Volume 72, Number 4, July-August 2020
Siriraj Medical Journal
SMJ
ISSN 2629-995XE-ISSN 2228-8082
SPECIAL ISSUE
272 Coronavirus Disease 2019 (COVID-19) and Its
Gastrointestinal and Hepatic Manifestations
Paul Wasuwanich, et al.
283 The Practice of Endoscopy during the COVID-19
Pandemic: Recommendations from the Thai Association
for Gastrointestinal Endoscopy (TAGE) in collaboration
with the Endoscopy Nurse Society (Thailand)
Pradermchai Kongkam, et al.
ORIGINAL ARTICLE
287 Assessment of Prehospital Management of Patients
Transported to a Thai University Hospital
Sattha Riyapan, et al.
296 Autoverification Improved Process Efficiency, Reduced
Staff Workload, and Enhanced Staff Satisfaction Using a
Critical Path for Result Validation
Sairung Nuanin, et al.
307 Sleep Quality and Burnout Syndrome among Residents in
Training at the Faculty of Medicine, Prince of Songkla
University
Thirapath Chatlaong, et al.
315 Effect of Home-based Rehabilitation Exercise Program for
Elderly Patients with Femoral Neck Fracture after Bipolar
Hemiarthroplasty
Chantanee Ninlerd, et al.
321 Short-term Postoperative Outcomes Compared Between
Before and After the Establishment of the Siriraj Upper
Gastrointestinal Cancer Center: A Propensity Score
Matched Analysis
Chawisa Nampoolsuksan, et al.
330 Cutaneous Manifestations and Associated Systemic
Findings of Patients with Zika Infections
Charussri Leeyaphan, et al.
336 Dynamic Contrast-Enhanced Computed Tomography
Findings that may Predict Poorly-Differentiated
Hepatocellular Carcinoma Prior to Treatment
Chananwat Manyanon, et al.
343 Factors Affecting Unfavourable Results from a Sinonasal
Inverted Papilloma Surgery
Anan Bedavanija, et al.
352 Long-Term Vipassana Meditation Enhances Executive
Function in Adult Meditators
Thawatchai Lukseng, et al.
361 Non-Infectious Scleritis and Systemic Collagen Vascular
Disease Association
Sutasinee Boonsopon, et al.
LETTER TO EDITOR
368 Emergence of Influenza Pandemic in Bangkok in 1918:
Historical Review
Sanya Sukpanichnant
https://he02.tci-thaijo.org/index.php/sirirajmedj/index
E-mail: sijournal@mahidol.ac.th
International Association of Surgeons
Gastroenterologists & Oncologists
Thailand Chapter
Thai Association for Gastrointestinal
Endoscopy
Indexed by
By Pradermchai Kongkam, et al.
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Volume 72, No.4: 2020 Siriraj Medical Journal
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272
Special Issue
SMJ
Paul Wasuwanich, M.D.*,**, Supharerk awillarp, M.D.***, ammasin Ingviya, M.D.****,*****, Wikrom
Karnsakul, M.D.*
*Division of Pediatric Gastroenterology, Nutrition, and Hepatology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore,
MD, USA;** Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA; ***Department of Disease Control, Ministry
of Public Health, ailand; ****Medical Data Center for Research and Innovation, Prince of Songkla University, Songkhla, ailand; *****Department
of Family and Preventive Medicine, Prince of Songkla University, Songkhla, ailand.
Coronavirus Disease 2019 (COVID-19) and Its
Gastrointestinal and Hepatic Manifestations
ABSTRACT
Coronavirus disease 2019 (COVID-19) is a severe respiratory disease caused by the virus SARS-CoV-2 that
became classied as a pandemic on March 11, 2020. COVID-19 is known to produce similar clinical manifestations
to SARS of the last decade. Fever, dry cough, fatigue, myalgia, dyspnea, and sore throat are some of the most
common symptoms and the median incubation period is around 4 days. While the respiratory symptoms oen
bring the patients to medical attention, clinical manifestations on the gastrointestinal tract and hepatobiliary system
have also been cautiously observed. It has been reported that approximately 1-5% of cases developed diarrhea and
nausea or vomiting, sometimes preceding the respiratory symptoms. As hemorrhagic colitis was reported in one
case with SARS-CoV-2, detected in stool, there is a possibility of fecal-oral transmission of the virus is possible
in humans. us, it is widely recommended that non-urgent and low prior endoscopic procedures be postponed.
For patients requiring urgent endoscopic procedures, SARS-CoV-2 nucleic acid testing from the throat swabs is
used as a screening test within 48 hours prior. Minimal personnel, infection control training, and usage of negative
pressure rooms are recommended. Abnormal liver function tests have been commonly reported. Patients infected
with SARS-CoV-2 can have a true liver injury, which is however mild. e abnormal liver function test values may
be caused, at least partially, by muscle injury or hemolysis. Nevertheless drugs with hepatotoxicity should be used
with increased caution.
Keywords: Epidemiology; Hepatology; SARS-CoV-2; Transplantation; Endoscopy (Siriraj Med J 2020; 72: 272-282)
Corresponding author:Wikrom Karnsakul
E-mail: wkarnsa1@jhmi.edu
Received 3 April 2020 Revised 15 May 2020 Accepted 16 May 2020
ORCID ID: http://orcid.org/0000-0001-7288-5459
http://dx.doi.org/10.33192/Smj.2020.37
Virology and Epidemiology
e coronavirus disease 2019 (COVID-19) is caused
by the novel virus, severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2) which originated from
Wuhan, China in 2019.
1
SARS-CoV-2 is a positive-sense,
RNA virus in the genus Betacoronavirus, genetically
distinct from other severe coronaviruses such as Middle
East respiratory syndrome coronavirus (MERS-CoV) and
severe acute respiratory syndrome coronavirus (SARS-
CoV) with only 50% and 79% similarity, respectively.
