3). e sensitivity and specicity of the
allele predicting OXC-induced cADRs were 66.6% and
76.7%, respectively.
e clinical characteristics of the 12 individuals
with OXC-induced MPE are presented at Table 4. e
OXC-induced cADRs patients aged from 21 to 84 years
and maximal tolerable dose of OXC ranged from 150-
1200 mg/day. e cADRs could occur as early as 2 days
or up to 34 days aer the rst dose.
TABLE 1. Demographic and clinical characteristics of patients receiving oxcarbazepine (OXC).
Characteristics N = 494
Gender
Male 194 (39.3)
Female 300 (60.7)
Age (yr) 59.0 ± 18.7
Body mass index (kg/m
2
) 25.1 ± 5.7
OXC indication
Neuropathic pain 407 (82.4)
Epilepsy 30 (6.1)
Mood disorder 57 (11.5)
History of drug allergy
Other drugs 123 (24.9)
Other AEDs 20 (4.0)
e data are presented as mean ± standard deviation or n (%).
Abbreviations: AEDs = antiepileptic drugs; OXC = oxcarbazepine
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Original Article
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TABLE 2. Potential risk factors associated with OXC-induced cADRs.
Number of patients
Risk factors OXC-induced OXC-tolerant Odds ratio 95% CI p-value
cADRs (N = 12) (N = 482)
Male 4 (33.3) 190 (39.4) 1.30 0.39-4.38 0.772
BMI 23.2 ± 4.9 25.1 ± 5.7 - - 0.255
History of other drug allergies 4 (33.3) 119 (24.7) 1.53 0.45-5.16 0.504
History of other AED allergies 2 (16.7) 18 (3.73) 5.16 1.05-25.27 0.043*
e data are presented as mean ± standard deviation or n (%). *p < 0.05 was statistically signicant
Abbreviations: AED = antiepileptic drug; BMI = body mass index; cADRs = cutaneous adverse drug reactions; CI = condence interval;
OXC = oxcarbazepine
TABLE 3. Association of the HLA-B*15:02 allele with OXC-induced cADRs.
TABLE 4. Clinical characteristics of patients with OXC-induced MPE.
Number of patients
HLA-B* OXC-induced OXC- Odds Positive Negative
15:02 cADRs tolerant ratio 95% CI likelihood likelihood p-value
allele (N = 6) (N = 73) ratio ratio
Positive 4 17 6.58 1.11-39.15 2.86 0.43 0.040*
Negative 2 56
e data are presented as n (%). *p < 0.05 was statistically signicant
Sensitivity 66.6%; Specicity 76.7%; Positive predictive value 19%; Negative predictive value 96.6%
Abbreviations: cADRs = cutaneous adverse drug reactions; CI = condence interval; OXC = oxcarbazepine
No. Sex Age Indication Maximum HLA-B*15:02 Latency History of
dose (mg) (days) other
drug allergies
1 F 84 Pain 900 Negative 30 No
2 F 54 Pain 1,200 Positive 28 No
3 M 44 Pain 300 Positive 4 No
4 M 32 Pain 450 Positive 14 No
5 F 52 Pain 900 Positive 14 Carbamazepine
6 M 21 Pain 150 Negative 3 No
7 F 35 Pain 1,200 NA 2 No
8 F 74 Pain 600 NA NA Actifed
®
9 F 35 Pain 600 NA 9 No
10 F 39 Pain 300 NA 10 Phenytoin
11 F 43 Pain 600 NA NA No
12 M 64 Pain 900 NA 34 Ceftriaxone
Abbreviations: F = Female; M = Male; NA = not available
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Euasobhon et al.
DISCUSSION
Oxcarbazepine is considered as an alternative AED,
and there is evidence to suggest that it has a safer prole,
and a better tolerance than CBZ. On the other hand,
OXC and CBZ have an allergic cross-reaction of about
25%-30%.
13,20
Incidence of OXC-induced cADRs in ais
e present study found the overall incidence of
OXC-induced cADRs was 2.4% (12/494), while that of SJS/
TEN induced by OXC was 0% (0/494). e latter gure
was comparable to that published in the 2016-version of
the ai-FDA’s annual report on ADRs (the incidence
of OXC-induced SJS/TEN was 0.02%). Moreover, this
study’s overall gure of 2.4% for OXC-induced cADRs
was similar to the 2% incidence found in Han Chinese;
14
and the present study’s gure of 0% for OXC-induced
SJS/TEN was lower than corresponding gure reported
in Taiwanese, which was 0.08% (8.26/10,000 new users).
16
e ndings of the current study therefore conrm
previous reports that the incidence of SCARs is lower
with OXC than CBZ.
Association between HLA-B*15:02 and OXC-induced
cADRs
e present research determined that there is a
correlation between the HLA-B*15:02 allele in the ai
population and MPE induced by OXC, the odds ratio
being 6.58 (95% CI 1.11-39.15; p = 0.040). A similar
result, but not statistically signicant, was found in a
case-control association study by Hu et al.
21
(odds ratio
6.4; 95% CI 0.55-74.89; p = 0.294). We therefore suggest
that if a ai patient carries the allele, the attending
physician should take the risk of OXC-induced MPE
into consideration. e prescribing of alternative non-
aromatic AEDs would be prudent; however, if OXC
is prescribed, it should be done with caution, with the
patient being informed about the risk of drug allergies
and requested to closely observe for any symptoms to
ensure the earliest detection of potential problems.
Nevertheless, two studies in Han Chinese population
determined that the inter-relationship between the
HLA-B*15:02 allele and OXC-induced cADRs is not
signicant; rather, they identied two other genotypes
(HLA-B*1302
14
and HLA-B*3802
22
) as risk factors. Similarly,
a study by Moon et al.
23
demonstrated that two dierent
genotypes, HLA-B*40:02 and HLA-DRBI*04:03, are risk
factors among Koreans. e results of those three studies
show that dierent genomic types might be specically
associated with particular ethnic populations.
Recommendation of HLA-B*15:02 testing prior to OXC
prescription
Many studies have found no correlation between
HLA-B*15:02 and SJS/TEN induced by OXC.
14,22,23
However,
a recent prospective study reported that, in Han Chinese
and ais, the allele is signicantly related to OXC-induced
SJS/TEN (odds ratio 27.90; 95% CI 7.84-99.23, positive
predictive value 0.73%).
16
is supports a concern of
avoiding OXC for patients with HLA-B*15:02 allele,
although OXC-induced SJS/TEN is less severe and has
a lower incidence than CBZ-induced SJS/TEN.
16
is
advice may not be applicable for some populations
as HLA-B*15:02 is very commonly found in certain
populations in Asia
3
(5.7%-14.5% in Han Chinese, 12%-
15.7% in Malays and 15.9% in ais
24
).
In addition, there have also been reports of an
allergic cross-reaction between CBZ and OXC. In the
present study, we found 1/9 case who had an allergy to
CBZ and OXC, and who was HLA-B*15:02 positive.