2
e SARS-CoV-2 outbreak was ocially declared a
pandemic by the World Health Organization on March
11, 2020.
3
As of April 1, 2020, there have been more than
850,000 cases of COVID-19 globally aecting almost
every country in the world (180 of the 195 countries)
including the United States.
4,5
e reported COVID-19
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273
cases from the United States have surpassed 200,000 cases
putting the United States’ patient count as the highest
globally with an epicenter in the state of New York. A
similar trend was observed in deaths with reports of
approximately 5,000 deaths and rising. e scale of the
pandemic has overwhelmed New York’s healthcare
capacity and stressing several medical supply chains
including ventilators, drug supplies, and personal protective
equipment causing hospital administrators all over the
United States and abroad to prepare for the worst-case
scenarios.
6
Clinical Manifestations
COVID-19 clinical presentation was similar to
SARS from the last decade. Fever, dry cough, fatigue,
myalgia, dyspnea, and sore throat are some of the most
common symptoms.
7-9
e median incubation period
was 4 days in an interquartile range (IQR) of 2 to 7 days.
10
e incubation period range of 2 to 14 days is commonly
used in public health such as the United States Centers
for Disease Control and Prevention (CDC) though that
information has been based on the known incubation
period of MERS-CoV viruses. However, Lauer et al.
recently modeled that with a 14-day quarantine less
than 1% of infected cases could develop symptoms aer
14 days.
11
According to current evidence, SARS-CoV-2
can be transmitted through close contact or droplets,
similar to inuenza, via coughing or sneezing with a
transmission radius of pathogen-bearing droplets of all
sizes of 23 to 27 feet (~7-8 meters). Social distancing for
a radius of 6 feet (~2 meters) is typically recommended
by public health institutions though this should be seen
as a minimum.
12–17
Currently, there have been no reports
of airborne transmission of SARS-CoV-2, and the basic
reproduction number (R
0
) of SARS-CoV-2 is known to
be approximately 2.2, lower than airborne diseases such
as measles and rubella.
12,18
A study by van Doremalen
et al. found that SARS-CoV-2 is viable and has a half-
life of 1.1 hours in aerosol, similar to SARS-CoV.
19
is
suggests that airborne transmission is possible, but it
should be noted that SARS-CoV, which has similar
survivability to SARS-CoV-2 in aerosol, is not known
to be transmitted via aerosol. SARS-CoV-2 was found
to be most stable on stainless steel and plastic surfaces
with half-lives of 6-7 hours, and least stable on copper
and cardboard surfaces with half-lives of 1-3 hours.
19
Transmission of SARS-CoV-2 by asymptomatic cases
have been reported.
20
Although asymptomatic spread can
occur during the prodromal phase particularly during
the rst week aer infection, respiratory viral shedding
is greatest when symptoms appear.
21
Older patients and patients with signicant chronic
medical conditions including cardiopulmonary diseases,
diabetes, chronic kidney disease, decompensated cirrhosis,
HIV with low CD4 cell count, immunosuppression, and solid
organ transplant recipients are at higher risk of acquiring
and developing more serious presentation and outcomes
such as acute respiratory distress syndrome and multi-
organ failure.
10,22–27
Pregnant women with COVID-19 do
not appear to have additional complications compared to
the non-pregnant population with COVID-19 and vertical
transmission of SARS-CoV-2 does not appear to occur.
28
e case-fatality rate is around 5%.
5
e pediatric population
appear to have milder symptoms and may harbor the virus
while appearing asymptomatic.
29
No data are currently
available in children with immunocompromised conditions
or chronic lung diseases. In addition to respiratory clinical
manifestation, during the early report of COVID-19 in
China in December 2019, several gastrointestinal symptoms
were reported along with elevated liver enzyme values.
30
Hepatic manifestations have been suspected in multiple
studies, but the evidence is not completely clear.
In this study, we reviewed the currently available
published data on SARS-CoV-2 or COVID-19 and given
gastrointestinal and hepatic manifestations, clinical outcomes,
and management. Herein, we discuss recommendations
and guidelines to ensure safety to healthcare providers
and patients.
Review Methodology
We conducted a systematic search on PubMed
and Google Scholars for research articles with the main
keywords “COVID-19,” “coronavirus disease 2019,” “2019
novel coronavirus,” or “2019-nCoV.” ese keywords were
supplemented with “liver,” “hepatic,” “characteristics,”
“gastrointestinal,” and “endoscopy.” Non-English research
articles, if translatable, were also reviewed. All relevant
research articles found in the search were reviewed.
Unpublished articles that have not been peer-reviewed
were generally avoided. We reviewed research articles
published between June 1, 2019 to March 30, 2020.
Gastrointestinal Manifestations and Considerations
In numerous studies of COVID-19, diarrhea was
reported as a complication of the disease, ranging from
1-5% of cases.
1,10,22,23,31,32
Nausea or vomiting was reported
in 1-5% of cases.
10,22,23,31
e frequency of gastrointestinal
symptoms including nausea and/or diarrhea have typically
been reported to be below 5% but a small study by Zhang
et al. of 28 patients reported diarrhea in 50% of cases.
33
We believe the report by Zhang et al. would likely be an
outlier and the cohort of patients studied may have been
Wasuwanich et al.
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exposed to co-infections or local environmental factors
independent of SARS-CoV-2 that result in diarrhea.
ere have been some reports of just diarrhea as a rst
presentation preceding cough and fever which are the
most common presentations with cough at 67.8%, fever
at 43.8%, fatigue at 38.1%, sputum production at 33.7%,
and shortness of breath at 18.7% of cases.