Regarding other predicting factors, a study by He
et al.
14
found that a history of AED or non-AED allergies
were strong predicting factors for OXC-induced cADRs,
but especially an allergy to other AEDs (OR 121.23, 95%
CI 3.99-3686.59, p = 0.005). However, our study found a
signicant association with only a history of other AED
allergies (OR 5.16, 95% CI 1.05-25.27, p = 0.043), but
not with a history of non-AED allergies (OR 1.53, 95%
CI 0.45-5.16, p = 0.504).
Taking all this into consideration, OXC-induced
cADRs have a minor impact on allergic patients, who
can simply discontinue use of the drug. Given that
the positive predictive value of the allele is only 19%
for MPE and 0.73% for SJS/TEN
16
, HLA-B*15:02 test
before prescribing OXC is still recommended in order to
surveil SCARs. ere may be patients who test positive
to genomic testing but may still benet from sodium
channel blocking antiepileptics to treat their pain, such
as those with trigeminal neuralgia and painful tonic
spasm.
25
HLA-B*15:02 has a high prevalence in ai
populations, so it is reasonable to prescribe OXC rather
than CBZ with good patient-education, close monitoring
of MPE and discontinue the drug immediately if a rash
occurs.
Limitations
e incidence of OXC-induced cADRs may be
higher than reported due to undocumented histories of
rash or unclear medical records (which were excluded).
Moreover, some individuals were lost to follow-up aer
receiving the drug, while others did not register at the
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179
Original Article
SMJ
ADR center, resulting in their cases not being recorded
in the hospital’s electronic record system.
In addition, there has been no standard recommendation
to test for HLA-B*15:02 prior to prescribe OXC. e
genomic testing is also costly and time-consuming, with
the results taking 1-2 weeks to be reported. erefore,
only 79/494 patients had been tested for HLA-B*15:02.
is study also had too small a sample size to detect
the incidence of SCARs induced by OXC. us, we
support the conduct of a further study to establish the
inter-relationship between the allele and OXC-induced
cADRs/SJS/TEN/DRESS by using a larger sample size
and a multicenter design in ailand.
Our study demonstrated that the association between
the HLA-B*15:02 allele and MPE induced by OXC is
signicant. Patients with a history of other AED allergies
also had an increased risk of developing OXC-induced
MPE. However, a larger sample size and multicenter
study should be conducted.
ACKNOWLEDGMENTS
e authors thank Julaporn Pooliam for the statistical
analyses, Nattaya Bunwatsana and Sunsanee Mali-ong
for her administrative work. We really appreciate the
clinical assistance of Janravee Laurujisawat and Isaraporn
Tipapakoon. We are also very grateful to David Park for
proofreading the manuscript.
Funding: Siriraj Research Development Fund, Faculty
of Medicine Siriraj Hospital, Mahidol University.
Disclosure of conicts of interest: None of the authors
has any conict of interest to disclose.
Ethical Publication Statement: We conrm that we have
read the Journal’s position on issues involved in ethical
publication and arm that this report is consistent with
those guidelines.
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Review Article
SMJ
Voraboot Taweerutchana, M.D.*, arathorn Suwatthanarak, M.D.*, Nicha Srisuworanan, M.D.*, Nicole
Christienne Rich, M.D., MPH**
*Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, ailand, **University of California, San Francisco, USA.
The First Robotic Bariatric Surgery Performed in
Thailand – Surgical Techniques and Review of the
Literature
ABSTRACT
Morbid obesity is associated with multiple life-threatening comorbidities. Bariatric surgery is the most eective
intervention to achieve the long-term weight loss required to reverse many of these comorbid conditions. Laparoscopic
bariatric surgery is the current gold standard approach; however the robotic approach has potential intraoperative
and postoperative advantages that may be realized if limitations to instrument torque eect are overcome. We
review the literature about the robotic bariatric surgery and describe our rst robotic sleeve gastrectomy (RSG)
and a single docking operative approach to robotic Roux-en-Y gastric bypass (RRYGB) in Siriraj Hospital, and
also the rst in ailand. We demonstrate the operative room setup, the port sites, the technical details, and the
key step illustrations, that both operative procedures were performed using the da Vinci® Si platform. According
to the literature review, a robotic approach to bariatric surgery is an alternative option with comparable outcomes
to laparoscopic approach and the potential for intraoperative and postoperative advantages. It is safe, feasible, and
provides good clinical outcomes that are comparable to a conventional laparoscopic method.
Keywords: Bariatric surgery; robotic bariatric surgery; robotic Roux-en-Y gastric bypass; robotic sleeve gastrectomy;
robotic surgery (Siriraj Med J 2020; 72: 181-187)
Corresponding Author: arathorn Suwatthanarak
E-mail: bankythara@gmail.com
Received 21 October 2019 Revised 11 December 2019 Accepted 16 December 2019
ORCID ID: http://orcid.org/0000-0002-5409-284X
http://dx.doi.org/10.33192/Smj.2020.24
INTRODUCTION
Morbid obesity has become a serious worldwide
health issue because it is associated with multiple life-
threatening comorbidities. Bariatric surgery is considered
to be the most eective strategy to achieve long-term and
sustained meaningful weight loss for obese patients with
very low postoperative morbidity and mortality. Although
conventional laparoscopy is the current gold standard for
almost all bariatric procedures, there are some limitations
of the laparoscopic approach, especially in super morbidly
obese patients. Laparoscopic procedures in the super
morbidly obese can be physically challenging for the
surgeon and for the equipment due to limited torque eect
of instruments in patients with hepatomegaly, increased
intraabdominal fat, and extremely thick abdominal
walls.
1-3
Robotic surgical systems were introduced in 1997 to
overcome the disadvantages of a traditional laparoscopic
approach. e application of robotic surgery has increased
signicantly in the eld of general surgery and has become
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182
Taweerutchana et al.
more popular in bariatric procedures. e advantages of
using robotic systems include better surgeon’s ergonomics,
a magnied 3D imaging system from the very stable
camera controlled by surgeon, the articulated robotic
wrists that increase degrees of movement degree in
enclosed spaces, and precision in tissue manipulation
with tremor ltration for the surgeon. Potential benets to
our patients include safer procedures, less complications,
less pain, and faster recovery, while the other benets of
minimally-invasive surgery are preserved. Horgan and
Vanuno described the rst Roux-en-Y gastric bypass
(RYGB) performing by the robotic system in 2001, and
Mohr and team reported the technique of a totally robotic
RYGB with a single docking position in 2005.
1,3-7
Fig 1. Operating room set up for robotic bariatric procedures.