10
In a case
report by Carvalho et al., a woman who was diagnosed
with COVID-19 presented initially with bloody diarrhea,
approximately 9 days before developing respiratory
symptoms. e woman was also found to have hemorrhagic
colitis which the authors have ruled out all other etiologies
except for SARS-CoV-2.
34
Reports from China have conrmed that SARS-CoV-2
can be detected in the feces of COVID-19 patients.
35
A study
by Zhang et al. on 14 patients with COVID-19 reported
that fecal specimens had similar accuracy to pharyngeal
swab specimens in the diagnosis of COVID-19.
36
Due to
this evidence, the possibility of fecal-oral transmission
of SARS-CoV-2 is of great concern. A study on the viral
structure of SARS-CoV-2 predicted that the virus would
have intermediate levels of fecal-oral transmission and
the authors also found that SARS-CoV-2 had the hardest
outer shell of the coronavirus family, harder than those
of SAR-CoV and MERS-CoV, suggesting that SARS-
CoV-2 would be more resilient in body uids and the
environment.
37
However, there are currently no reports
of human to human transmission via the fecal-oral route.
Recent evidence suggests the potential for SARS-
CoV-2 transmission via fecal shedding.
38,39
Since the
virus may be present in gastrointestinal secretions and
viral RNA is detectable in stool, potential fecal-oral
transmission from gastrointestinal contamination must
be considered. As the outbreak of COVID-19 has quickly
spread from China to other countries, governments and
the medical institutions are taking action to prevent
transmission, from common-sense recommendations
to more extreme quarantine measures.
40
is is quite
an unprecedented phenomenon.
Transplant Donor Considerations
Due to the potential of SARS-CoV-2 transmission
through the transplantation of human cells, tissues, or
cellular/tissue-based products, several public health
institutions have added recommendations on increased
precautions and screening of donors. On February 14,
2020, the United States Food and Drug Administration
has suggested considering the donor for the following
within the past 28 days of tissue recovery: travel to areas
with COVID-19 outbreaks, cohabitation with infected
individuals, or diagnosis/suspicion of COVID-19.
41
Similar
guidelines were published by the European Society for
Blood and Marrow Transplantation.
42
In Italy, an epicenter
of COVID-19 pandemic in Europe, stronger measures
were taken by the Italian National Transplant Center
which has recommended testing for COVID-19 in all
potential tissue and stem-cell living donors, as well as
deceased donors.
43
One of the transplantations of concern is fecal
microbiota transplantation, a novel treatment that has
been used in the management of recurrent Clostridium
dicile infection which is becoming increasingly more
widespread and standardized.
44
We believe that more
cautious measures are needed in addition to existing
guidelines for fecal microbiota transplantation such as
those by Cammarota et al. as the risk of transmitting
SARS-CoV-2 by fecal microbiota transplantation might
be higher than that in other tissue transplants as evidence
has shown that the SARS-CoV-2 can be found in feces
and stool samples can remain positive for SARS-CoV-2
even aer it is undetectable in respiratory tract.
39,45
To prevent potential SARS-CoV-2 transmission,
Ianiro et al. have recommended the following additions
to current guidelines for fecal microbiota transplantation.
Physicians should screen donors for the following within
the previous 30 days: common COVID-19 symptoms
such as fever, fatigue, dry cough, myalgia, dyspnea, and
headache within the previous, donor's history of travel
to regions known to be aected by COVID-19, or close
contact with individuals known or suspected of having
COVID-19. If any of the above is positive, the potential
donor should either be tested for SARS-CoV-2 or simply
be rejected. In countries where COVID-19 is widespread
such as the United States and Italy, the SARS-CoV-2
testing should be considered in all donors, even those
who appear asymptomatic or lack a history of high-risk
travel or contact. An alternative method if SARS-CoV-2
testing is limited is that donor stools could be stored and
quarantined for 30 days before use and released only if
the donor does not develop symptoms. For stool already
stored in stool banks, physicians should retrospectively
check the health status of the donor before using frozen
feces if the donation was made aer community spread
of COVID-19 had occurred in the country to avoid
further potential spreading of SARS-CoV-2.
40
Fecal-Oral Transmission Route Poses a Threat to
Inammatory Bowel Disease Patients
Due to the potential risk of fecal-oral transmission
of SARS-CoV-2 and its presence in the gastrointestinal
tract, patients with inammatory bowel disease (IBD)
are suspected of being a vulnerable group. Because
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275
reports on the characteristics of COVID-19 on patients
with IBD were lacking, SECURE-IBD (Surveillance
Epidemiology of Coronavirus Under Research Exclusion
– Inammatory Bowel Disease) was created. SECURE-
IBD is an international collaboration to create a global
pediatric and adult registry to monitor and report on
outcomes of COVID-19 occurring in IBD patients. e
database contains only de-identied data and the summary
data is displayed on the website at https://covidibd.org/.
As of April 1, 2020, 239 cases have been reports on the
SECURE-IBD database globally with preliminary data
showing greater morbidity and mortality in patients
with ulcerative colitis compared to those with Crohn’s
disease or unspecied IBD.
46
Considerations in Patients Requiring Endoscopic
Procedures
Gastrointestinal contamination with SARS-CoV-2
poses potential risks during endoscopy and colonoscopy to
other patients, endoscopy personnel, as well as populations
without clean drinking water. Recommendations for
gastrointestinal endoscopy include rescheduling elective
non-urgent endoscopic procedures. Some non-urgent
procedures are high priority and may need to be performed
such as cancer evaluations, prosthetic removals, or evaluation
of signicant symptoms. Classication of procedures into
non-urgent/postpone and non-urgent/perform may be
useful.
47
Of note, the United States Surgeon General on
March 14, 2020 advised hospitals to postpone all elective
surgeries.
48
Pre-screening of all patients is mandatory for those
with a high risk of exposure or symptoms of fever or
respiratory symptoms, family members or close contacts
with symptoms of COVID-19, any contact with a conrmed
case of COVID-19, and recent travel to high-risk regions
or countries.
49
Before undergoing endoscopy, the patient
should also be checked for body temperature and symptoms
upon arrival at endoscopy unit.
50
An alternative strategy
that has been used in ailand is to quarantine non-urgert
patients in a hotel for 7-14 days or use mobile apps to
ensure that the patient has been quarantined at home
before arriving for the procedure.
In countries experiencing shortages of personal
protective equipment (PPE), conservation of PPE is critical.
Only essential medical personnel should be present for
the endoscopy procedures. As for the endoscopy team,
appropriate PPE should be reviewed and prepared for
the availability on the day of procedures including gloves,
masks, eyeshield/goggles, face shields, and gown per the
guideline from the United States CDC.
51
All members of
the endoscopy team should be trained in proper usage
of PPE and any additional requirements given by public
health institutions due to COVID-19.
50
For patients conrmed to have COVID-19 or patients
under investigations awaiting test results, isolation
precautions should be taken with procedures performed
in negative pressure rooms. Aerosolizing procedures
should also be done in negative pressure rooms.
50,52
Aer
the procedure, we recommend a follow-up by phone call
within 7-14 days to inquire about a potential COVID-19
diagnosis or development of COVID-19 symptoms.
Telemedicine should be utilized whenever possible for
pre-procedure and post-procedure care.
53,54
Recently
published recommendations from the North American
Society for Pediatric Gastroenterology, Hepatology, and
Nutrition (NASPGHAN) provide similar guidelines for
pediatric patients.
55
e use of an “aerosol box,” basically a transparent
box designed to cover the head or upper body of
a patient, has been suggested as a method to reduce
droplet contamination during endoscopic procedures.
Canelli et al. found that the use of an “aerosol box”
during endotracheal intubation can eectively contain
droplet contamination within the box.
56
Ljubicic et al.
demonstrated the successful use of an “aerosol box” during
lower endoscopy, specically endoscopic retrograde
cholangiopancreatography (ERCP).
57
While the use of
an “aerosol box” during upper endoscopy has not been
reported in the published literature, commercial “aerosol
boxes” designed to be used during upper endoscopy such
as EndoSim’s AerosolBarrier (TM). Although the “aerosol
box” can reduce droplet spread, it is not recommended
as a replacement of standard PPE, but rather a tool to be
used with standard PPE. Since the box is not designed to
be disposable, safe and eective methods for handling
and sterilizing the box aer procedures have to be in
place.
Hepatic Manifestations and Considerations
During the past outbreaks of SARS and MERS, cases
of liver injury have been reported in multiple studies with
prevalence, based on elevated ALT, ranging from 53-87%
in SARS and 11-56% in MERS.
58–64
is suggested that
SARS-CoV-2 may have similar hepatic complications.
Abnormal liver enzymes have been observed in
approximately 20-30% of patients with COVID-19.
Multiple studies have reported liver injury in patients
with COVID-19 indirectly with serum biomarkers
such as aspartate aminotransferase (AST) and alanine
aminotransferase (ALT); however, there have been no
direct conrmations via liver biopsies.
1,10,65
ALT was
found to be elevated in 21-31% of cases and AST was
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found to be elevated in 16-53% of cases.
1,10,22,23,31,66,67
Additionally, elevated total bilirubin was reported in
11-18% of cases, elevated lactate dehydrogenase was
reported in 41-76% of cases, and low albumin was reported
in 38-98% of cases.
1,10,22,23,66
In a large study of 1,099
patients with COVID-19 in China, Guan et al. found
that 2.1% had a preexisting hepatitis B infection.
10
Acute
liver injury has also been reported in an infant whose
liver enzymes returned to normal aer the virus was
cleared.
68
Patients admitted to the ICU were reported
to have higher frequencies of acute liver injury, 66.7%
versus 26.2% according to a study of 102 patients with
COVID-19 in China.
69
Additionally, patients admitted
to the ICU were found to have signicantly higher ALT,
higher AST, higher lactate dehydrogenase, higher total
bilirubin, and lower albumin levels compared to those
not admitted to the ICU.
1,13
A study by Guan et al. explored the mechanism of
liver injury in COVID-19 patients through mouse models.
ey found that angiotensin-converting enzyme 2 (ACE2),
the entry point into cells for SARS-CoV-2, is expressed
in cholangiocytes, but scarcely expressed in hepatocytes.
However, when there is inammation in the liver, there
is an up-regulation of ACE2 expression in the liver due
to compensatory proliferation of hepatocytes derived
from cholangiocytes which express ACE2 potentially
allowing these hepatocytes to be infected by SARS-
CoV-2.
70
In an unpublished study by Tian et al., autopsies
of four patients who died from COVID-19, one of whom
had abnormal liver enzyme values including elevated
gamma-glutamyltransferase (GGT), revealed that the liver
exhibited mild lobular inltration by small lymphocytes,
centrilobular sinusoidal dilation, and patchy necrosis.
SARS-CoV-2 was also detected in liver tissue in one case.
71
Cytokine storm syndrome and drug-induced liver injury
are common theories for mechanisms of liver injury in
COVID-19 patients, however, histological evidence is
lacking for these theories.
As there has been no direct conrmation of liver
injury in COVID-19 patients, the abnormal biomarker
values typically associated with the liver may have been
caused extrahepatically. Elevated AST, ALT, and lactate
dehydrogenase can be caused by muscle inammation
and hemolysis can account for elevated total bilirubin
and lactate dehydrogenase.