Fig 2. (A) Port placement for robotic sleeve gastrectomy (B) Port placement for robotic RYGB
In this manuscript, we describe our initial experiences
with a robotic approach to bariatric surgery at Siriraj
Hospital, Bangkok, ailand. We present our step-by-
step single docking robotic approach to operate sleeve
gastrectomy and Roux-en-Y gastric bypass by the da
Vinci® Si robotic system (Intuitive Surgical, Sunnyvale,
CA, USA).
e Surgical Techniques of Robotic Sleeve Gastrectomy
(RSG):
e patient was positioned supine with both arms
adduction. A 36-French orogastric tube was placed. A
Veress needle was used to enter the abdomen at Palmer’s
point and the abdomen was insuated with carbon
dioxide gas to 15-18 mmHg. A 12-mm camera port was
placed 18 cm inferior to the xiphoid and 4 cm to the le
of midline using an Optiview trocar and a 10-mm zero-
degree laparoscope in visual entry fashion. Aer entry,
this was exchanged for a 30-degree laparoscope. Under
direct visualization, the Veress needle was removed aer
conrming no injury was sustained upon insuation.
Additional 8-mm ports were placed 2 cm below the right
costal margin in the midclavicular line, and 2 cm below
the le costal margin in the anterior axillary line. Finally,
a 15-mm laparoscopic assistant’s port was placed 18 cm
inferior to the xiphoid and 2 cm to the right of midline.
Another small stab incision was made in the epigastric
area, 1 cm right of midline, then the strong arm Nathanson
liver retractor was advanced through this incision to
elevate the le hepatic lobe so that the inferior phrenic
vein was clearly identied. e patient was set in reverse
Trendelenburg position. Two working arms of the da
Vinci® Si system were docked to the 8-mm port sites,
and an additional arm was docked to the 12-mm camera
port. e robotic Harmonic shears were used to divide
(A) (B)
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the greater omentum from the gastric greater curvature,
from 6 cm proximal to the pyloric ring to the angle of His.
e short gastric arteries were also ligated with Harmonic
shears, double-shot technique, during dissection.
Using the OG tube as a guide, the robotic hook
cautery was used to mark the planned line of resection.
e iDrive
TM
Stapling System (Medtronic, Dublin, Ireland)
was then introduced via the laparoscopic assistant’s
port, and using multiple res of 60-mm iDrive
TM
black
and purple cartridges, the gastric greater curvature was
stapled o. e posterior wall of the gastric tube was
secured to the posterior fat pad with interrupted 2-0
Ti-Cron stitches (Medtronic, Minneapolis, USA).
Fig 3. Gastric division by autostapler via assistant port.
Hemostasis was checked then the resected stomach
was removed using an EndoBag (Medtronic, Dublin,
Ireland) via the 15-mm port incision. e 12 and 15-mm
port sites were closed using 1-0 Vicryl suture on a suture
passer. All ports were removed, the robotic system was
undocked, and the skin was closed in standard fashion.
e Surgical Techniques of Robotic Roux-En-Y Gastric
Bypass (RRYGB):
e patient was positioned supine with both arms
tucked. A 36-French orogastric tube was placed. A Veress
needle was used to enter the abdomen at Palmer’s point
and the abdomen was insuated with carbon dioxide
gas to 15-18 mmHg. A 12-mm camera port was placed
20 cm inferior to the xiphoid and 2 cm to the le of
midline using an Optiview trocar and a 10-mm zero-
degree laparoscope in visual entry fashion. e camera
was exchanged for a 30-degree laparoscope, the Veress
needle was removed, then two additional 8-mm working
ports were placed to the le of the camera port; the
rst with 8 cm of lateral clearance and approximately
2 cm superior to the camera port, the second at 8 cm
lateral to and 2 cm superior to the former 8-mm port.
An additional 8-mm working port was placed in the
right upper quadrant, 2 cm below right costal margin
in midclavicular line, and then a 12-mm laparoscopic
assistant’s port was placed 18 cm inferior to the xiphoid
and 4 cm to the right of midline.
Another small stab incision was made in the
epigastric area, 1 cm right of midline, and the strong
arm Nathanson liver retractor was advanced through
this incision to elevate the le hepatic lobe so that the
inferior phrenic vein was clearly identied. Using a
laparoscopic Harmonic scalpel, the greater omentum
was split in a le paramedian plane to 1 cm away from
the transverse colon. While the assistant retracted the
mesocolon caudally, the Ligament of Treitz was identied.
Two interrupted 3-0 Vicryl stitches were placed to mark
the jejunum at 100 cm and 200 cm. e loop of jejunum
marked at 100 cm distal to the Treitz’s ligament was
then sutured to the anterior gastric antral wall using
two interrupted 3-0 Vicryl stitches.
Fig 4. e marked jejunal loop was xed to gastric antrum.
e patient was then placed in reverse Trendelenburg
position and three working arms and a camera arm
of the da Vinci Si® robotic system were docked to the
8-mm ports and the 12-mm camera port, respectively.
Using the robotic hook cautery, the lesser omentum was
entered at the level of the second vein (about 6 cm from
the esophagogastric junction) to create the gastric pouch.
en the iDrive
TM
Stapling System with a 45-mm purple
cartridge was introduced via the laparoscopic assistant’s
port and red horizontally across the stomach from the
defect in the lesser omentum. Sequential vertical res
of the iDriveTM Stapling System with 60-mm purple
cartridges were used to carry the staple line upward to a
point just lateral to the angle of His, ensuring complete
gastrogastric division.
Using the hook electrocautery, enterotomies were
made in the posterior wall of the gastric pouch and the
jejunum that had been previously tacked to the greater
curvature of stomach. e tacking stitches were removed
and a 45-mm purple cartridge in the iDrive
TM
Stapling
System was used to create a 2-cm linear gastrojejunostomy.
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184
A 60-mm tan cartridge was used to divide the
biliopancreatic limb just proximal to the gastrojejunostomy.
e hook cautery was used to create enterotomies in the
distal biliopancreatic limb and at the site of the jejunal
marking stitch that had been previously placed at 200
cm beyond the Ligament of Treitz. Using a 45-mm tan
cartridge, a 45-mm stapled jejunojejunostomy was made
between the biliopancreatic limb and jejunum to create
a 100-cm Roux limb. e enterotomy site was closed
using continuous 3-0 Vicryl suture and the mesenteric
defect was closed to its base with continuous 2-0 Ti-Cron
suture. Reinforcing and anti-kink stitches were placed
between the biliopancreatic and Roux limbs using 3-0
Vicryl suture.
Fig 5. Gastrojejunostomy creation using the iDrive
TM
Stapling System
with 45-mm purple cartridge.