72,73
Evidence exists for this
alternative mechanism in COVID-19 patients; however,
the evidence is not strong. Creatine kinase elevation
likely indicates muscle inammation, however, studies
on COVID-19 patients have found varying results. A
large study by Guan et al. found that creatine kinase was
elevated in 19.0% of severe cases and 12.5% of non-severe
cases, but statistical testing was not done to conrm the
dierence.
10
In a smaller study by Huang et al, creatine
kinase was reported to have a median of 132.0 U/L (IQR:
82.0-493.0) in severe cases and 133.0 U/L (IQR: 61.0-189.0)
in non-severe cases (p=0.31).
1
In another study, creatine
kinase was found to be elevated 13% of cases, but also low
in 23% of cases.
22
In a review, Zhang et al. reported that
54% of their cohort of 56 COVID-19 cases had elevated
GGT levels, however, this result was unpublished.
26
In
a detailed study of 3 patients with COVID-19 by Cao
et al., one patient without a history of any liver disease
had elevated GGT, AST, ALT, lactate dehydrogenase,
low albumin, and normal total bilirubin. However, he
also had a greatly elevated creatine kinase of 1081 U/L.
is suggests that while this patient has evidence of mild
liver injury, the muscle injury appears to contribute to
the elevated ALT, AST, and lactate dehydrogenase.
74
Additionally, a study by Zhou et al. found that
19% of cases had coagulopathy, a sign on potential liver
injury.
23
And in other studies, low platelet count was
reported in 36.2% of cases.
10
is evidence suggests that true liver injury due
to COVID-19 is likely occurring but the level of injury
appears to be mild because while there are reports of
abnormal liver function tests and coagulopathy, there
were no reports of liver failure or signs of jaundice, ascites,
hyperammonemia, or portal hypertension. While there
have been reports of multiple organ failure, likely due to
sepsis or acute respiratory distress syndrome, there have
so far been no reports of severe liver injury such as acute-
on-chronic liver failure or fulminant hepatitis caused
directly by SARS-CoV-2.
22
As the liver and kidneys can
be damaged in patients with COVID-19, considerations
should be made on the dosage of drugs, especially those
with known hepatotoxicity or renal toxicity risks. And
liver and kidney functions should be monitored until
the patient has cleared the virus.
75
For patients with pre-
existing cirrhosis, especially those with decompensated
cirrhosis, the hepatotoxicity of drug treatment options for
COVID-19 must be highly considered as these patients
have a high risk of developing a drug-induced liver injury.
Remdesivir, a repurposed drug originally developed to
treat Ebola, is currently one of the most promising drug
treatments available for COVID-19.
76,77
Remdesivir has
not been tested in patients with cirrhosis and due to
its novelty, it is unknown whether this drug can cause
hepatotoxicity.
78
Adeoye et al. predicted that remdesivir
would be hepatotoxic, but this remains to be proven.
79
Liver function should be closely monitored in cirrhosis
patients if remdesivir is administered. Chloroquine and
hydroxychloroquine have been in use for decades and
Volume 72, No.4: 2020 Siriraj Medical Journal
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277
have rarely been associated with liver injury according to
the LiverTox database.
78
Baricitinib, another candidate
drug for the treatment of COVID-19, may cause ALT
elevations, but there have been no reports of hepatotoxicity
associated with its use, thus, it is considered unlikely to
be a cause of liver injury.
78
Individuals without COVID-19 who are on
immunosuppressive drugs for liver transplants or
autoimmune-related conditions such as autoimmune
hepatitis should continue taking their medications as
the risk of organ rejection or autoimmune disease ares
outweighs the chance acquiring SARS-CoV-2.
80
A case
report by Qin et al. described an adult patient with
COVID-19 who had liver transplantation within days of
the viral infection. e patient managed to clear SARS-
CoV-2 aer 34 days of hospitalization while continuing
to take immunosuppressive medication.
81
ese patients
and their caretakers should follow guidelines of the
United States CDC for at-risk groups and they should
avoid crowds, practice social distancing, and limiting
travel.
82
CONCLUSION
As COVID-19 becomes increasingly more widespread
globally and within countries, increased precaution is a
general trend across medical departments. Non-urgent
and low priority surgeries and operations including
endoscopy should be postponed. ere is a risk of fecal-
oral transmission of SARS-CoV-2 as the live virus has
been found in the stool sample so endoscopies should
be done with increased precaution and safety measures.
e current evidence suggests that there are indeed
cases of true liver injury caused by COVID-19, however,
the injury appears to be mild as severe injuries such
as liver failure, independent of multiple organ failure,
have not been reported. Histological evidence of liver
injury has been reported. A plausible mechanism of
liver injury is via the infection of hepatocytes derived
from cholangiocytes which express ACE2 potentially
allowing these hepatocytes to be infected by SARS-
CoV-2. COVID-19 related liver injury was based on
abnormal liver function tests or enzymes, which can
have extrahepatic contributors such as muscle injury
or hemolysis.
Fig 1. Frequency of hepatic panel and laboratory abnormalities in COVID-19 cases across multiple studies arranged from largest to smallest
study.
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; GGT = gamma-glutamyltransferase; LDH = lactate
dehydrogenase; TBIL = total bilirubin; CK = creatine kinase; ALB = albumin.
1. Abnormal biomarker values were dened as having biomarkers values above the upper limit (or below the lower limit for
albumin) of reference values specied by that particular study.
2. Some studies reported low creatine kinase levels, however, for the purposes of this gure, only elevated creatine kinase levels
were concerned abnormal.
Wasuwanich et al.
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278
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TABLE 1. Hepatic panel and laboratory values in overall COVID-19 cases.
Reference Cohort ALT(U/L) AST(U/L) GGT(U/L) LDH(U/L) TBIL(μmol/L) CK(U/L) ALB(g/L) Notes
Size, N Overall Overall Overall Overall Overall Overall Overall
Zhou et al.
23
191 30.0 (17.0-46.0) - - 300.0 (234.0-407.0) - 21.5 (13.0-72.4) 32.3 (29.1-35.8)
Wang et al.
13
138 24 (16-40) 31 (24-51) - 261 (182-403) 9.8 (8.4-14.1) 14 (10-18) -
Chen et al.
22
99 39.0 (22.0-53.0) 34.0 (26.0-48.0) - 366.0 (260.0-447.0) 15.1 (7.3)* 85.0 (51.0-184.0) 31.6 (4.0)*
Shi et al.
31
81 46.2 (29.5)* 40.8 (17.9)* - - 11.9 (3.6)* - 32.9 (8.1)*
Cai et al.
32
80 22.5 (15.0-26.3) 25.1 (18.0-28.0) 25.5 (14-31.1) - - - - Values were
before
intervention
Xu et al.
67
62 22 (14-34) 26 (20-32) - 205.0 (184.0-260.5) - 69.0 (40.5-101.0) -
Huang et al.
1
41 32.0 (21.0-50.0) 34.0 (26.0-48.0) - 286.0 (242.0-408.0) 11.7 (9.5-13.9) 132.5 (62.0-219.0) 31.4 (28.9-36.0)
Chen et al.
66
21 26.0 (16.0-42.0) 27.0 (21.0-47.0) - 336.0 (221.0-537.0) 8.8 (6.8-10.3) 73.0 (63.0-287.0) 33.7 (29.6-37.4)
Cao et al.
74
3 20 (15-52) 36 (25-54) 17 (15-87) 308 (163-651) 15.0 (8.4-15.5) 267 (46-1081) 33.4 (32.4-39.3) Values were
before
immunoglobin
intervention
Cui et al. J.
68
1 84 100 - - 33.7 46 - Infant;
DBIL=25.2
μmol/L
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; GGT = gamma-glutamyltransferase; LDH = lactate dehydrogenase; TBIL = total bilirubin; CK = creatine kinase;
ALB = albumin.
1. Values are generally reported as medians with an interquartile range within parenthesis, however, some studies
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279
TABLE 2. Hepatic panel and laboratory values in severe and non-severe subgroups of COVID-19.
Reference CohortALT(U/L)AST(U/L) LDH(U/L) TBIL(μmol/L)CK(U/L)ALB(g/L) Notes
Size, N Severe Non- Severe Non- Severe Non- Severe Non- Severe Non- Severe Non-
Severe Severe Severe Severe Severe Severe
Zhou et al.
23
191 40.0 27 - - 521.0 253.5 - - 39.0 18.0 29.1 33.6 Severe
(24.0- (15.0- (363.0- (219.0- (19.5- (12.5- (26.5- (30.6- cases were
51.0) 40.0) 669.0) 318.0) 151.0) 52.1) 31.3) 36.4) deceased
cases
Wang et al.
13
138 35 23 52 29 435 212 11.5 9.3 18 13 - -
(19- (15 (30 (21 (302 (171 (9.6 (8.2 (12 (10
57) -36) -70) -38) -596) -291) -18.6) -12.8) -35) -14)
Yang et al.
65
52 - - - - - - 19.5 13.1 - - - - Severe
(4.3)* (11.6)* cases were
deceased
cases
Huang et al.
1
41 49.0 27.0 44.0 34.0 400.0 281.0 14.0 10.8 132.0 133.0 27.9 34.7
(29.0- (19.5- (30.0- (24.0- (323.0- (233.0- (11.9- (9.4- (82.0- (61.0- (26.3- (30.2-
115.0) 40.0) 70.0) 40.5) 578.0) 357.0) 32.9) 12.3) 493.0) 189.0) 30.9) 36.5)
Chen et al.
66
21 42.0 16.0 47.0 24.0 537.0 224.0 8.8 7.8 214.0 64.0 29.6 37.2
(32.5- (13.3- (28.0- (21.5- (433.5- (200.3- (7.9- (6.4- (90.0- (57.5- (28.6- (35.8-
50.0) 21.8) 74.5) 26.5) 707.5) 251.8) 10.5) 9.5) 329.0) 83.5) 33.0) 38.8)
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; GGT = gamma-glutamyltransferase; LDH = lactate dehydrogenase; TBIL = total bilirubin; CK = creatine kinase;
ALB = albumin.
1. Values are generally reported as medians with an interquartile range within parenthesis, however, some studies or biomarkers have been reported as means with a standard deviation
within parenthesis which we have indicated by * in the table cell.
Wasuwanich et al.
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option for deteriorating patients with Coronavirus Disease
2019. Open Forum Infect Dis 2020;ofaa102.
69. Rismanbaf A, Zarei S. Liver and Kidney Injuries in COVID-19
and eir Eects on Drug erapy; a Letter to Editor. Arch
Acad Emerg Med 2020;8(1):e17.
70. D’Antiga L. Coronaviruses and immunosuppressed patients.
e facts during the third epidemic. Liver Transplant 2020
Mar 20;
71. Qin J, Wang H, Qin X, Zhang P, Zhu L, Cai J, et al. Perioperative
Presentation of COVID-19 Disease in a Liver Transplant
Recipient. Hepatology 2020 Mar 27;
72. Take Steps to Prevent Getting Sick [Internet]. Centers for
Disease Control and Preventation. 2020 [cited 2020 Apr 2].