Fig 6. Gastrojejunostomy defect closure by intracorporeal robotic
suturing.
e gastrojejunal enterotomy site was closed using
running 3-0 absorbable V-loc suture (Medtronic, Dublin,
Ireland) and the corners were reinforced with interrupted
2-0 Ti-Cron stitches. A leak test was then performed by
instilling 50 mL of dilute methylene blue solution (2 mL
per 100 mL of normal saline solution) into the orogastric
tube. e Petersen’s defect was closed by suturing the
mesentery of the Roux limb to the transverse mesocolon
using running 2-0 Ti-Cron suture. e liver retractor was
removed and a 10-French JP drain was placed near the
gastrojejunostomy through the le upper quadrant port
site. e 12 and 15-mm port sites were closed using 1-0
Vicryl on a suture passer. All ports were removed, the
robotic system was undocked, and the skin was closed
in standard fashion.
e Siriraj’s Experience in Robotic Surgery and Robotic
Bariatric Surgery
About the rst robotic platform in Siriraj Hospital,
the da Vinci® S robot was purchased in 2007 which the
main users were the urological surgeons. e robotic
operation for general surgery eld in Siriraj Hospital
was started in 2008 then the robotic approach in general
surgery were developed consistently. Robotic-assisted
complete excision of choledochal cyst type I with
hepaticojejunostomy was the rst international report
of our institute by Minimally Invasive Surgery team in
2010. e da Vinci® Si Surgical System was our second
model that introduced to Siriraj Hospital since 2012,
and the latest one, da Vinci® Xi robotic platform, was
imported to our center in August 2019. Most of the
general surgery cases operated by robotic approach were
funded by Siriraj Foundation for educational purpose
in general surgery training program.
8
Our rst robotic operations for bariatric surgery in
Siriraj Hospital, and also rst in ailand, were performed
on March 6
th
, 2017 by Dr. Voraboot Taweerutchana and
team. Our rst patient for robotic sleeve gastrectomy is
a 26-year-old female with body weight 93 kg (BMI 40.79
kg/m
2
) and no comorbid disease. And our rst patient
for robotic Roux-en-Y gastric bypass is a 38-year-old
woman who weighed 110 kg (BMI 40.40 kg/m
2
) and
comorbidity of dyslipidemia. In our rst two patients
undergoing robotic bariatric surgery, total operative
time for robotic SG and robotic RYGB was 160 and 285
minutes, respectively. e estimated blood loss was 20
mL in both cases. eir postoperative pain was managed
by intravenous PCA routinely by the acute pain service
team. e postoperative average pain scores, visual analog
scale, at 2 hours, 12 hours, and 24 hours were 10, 5.5, and
4.58 in the patient who underwent RSG, and the scores
were 9, 5.4, and 4.2 in the patient who underwent RRYGB.
Intravenous PCA can be discontinued on postoperative
day 2 in RSG and day 3 in RRYGB patients. No further
requirement of oral paracetamol aer 2-day around-the-
clock prescription in both patients. e patients were
both discharged from the hospital on postoperative day
4. No open conversion, immediate complication, or 30-
day mortality was observed. e total hospital costs were
336,629 THB (ai baht) and 402,333 THB for robotic
Taweerutchana et al.
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Review Article
SMJ
SG and robotic RYGB, respectively. Excess weight loss
(EWL) at 6 months post robotic SG and robotic RYGB
were 60% and 52%, and at 12 months were 60% and
65%, respectively. e comorbidity of dyslipidemia in
the patient who underwent RRYGB has signicantly
improved and oral medication has been discontinued.
One of the challenges of the da Vinci® Si platform is
the inability to adjust the craniocaudal tilt of the operative
table once the robot has been docked to the port sites, which
makes it dicult to perform multi-quadrant procedures,
like Roux-en-Y gastric bypass. erefore, in our institute,
we initiated the robotic RYGB with the single docking
technique by performing the infracolic phase using a
laparoscopic approach, followed by a robotic approach
to the supracolic phase of the procedure, that considered
as the hybrid robotic operation. In the infracolic phase,
we placed marking stitches to the jejunum at 100 cm and
200 cm from Treitz’s ligament to identify the site of the
biliopancreatic limb and Roux limb to avoid the need
for running the small bowel once the robotic system has
been docked. en we secured the jejunum to the greater
curvature of stomach, making it easier to grasp the Roux
limb while performing the gastrojejunostomy with robotic
instruments in the supracolic phase. Nowadays, we perform
the totally robotic RYGB that infra- and supracolic phases
performed under the reverse Trendelenburg position
with hand-sewn gastrojejunostomy anastomosis by that
the report is now in process of the data collection and
analysis.
Laparoscopic Versus Robotic Approach to Bariatric
Surgery
e eld of bariatric surgery has evolved worldwide
in the recent decades due to its excellent results in treating
morbid obesity and its related comorbidities. With the
introduction of robotic surgery in recent years to the
practice of minimally invasive general surgeons, ecient
applications of robotic technology to bariatric surgery
have been sought. e advanced technology of the robotic
system enables the surgeon to operate the complex
surgical tasks, e.g. the hand-sewn gastrojejunostomy in
Roux-en-Y gastric bypass with more precision.
1,2,6,9
Laparoscopic RYGB remains a complex bariatric
procedure with a steep learning curve. It requires advanced
laparoscopic skills, such as intracorporeal suturing, knot
tying for the multiple anastomoses, ne manipulation
in various abdominal compartments, and redoubled
abdominal torque causing the operator’s fatigue. In the
former reports, the learning curve for robotic RYGB
seems to be shorter than that for laparoscopic RYGB,
10-20 cases versus ≥ 100 cases, respectively.
4,5,10,11
e disadvantages of robotic surgery are the larger
sized ports than used in traditional laparoscopic surgery
(8-mm versus 5-mm) and loss of tactile sensation and force
feedback, which may lead to bowel wall or visceral injury
during manipulation. e benets of the robotic approach
over laparoscopic bariatric surgery are still debated and
controversial. Multiple case series have shown the feasibility
and clinical safety of robotic bariatric surgery, and also
shown comparable results with laparoscopic bariatric
procedures, but some authors believe that there is no
advantage over standard laparoscopic techniques.
1,2,6,9,10
In our initial experience at Siriraj Hospital, the
results of robotic bariatric surgery demonstrated good
clinical outcomes. No immediate complication, leakage,
or mortality was detected in 30-day postoperative follow-
up. Excess weight loss and resolution of comorbidity at
6- and 12-months were comparable to a conventional
laparoscopic approach.
In terms of weight reduction, the robotic approach
has comparable results to laparoscopic bariatric surgery in
previously published reports. One meta-analysis showed
EWL of 34-67% at 6 months and 48-67.3% at 12 months
in the laparoscopic sleeve gastrectomy group, while
EWL was comparable at 39-66% at 6 months and 48.89-
65.5% at 12 months in the robotic approach for sleeve
gastrectomy. Other reports described excess BMI loss
aer Roux-en-Y gastric bypass at 1 month of 26.2% in the
robotic group and 26.3% in the laparoscopic group, and
at 12 months, 79.7% in the robotic group and 83.9% in
the laparoscopic group. In our cases, EWL at 12 months
was 60% in our RSG patient and 65% in our RRYGB
patient.
12,13
Systematic reviews and meta-analysis have shown no
signicant dierences between robotic and laparoscopic
bariatric procedures with regards to reoperation, open
conversion, the hospital stay interval, overall postoperative
complications, major complications, and mortality,
however there are some differences in outcomes as
follows.
1,4,9,13
Anastomotic leakage were signicantly
decreased overall aer robotic bariatric procedures compared
with laparoscopic procedures (OR 0.5, p = 0.005) and
totally-robotic RYGB compared with laparoscopic RYGB
(OR 0.22, p = 0.001). e additive learning eect from
laparoscopic cases performed prior to the introduction
of robotics and more precision in anastomosis suturing
by robotic systems may be the reasons for these results.
Moreover, minor complication rates were signicantly
decreased aer totally-robotic RYGB compared with
laparoscopic RYGB (OR 0.68, p = 0.04). Robotic sleeve
gastrectomy reduced the postoperative bleeding (0.16%
vs. 0.43%; p < 0.001) and stricture (0.19% vs. 0.33%;
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186
Taweerutchana et al.
p = 0.04) signicantly when compared with traditional
laparoscopic sleeve gastrectomy.
1,2,14,15
In review of the literature, no signicant dierence
of the operative time was found between totally-robotic
RYGB and laparoscopic RYGB (p = 0.42). On the other
hand, there was increased operative time for robotic-
assisted RYGB versus laparoscopic RYGB (158.29 ± 65 vs.
120.17 ± 56; P < 0.001), and for robotic sleeve gastrectomy
compared with laparoscopic sleeve gastrectomy (102.58
± 46 vs. 73.38 ± 36; P < 0.001). A robotic set up time
did not vary signicantly and remained at a mean of 13
± 4 min in the previous report. Finally, we believe that
the operative time in robotic approach can be reduced
once the learning curve is overcome, just as with other
robotic procedures.
1,13-15
Although robotic procedures seem to be more expensive
than laparoscopic surgery due to initial purchase costs of
the robot and the robotic instruments and accessories, as
well as yearly maintenance fees that are associated with
signicant costs. From the University Health System
Consortium (UHC) Clinical Database, the mean cost
of robotic gastric bypass was $12,670, versus $10,105
for laparoscopic RYGB (p < 0.05). Moreover, the mean
costs of robotic and laparoscopic sleeve gastrectomy were
$10,556 versus $8,795 (p < 0.05), respectively. Despite
this, previous analyses have concluded that robotic RYGB
can be cost eective as a result of a decrease of costly
anastomotic complications and avoiding stapler use
in the case of hand-sewn anastomoses. In the event
of postoperative leak, readmission is costly, and these
authors demonstrated higher leak rates in the laparoscopic
group.
1,16,17
e Future Trends in Robotic Bariatric Surgery
e new medical technologies, included the robotic
surgery system, are always updated to provide the patients’
benet. Nevertheless, the overall costs of robotic approach
for bariatric surgery seemed to be more expensive than
the laparoscopic surgery, which is the standard treatment
in this era, and there were a few evidences to support
the clear benet of robot over the laparoscopic one, the
usages of robot in bariatric surgery remained controversial,
especially in the expert bariatric surgeons who familiar
with their laparoscopic skills.
As the oldest and largest hospital and medical school
in ailand, Siriraj Hospital cannot avert the robotic
surgery due to academic purposes. To utilize the maximal
technology abilities, to clearify the cost-eectiveness of the
robotic approach by the data analyses and publications,
and to manage the ecient usages of the robotic system
are Siriraj’s duties. e robotic bariatric surgery cases
will be maintained for these objectives in Siriraj Hospital.
Although Siriraj Foundation was the main supporter in
funding of robotic approach in general surgery cases, the
eective hospital resource management can also reduce
the overall robotic surgery costs, for example, to increase
the robotic case volume and the patient ow.
8
Furthermore, revisional bariatric surgery may be
a eld that robotic bariatric surgery becomes a favored
approach, because of its ability to provide ne movement
and a high-degree of articulation in a challenging operative
eld. ese special properties of the robotic system facilitate
the surgeon’s ability to perform a dicult operation
more precisely and comfortably, despite intraabdominal
adhesions and distorted anatomy.
Although there were some potential advantages
of the robotic approach in bariatric surgery from the
previous studies as mentioned above, there have been
no well-designed randomized trials to compare the
outcomes between conventional laparoscopic bariatric
surgery with the robotic surgery. To improve the value
of this research eld, a large-scale comparative study
using a randomized controlled trial technique should
be considered. In the future, if the clear benets of using
robots in bariatric surgery are well-supported, the robotic
system investors will be increased in the market and
the overall robotic costs will be reduced. Moreover, the
treatment costs by robotic system may be concerned
and covered by the health insurance system.
CONCLUSION
Using robotic approach in bariatric surgery is still
controversial due to its cost and availability. e operative
room setup, the port sites, the instruments, the technical
details, and the key step illustrations for robotic SG and
robotic RYGB are described by Siriraj’s experiences. From
the current evidences, a robotic approach for bariatric
surgery is demonstrated to be a feasible alternative to
laparoscopic bariatric surgery. It is shown to be equally
as eective and safe as a laparoscopic approach, and
provides comparable clinical outcomes to the conventional
laparoscopic method.
REFERENCES
1. Li K, Zou J, Tang J, Di J, Han X, Zhang P. Robotic Versus
Laparoscopic Bariatric Surgery: a Systematic Review and
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2. Tieu K, Allison N, Snyder B, Wilson T, Toder M, Wilson E.
Robotic-assisted Roux-en-Y gastric bypass: update from 2
high-volume centers. Surg Obes Relat Dis 2013;9:284-8.
3. Jung MK, Hagen ME, Buchs NC, Buehler LH, Morel P. Robotic
bariatric surgery: A general review of the current status. Int J
Med Robot 2017;13:1-8.
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review. Surg Obes Relat Dis 2012;8:483-8.
5. Aggarwal S, Sharma AP, Kumar R, Anand S. Totally Robotic
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6. Akaraviputh T, Trakarnsanga A, Suksamanapun N. Robot-assisted
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review literature. World J Surg Oncol 2010;8:87.
7. Mohr CJ, Nadzam GS, Alami RS, Sanchez BR, Curet MJ.
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from 75 patients. Obes Surg 2006;16:690-6.
8. Yiengpruksawan A, Akaraviputh T, Methasate A, Chinswangwatanakul
V. Robotic Surgery in ailand: Current Status and Future
Development. Siriraj Medical Journal 2018;70:466-70.
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C, et al. Current status of robotic bariatric surgery: a systematic
review. BMC Surg 2013;13:53.
10. Moon RC, Gutierrez JC, Royall NA, Teixeira AF, Jawad MA.
Robotic Roux-en-Y Gastric Bypass, is it Safer than Laparoscopic
Bypass? Obes Surg 2016;26:1016-20.
11. Bustos R, Mangano A, Gheza F, Chen L, Aguiluz-Cornejo
G, Gangemi A, et al. Robotic-Assisted Roux-en-Y Gastric
Bypass: Learning Curve Assessment Using Cumulative Sum
and Literature Review. Bariatr Surg Pract Patient Care 2019;14:
95-101.