Available from: https://www.cdc.gov/coronavirus/2019-ncov/
need-extra-precautions/get-ready.html
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Pradermchai Kongkam, M.D.*, Kasenee Tiankanon, M.D.*, Siriporn Ratanalert, R.N.**, Vachira Janthakun,
R.N**, Taya Kitiyakara, M.D.*, Phonthep Angsuwatcharakon, M.D.*, Tanyaporn Chantarojanasiri, M.D.*, Parit
Mekaroonkamol, M.D.*, Wiriyaporn Ridtitid, M.D.*, Satimai Aniwan, M.D.*, Rapat Pittayanon, M.D.*, Siriboon
Attasaranya, M.D.*, Sittikorn Linlawan, M.D.*, Nonthalee Pausawasdi, M.D.*, awatchai Akaraviputh, M.D.*,
awee Ratanachu-ek, M.D.*, Rungsun Rerknimitr, M.D.
*ai Association for Gastrointestinal Endoscopy (TAGE), **e Endoscopy Nurses Society (ailand): ENST
ThePracticeofEndoscopyduringtheCOVID-19
Pandemic:RecommendationsfromtheThai
Association for Gastrointestinal Endoscopy (TAGE)
in collaboration with the Endoscopy Nurse Society
(Thailand)
ABSTRACT
For management of endoscopy units during the worldwide coronavirus disease 2019 (COVID-19) outbreak
caused by the new coronavirus SARS-CoV-2 in ailand, a working group of the ai Association for Gastrointestinal
Endoscopy (TAGE) in collaboration with the Endoscopy Nurse Society (ailand) (ENST) has developed the
following recommendations for ai doctors and medical personnel working in gastrointestinal endoscopy (GIE)
units.
Upper and lower GIE is considered as an aerosol generating procedure (AGP). Information regarding chance of
infection in patients must be obtained before performing endoscopy to help determine the level of risk. Endoscopies
should only be performed in emergency/urgency cases. Hospitals that have no conrmed cases with low incidences
of infection in their coverage area may consider performing selective endoscopies.
For the conrmed infected patient, the recommendations are as follows; the endoscopist who performed
the procedure must be an experienced one, wear the enhanced personal protective equipment (PPE) with correct
practice how to wear and take o PPE, and strict hand hygiene. e endoscopic procedure should be performed in
a negative pressure room; however, If not available, a bedside procedure in the cohort ward should be performed.
Endotracheal tube intubation and removal should be done by an anesthesiologist. Most enzymatic detergent solutions
can eliminate SARS-CoV-2. e use of an additional pre-cleaning process in order to prevent AGP from occurring
during endoscope reprocessing is recommended.
Patient(s) under investigation (PUI) should wait for the test result before considering endoscopic procedure.
For the low risk patient for COVID-19 infection who needs an endoscopic procedure, standard PPE is recommended.
Due to the limitation of medical resources, only medical personnel who are necessary for the procedure and at risk
of COVID-19 infection should be allowed to use the recommended PPE.
Keywords: COVID-19; endoscopy, coronavirus SARS-CoV-2; ailand; aerosol generating procedure; ai
Association for Gastrointestinal Endoscopy (TAGE); enhanced personal protective equipment (PPE), patient(s)
under investigation (PUI); Endoscopy Nurse Society (ailand) (ENST) (Siriraj Med J 2020; 72: 283-286)
Corresponding author: Rungsun Rerknimitr
E-mail: ercp@live.com
Received 3 April 2020 Revised 4 June 2020 Accepted 5 June 2020
ORCID ID: http://orcid.org/0000-0001-6866-6886
http://dx.doi.org/10.33192/Smj.2020.38
Kongkam et al.
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INTRODUCTION
e following recommendations are for ai doctors
and medical personnel working in gastrointestinal endoscopy
unit. is advice was written on 25
th
March 2020, based
on data and suggestions from the experts in ailand
and other countries, as an appropriate guideline to the
current situation in ailand.
e spread of the new coronavirus SARS-CoV-2
has recently led to the worldwide coronavirus disease
2019 (COVID 19) outbreak.
1
In this article, infected
patients refer to persons who have been infected with
COVID-19, and include both those with and without
symptoms. Current data shows that COVID-19 infected
patients had 1-3% mortality rate. is virus can also
be found from the oral cavity and stools of infected
patients.
2-4
Patients with the highest risk of death include
the elderly, those with chronic medical conditions and
immunocompromised status.
5
Recommendations
1. Upper gastrointestinal endoscopy is considered as
an aerosol generating procedure (AGP).
1
is procedure
can cause high risk of viral spreading to endoscopists
and surrounding medical personnel (Fig 1).
6
Lower
gastrointestinal endoscopy (Colonoscopy) is considered
as AGP as well, produced by the expulsion of luminal
gas per rectum during the procedure.
7
2. Information that must be obtained before
performing endoscopy to help determine the level of risk
include: fever (body temperature >37.5 Celsius), travel
history, risk occupation, history of contact to conrmed
infected patients, and the history of close contact with
unfamiliar people.
3. Due to limited resources in the hospital during
the COVID-19 outbreak, endoscopies should only
be performed in emergency/urgency cases. Elective
endoscopies in suspected or conrmed infected patient
must be postponed. Hospitals that have no conrmed
cases with low incidence of infection in their coverage
area may consider performing selective endoscopies.
We propose a classication of endoscopic procedures
according to the urgency of the indication in Fig 2.
8
4. For the conrmed infected patient who needs an
endoscopic procedure, the recommendations as follows
must be practiced.
1. e endoscopist who performed the procedure
must be an experienced one. To reduce the risk of infection
and the consumption of PPE, no trainee should be allowed
in the endoscopy room during the procedure.