12. Buchs NC, Morel P, Azagury DE, Jung M, Chassot G, Huber
O, et al. Laparoscopic versus robotic Roux-en-Y gastric bypass:
lessons and long-term follow-up learned from a large prospective
monocentric study. Obes Surg 2014;24:2031-9.
13. Magouliotis DE, Tasiopoulou VS, Sioka E, Zacharoulis D.
Robotic versus Laparoscopic Sleeve Gastrectomy for Morbid
Obesity: a Systematic Review and Meta-analysis. Obes Surg
2017;27:245-53.
14. Ayloo SM, Addeo P, Buchs NC, Shah G, Giulianotti PC.
Robot-assisted versus laparoscopic Roux-en-Y gastric bypass:
is there a dierence in outcomes? World J Surg 2011;35:637-42.
15. Sebastian R, Howell MH, Chang KH, Adrales G, Magnuson T,
Schweitzer M, et al. Robot-assisted versus laparoscopic Roux-en-Y
gastric bypass and sleeve gastrectomy: a propensity score-matched
comparative analysis using the 2015-2016 MBSAQIP database.
Surg Endosc 2019;33:1600-12.
16. Hagen ME, Pugin F, Chassot G, Huber O, Buchs N, Iranmanesh
P, et al. Reducing cost of surgery by avoiding complications: the
model of robotic Roux-en-Y gastric bypass. Obes Surg 2012;22:
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17. Villamere J, Gebhart A, Vu S, Nguyen NT. Utilization and
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González et al.
Alejandro Felipe González, M.Sc.*, Luc Pieters, Ph.D.**, René Delgado Hernández, Ph.D.***
*Department of Pharmacy, Institute of Pharmacy and Food, University of Havana, Havana, Cuba, **Natural Products & Food Research and Analysis
(NatuRa), Department of Pharmaceutical Sciences, University of Antwerp, Antwerp, Belgium, ***Center for Research and Biological Evaluation,
Institute of Pharmacy and Food, University of Havana, Havana, Cuba.
Effectiveness of Herbal Medicine in Renal Lithiasis:
A Review
ABSTRACT
e renal lithiasis is a frequent disease that aect between 4-15% of worldwide population with a high percentage
of recurrences. e composition of the stone is variated, but, more than 80% of uroliths are of calcium oxalate.
e mechanisms involved in the formation of calcic stones are not fully understood and the available treatment
not permit the prevention and destruction of the stones at same time. For these reasons, many studies have been
focused to understand the mechanism involved in the renal lithiasis and in the development the new drugs for the
treatment and prevention of this pathology and its recurrences. In this paper, it is shown a review about formation
of calcic stones, their treatment and the eectiveness of the herbal medicine as alternative treatment. Also, a list
of antilithiatic remedies of cuban herbal medicine is showed.
Keywords: Renal lithiasis; pharmacology; therapeutic; herbal medicine (Siriraj Med J 2020; 72: 188-194)
Corresponding Author: Alejandro Felipe González
E-mail: afelipe860126@gmail.com, afelipe@ifal.uh.cu
Received 18 April 2019 Revised 6 November 2019 Accepted 11 November 2019
ORCID ID: http://orcid.org/0000-0003-2287-254X
http://dx.doi.org/10.33192/Smj.2020.25
INTRODUCTION
Renal lithiasis can be dened as the deposition of
stones in urinary tract due to an alteration of the normal
crystallization conditions of urine.
1
It is explained through
of the loss of the equilibrium between promoters and
inhibitors of the crystallization,
2
urine composition and
renal morphoanatomy.
3
Currently, it is the third most frequent urological
disease aer urinary tract infections and prostate problems.
4
It has a prevalence that ranges between 4-15% of the
world population
5
and a high recurrence rate, that is, the
probability of repeating a renal lithiasis episode is 40%
aer 5 years of the rst calculi and 60% aer 10 years.
6
It is a health problem with greater incidence in people
between 30-60 years of age and more common in men
than in women.
7
e dierence in prevalence between countries is
associated with the combination of genetic and environmental
factors, including dietary habits, climatic conditions and
socio-economic status.
4
For example, several studies
show that the incidence is higher in populations of warm
countries compared to populations in cold countries. It
has also been found that high consumption of salt, animal
protein, calcium, fatty acids and sugar are risk factors for
the development of kidney stones.
4,7
Finally, renal lithiasis
has been associated with a family history of kidney stones
and with some diseases such as diabetes, hypertension,
hyperthyroidism, obesity, metabolic syndromes, gout
and urinary tract infections.
4,8
e stones may be composed of calcium phosphate,
uric acid, struvite, cystine and oxalate calcium. e
oxalate stone are the most frequent, being present in
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Review Article
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more than 80% of the uroliths.
8
For this reason, this
study will focus on oxalate stones.
e mechanisms involved in the formation of calcic
stones are not fully understood.
5
It is generally agreed that
urinary lithiasis is a multifaceted biological process that
involves physicochemical changes and supersaturation
of urine
9
leading to crystal nucleation, aggregation and
growth of insoluble particles.
10
For the treatment of renal stones minimally invasive
surgery is used, it’s eectiveness to broke the calculi but
it has not reduced recurrence rates.
7,10
On the other hand,
many drugs have been used, such as, thiazide diuretics,
potassium citrate, non-steroidal anti-inammatory drugs
(NSAIDs); but they’re only used for prevent or treat the
symptoms.
7,8,10
For these reasons, many studies have been focused
to understand the mechanism involved in the renal
lithiasis and in the development the new drugs for the
treatment and prevention of this pathology and its
recurrences. Herein, in this paper, it is shown a review
about formation of calcic stones, their treatment and
the pharmacological models to study of the antilihtiatic
activity in oxalate stone.
Formation of renal stones
e mechanisms involved in the formation of calcic
stones are not fully understood.
5
Renal stone formation
is a biological process that involves physicochemical
changes and supersaturation of urine.
9
It is explained
through of the loss of the equilibrium between promoters
and inhibitors of the crystallization,
2
urine composition
and renal morphoanatomy.
3
Recently, the promoters and inhibitors of the urine has
been referred as modulators, which can be small molecules
or low-molecular weight that modify supersaturation of
the urine by serving as chelators of calcium and oxalate by
forming soluble complex. e formation of this complex
depends on numerous physicochemical factors such as
the concentration of individual (competing) chemical
species, the relative magnitude of the formation constants
of the complexes themselves, the pH and ionic strength
of the urine in which the process occurs.
11
As a result
of supersaturation, solutes precipitate in urine leads to
nucleation and then crystal concretions are formed.
9
The first step in the formation of kidney stone
begins by the formation of nucleus (termed as nidus),
normally of apatite (calcium phosphate) due to that the
heterogeneous nucleation is easier than homogeneous
nucleation in physiological conditions of the urine.
12
It
is the transformation from a liquid to a solid phase in a
supersaturated solution.
13
A widely held theory is that
of Randall’s plaques, which proposes that subepithelial
interstitial calcium-based deposits act as nuclei for stone
formation. ese plaques originate adjacent to the thin
limbs of loops of Henle as spherical particles, which
could be related to the high local ion concentrations at
this site, and can extended to the interstitium.
14-16
Recent
studies have investigated the role of oxalate-degrading
bacteria. ese form apatite structures that serve as a
crystallization center for the formation of stones and
could be a pharmacological target to avoid the nucleation
process. Also, existing epithelial cells, urinary casts, RBCs,
and other crystals in urine too can act as nucleating
centers in the process of nuclei formation termed as
heterogeneous nucleation.
9
e growth process is very important due to the small
stones are expulsed by urine, but the big stones require
medical treatment. Its mechanism is simple because only
requires the addition of new particles of the urine.
12
is
process can be favored by the retention of microcrystals
in the urothelium and controlled by the lithogenesis
inhibitors.
3,17
Recent studies have demonstrated that
oxalate produce damage to renal cell by the generation
of reactive oxygen species
18
; which increase the surface
expression of phosphatidylserine, sialic acid, hyaluronan,
osteopontin, or the glycoprotein receptor CD44, resulting
in more crystal adhesion and formation of the nidus for
the formation of stone.
5
On the other hand, the presence
of renal cavities with low urodynamic ecacy retain
urine by long periods of time in the upper urinary tract,
which favors the formation of stone.
19
Finally, there are
substances in the urine act as inhibitors of lithogenesis
through of the inhibition in the crystal surface; also,
there substances have complexing properties with some
ions involved in the precipitation process decreasing its
concentration.
12
Several inhibitors have been found in the
urine as citrate, phytate, magnesium and pyrophosphate
ions
3
and other molecules as uropontin, osteopontin,
bikunin, and Tamm-Horsfall protein
15
; but citrate,
magnesium and phytate have been the most studied.
19-20
Treatment of renal stones
e treatment of the calculi will depend of their size
and site, and of any symptoms and signs, particularly of
obstruction. When the stones are less than 10 mm can be
expulsed with pharmacologic treatment, but, when the
calculi are higher than 10 mm or can’t be expulsed with
pharmacologic treatment, it is necessary to use of minimally
invasive surgery,
8,14
such as extracorporeal shockwave
lithotripsy (ESWL), percutaneous nephrolithotomy
(PCNL), or ureteroscopy (URS), which has revolutionized
acute and complex stone management.
5
e problem
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190
González et al.
is that these techniques don’t prevent the likelihood of
new stone formation because oen result in incomplete
stone clearance.
5,10,18
en, to reduce the rate of stone
recurrence is necessary the intervention in the form of
lifestyle advice and some forms of medical therapy.
5
For
example, the increase of liquid, potassium, magnesium,
calcium, vegetable and fruit intake and the decrease of
sodium, animal protein and fat consumption has been
associated with reduction of renal stone.
1,7,14,21,22
On the
other hand, many drugs have been used to prevent the
recidives, for example, thiazide diuretic, potassium citrate,
allopurinol, NSAIDs, calcium antagonist, pirydoxine,
alfa-blockers.
8,14,21,22
However, the scientic evidence
about the ecacy of the pharmacologic therapy is less
convincing.
10,17,23
All these facts indicate the need for
new therapeutic approaches for the treatment of renal
stones,
18
therefore, new alternatives are being tested
using herbal medicine or phytotherapy.
17
Traditional medicine in renal lithiasis: a therapeutic
solution?
e use of medicinal plants dates from the beginnings
of humanity, when people had no other eective therapeutic
resources to treat their diseases. is knowledge was
transmitted through legends, pictographs and various
monographs until our days.
24
e oldest written evidence of
medicinal plants’ usage for preparation of drugs has been
found on a Sumerian clay slab from Nagpur, approximately
5000 years old. Other ancient references were showed
in «e Chinese book on roots and grasses» written by
Emperor Shen Nung around 2500 BC, «e Indian holy
books Vedas» and “e Ebers Papyrus”, written about
1550 BC.
25
According to data from the World Health Organization
(WHO), 80% of the world’s population uses plants as a
remedy to cure their diseases.
26
On the other hand, it is
known that around 20% -30% of the medicines available
in the market are derived from natural products.
27
Recently the use and commercialization of medicinal
herbs has increased in developed and developing countries,
linking several multinational companies, which have
obtained benets of up to $ 7.00 billion in Europe, $
3.2 billion in the United States and $ 2.3 billion in Asia
(Table 1). e reasons for this increase are due to the
preference of consumers for natural therapies; concern
regarding undesirable side eects of modern medicines
and the belief that herbal drugs are free from side eects,
since millions of people all over the world have been using
herbal medicines for thousands of years; great interest
in alternative medicines; preference of populations for
preventive medicine due to increasing population age; the
belief that herbal medicines might be of eective benet
in the treatment of certain diseases where conventional
therapies and medicines have proven to be inadequate;
tendency towards self-medication; improvement in
quality, proof of ecacy and safety of herbal medicines
and high cost of synthetic medicines.
28
TABLE 1. Richness obtained from sales of herbal medicines in some countries in the year 1996.
Country Incomes (USD)
Germany $3.5 billion
United States of America $3.2 billion
Japan $2.1 billion
France $1.8 billion
Italy $700.0 million
United Kingdom $400.0 million
Spain $300.0 million
Netherlands $100.0 million
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e best acceptance of the population of herbal
medicine, the wide traditional knowledge about medicinal
plants, the few scientic studies that support the therapeutic
properties of these and the interest of the pharmaceutical
industry in the development of phytopharmaceuticals
constitute opportunities in the research of herbal medicines
as therapeutic alternatives for several diseases, especially
in those in which conventional medicine has not been
very eective. On the other hand, herbal medicines
usually contain a range of pharmacologically active
compounds. is could be an advantageous characteristic
for the therapeutic application of herbal medicine, since
sometimes benecial synergisms are established in the
treatment of some diseases, being able to be more eective
than synthetic drugs.
As mentioned earlier, several researchers have focused
their attention on herbal medicine for the treatment of
renal lithiasis because, currently, this pathology is treated
by minimal access surgery and pharmacological therapy
is less convincing.
e traditional knowledge about medicinal plants is
the rst clinical evidence on ecacy of herbal medicine,
however, scientic studies are necessary to corroborate
the ethnobotanical information.
28
Recently, a list of
antilithiatic plants used by population of dierent countries
of the world was published, where already 500 species
belonging to 106 families were identied. e families
more representative in this study were Asteraceae (87),
Fabaceae (71), Lamiaceae (58), Rubiaceae (17), Solanaceae
(12), Phyllanthaceae (9), Zingiberaceae (9), Rutaceae (9),
Polygonaceae (8) and Urticaceae (8).
29-31
Other reported
families were Rosaceae (41), Poaceae (24), Malvaceae
(23), Brassicaceae (20) and Boraginaceae (13).
32-33
e
wide traditional knowledge of antilithiatic plants favors
the researches of herbal medicine in this pathology
because it increases the chances of nding an eective
therapeutic treatment.
Cuban herbal medicine and renal lithiasis
In Cuba, the rst evidence about the use of medicinal
plants was found in the primitive community, where “el
behíque” was the second most important person into the
community. Among its functions was the treatment of
patients through remedies made with medicinal plants.
34
On the other hand, in the wars of independence (XIX
century), “los mambises” found in the Cuban flora
a solution to the cure of their wounds and diseases.
For example, José Martí mentioned in his Campaign
Diary the benets of “hijereta”, “cilantro” honey and
other remedies used in camps.
35
In 1945, the Cuban
scientist Juan Tomás Roig published his book «Plantas
Medicinales y Aromáticas de Cuba» where he described
more than ve thousand medicinal species used by the
Cuban population.
36
Recently, the Ministry of Public
Health of Cuba created the National Program of Natural
and Traditional Medicine and elaborated the National
Therapeutic Guide of Phytodrugs and beer-derived
products for its application in health institutions.
e great variety of medicinal plants in the Cuban
ora, together with the widely ethnobotanical knowledge
increases the opportunities for the search of new therapies
in the treatment of various diseases, of which, the renal
affections have been one of the most treated in the
ethnobotany. However, the phytotherapeutic potential
of the island is still virgin. For example, in ethnobotanical
studies made in Cuba, one hundred seventy-nine species
have been used in the renal system, of which only 9%
have been evaluated pharmacologically.
37-39
Table 2 shows
a compilation of some plants used for the treatment of
kidney stones according to ethnobotanical studies carried
out in dierent areas of the country.
Bashir and Gilani (2009) demonstrated the antilithiatic
activity of the methanol 30% extract from Bergenia
ligulata using in vitro and in vivo studies. e extract
showed capacity to evite the crystallization trough in vitro
calcium oxalate crystallization test. Also, the capacity to
decrease the renal damage produced by oxalate crystals
through generation of Reactive Oxygen Species (ROS)
was corroborated by DPPH assays. e diuretic activity
and antilithiatic activity of the extract was demonstrated
in Wistar rats.
44
Aer that, the authors evaluate the
antilithiatic activity of Berberine, an alkaloid described
for this plant, and they obtain similar results to the
methanol 30% extract.
10
A similar study was done in
Selaginella lepidophylla, but, in this case the antilithiatic
activity was related with the presence of polyphenols
and avonoids in the plant.
17
e antilithiatic eect
of other medicinal plants used by population, such as,
Costus spiralis, Phyllanthus niruri, Origanum vulgare,
Hibiscus sabdaria, Zea mays
10,45
, Berberis trifoliata
46
,
Punica granatum
23
and Terminalia arjuna
5
has been
demonstrated with promisorius results. Generally, this
eect has been attributed to polyphenols
47
and avonoids.
48
e ethnobotanical use and the scientic evidence
about the mechanism of action and related chemical
compound with antilithiatic activity is a proof of the
eectiveness of the medicinal plant in the treatment of
this pathology, however, the controlled clinical trials are
required. en, future studies should be leaded in this
way.
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González et al.
TABLE 2. Herbal medicine used by Cuban population to treat the lithiasis renal.
Plant Family Commun name Part(s) Preparation Ref.
Blechum pyramidatum Acanthaceae Mazorquilla Aerial Decoction [39]
Caesalpinia bahamensis Caesalpinaceae Brasilete Stem Decoction [40]
Chiococca alba Rubiaceae Bejuco verraco Root Decoction [41]
Cymbopogon citratus Poaceae Caña de limón Stem Decoction [40]
Cyperus rotundus Cyperaceae Caramamá Root Decoction [41]
Erythroxylum havanense Erythroxylaceae Jibá Root Decoction [41]
Guazuma ulmifolia Sterculiaceae Guásima Bark Decoction [41]
Heliotropium angiospermum Boraginaceae Alacrancillo Leaves Infusion [40]
Lepidium virginicum Brassicaceae Matuerzo Leaves Decoction [42]
Lonchocarpus pentaphyllus Fabaceae Guamá amarillo Stem, Root Decoction [39]
Momordica charantia Cucurbitaceae Cundeamor Leaves Infusion [40]
Peperomia pellucida Piperaceae Corazón de Hombre Aerial Decoction [41]
Polypodium polipodiodes Polypodiaceae Doradilla Leaves Decoction [39]
Rystonea regia Arecaceae Palma real Root Decoction [40]
Salpianthum purpurascens Bignoniaceae Nitro Aerial Decoction [40]
Trichilia glabra Meliaceae Siguaraya Leaves Infusion [40]
Urera baccifera Urticaceae Chichicate Root Decoction [40]
Xanthium strumarium Asteraceae Guizaso de caballo Root Decoction [40]
Xiphidium coerelum Haemodoraceae Cola de paloma Leaves Infusion [43]
Zea mays Poaceae Maíz Hair Infusion [40]
DISCUSSION
Renal lithiasis is an important global renal problem due
to its high incidence and the lack of eective pharmacological
treatments. Until now, the minimally invasive surgery is the
only option to destroy the renal calculi. en, the search
for new therapeutic alternatives continues being a topic
of interest in the scientic community, where medicinal
plants have gained an important place on research in this
eld. Despite the widespread use of plants in traditional
medicine, their therapeutic application is limited due to
the lack of scientic studies that support their therapeutic
properties, especially clinical studies.
28
However, a study
done by Newman & Cragg, (2016) shows that 50% of the
drugs approved in the period 1981 to 2014 originated in
natural products.
49
is evidence shows that plants are an
eective resource for the treatment of diseases, however,
studies that support their use in therapeutics are required,
which is one of the weaknesses in the clinical application
of herbal medicine. On the other hand, several in vitro,
in vivo and clinical studies have been developed in plants
traditionally used for the treatment of renal lithiasis with
promising results, however, the phytochemical studies
of the plants have been insucient. As a consequence,
the validity of the studies is limited because without
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193
Review Article
SMJ
phytochemical characterization, quality control is dicult
and reproducibility of results questionable. e available
information shows that some possible mechanisms of
action of plant extracts include an increased excretion of
urinary citrate, decreased excretion of urinary calcium
and oxalate, ability to inhibit the crystallization process
of oxalate calcium or could be attributable to diuretic,
antioxidant or antibacterial eects.
50
Summarizing, the best acceptance of natural products
in the world population, the interest of the pharmaceutical
industry in the development of these, the traditional
knowledge of a great variety of plants for the treatment
of lithiasis and the promising results of the scientic
studies carried out are elements that support the theory
that plants could be an eective therapeutic resource for
the treatment of renal lithiasis, however, still requires
phytochemical and biological studies that reinforce this
theory.
CONCLUSION
e higher incidence and prevalence of renal lithiasis
and the lack of an eective pharmacological therapy
for its treatment are focused of attention for several
researchers in the development of new drugs, being the
natural products a potential source of bioactive molecules
for this pathology.
Conict of Interest: e authors declare not conict
of interests.
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