2. The endoscopist must wear the enhanced
personal protective equipment (PPE) (Fig 3), including
1. Respirator mask (N95, FFP2/FFP3,
CAPR) if available
2. Medical protecting coverall
3. Double disposable gloves
4. Medical cap/hood
5. Goggles/ eyes-visors and face shield
6. Waterproof leg covers
3. Practice how to wear and take o PPE in
the correct way, using a buddy system to check for and
prevent any errors.
6
4. Strict hand hygiene is necessary to reduce
contamination while wearing and taking o PPE.
5
5. e endoscopic procedure should be performed
in a negative pressure room. If one is not available, a
bedside procedure in the cohort ward should be performed.
6. Endoscopic retrograde cholangiopancreatoscopy
(ERCP) can be performed in the endoscopic unit, the
operating room or at the bedside in the cohort ward
with a portable uoroscopy machine. is depends on
the circumstances of each hospital.
7. Endotracheal tube intubation and removal
should be done by an anesthesiologist. Endoscopists
and the surrounding endoscopic medical personnel
should stay outside of the room during endotracheal
tube intubation and removal.
8. e endoscopic unit should be disinfected
before and aer the procedure. Most enzymatic detergents
solutions can eliminate SARS-CoV-2.
9. Standard endoscope reprocessing steps are
sucient for SARS-CoV-2 disinfection. However, we
recommend the use of an additional pre-cleaning process
in order to prevent AGP from occurring during endoscope
reprocessing (Fig 4).
5. Patient(s) under investigation (PUI) should
wait for the test result before considering endoscopic
procedure. But in an emergency situation, endoscopy
should be performed with caution in the same way as
for a conrmed infected patient.
6. For the low risk patient for COVID-19 infection
who needs an endoscopic procedure, standard PPE
including hair net, goggles, surgical mask, waterproof
gown, disposable gloves, and shoe covers is recommended
(Fig 3).
7. e use of mask respirators including N95 will
depend on the local prevalence of COVID-19 and the
availability of masks and other medical resources in the
hospital. However it should be noted that asymptomatic
infected patients can also spread the infection.
8. Due to the limitation of medical resources, only
medical personnel who are necessary for the procedure
and at risk of COVID-19 infection should be allowed to
use the recommended PPE.
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285
Fig 1. All GI endoscopies are considered as the aerosol generating procedures (AGP) and risk viral spreading
Fig 2. Classication of endoscopic procedures according to the urgency of indication
Fig 3. ree types of personal protective equipment (PPE) according to risk level of COVID-19 transmission
Kongkam et al.
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REFERENCES
1. Chiu PWY, Ng SC, Inoue H, Nageshwar Reddy D, Hu EL, Cho
JY, et al. Practice of endoscopy during COVID-19 pandemic:
position statements of the Asian Pacic Society for Digestive
Endoscopy (APSDE-COVID statements). Gut [Internet]. 2020
Apr 2 [cited 2020 Apr 3]; Available from: https://gut.bmj.com/
content/early/2020/04/02/gutjnl-2020-321185.info
2. Gu J, Han B, Wang J. COVID-19: Gastrointestinal manifestations
and potential fecal-oral transmission. Gastroenterology [Internet].
2020 Mar 3; Available from: http://dx.doi.org/10.1053/j.gastro.
2020.02.054
3. Song Y, Liu P, Shi XL, Chu YL, Zhang J, Xia J, et al. SARS-CoV-2
induced diarrhoea as onset symptom in patient with COVID-19.
Gut [Internet]. 2020 Mar 5; Available from: http://dx.doi.org/
10.1136/gutjnl-2020-320891
4. Xiao F, Tang M, Zheng X, Liu Y, Li X, Shan H. Evidence for
gastrointestinal infection of SARS-CoV-2. Gastroenterology
[Internet]. 2020 Mar 3; Available from: http://dx.doi.org/10.1053/j.
gastro.2020.02.055
5. Soetikno R, Teoh AYB, Kaltenbach T, Lau JYW, Asokkumar R,
Cabral-Prodigalidad P, et al. Considerations in performing
endoscopy during the COVID-19 pandemic. Gastrointest Endosc
[Internet]. Available from: https://doi.org/10.1016/j.gie.2020.03.3758
6. Johnston ER, Habib-Bein N, Dueker JM, Quiroz B, Corsaro E,
Ambrogio M, et al. Risk of bacterial exposure to the endoscopist’s
face during endoscopy [Internet]. Vol. 89, Gastrointestinal
Endoscopy. 2019. p. 818–24. Available from: http://dx.doi.
org/10.1016/j.gie.2018.10.034
7. Chapman S. Hot air? BMJ: British Medical Journal: International
Edition [Internet]. 2001;323(7327):1449–1449. Available from:
https://elibrary.ru/item.asp?id=4282221
8. Join ABE, Partner AI, Edge AL. JOINT GI SOCIETY MESSAGE:
COVID-19 Clinical Insights for Our Community of
Gastroenterologists and Gastroenterology Care Providers.
Available from: https://www.asge.org/home/joint-gi-society-
message-covid-19
Fig 4. Recommended endoscope reprocessing steps during the COVID-19 outbreak
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287
Sattha Riyapan, M.D., MPH, Jirayu Chantanakomes, M.D., Onlak Ruangsomboon, M.D., Wansiri Chaisirin,
M.D., Chok Limsuwat, M.D., Nattakarn Prapruetkit, M.D., Tipa Chakorn, M.D., Apichaya Monsomboon, M.D.
Department of Emergency Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, ailand.
AssessmentofPrehospitalManagementofPatients
Transported to a Thai University Hospital
ABSTRACT
Objective: To assess the quality of prehospital care given to patients transported to a ai university hospital.
Methods: is prospective observational study collected data from EMS providers who transported patients to Siriraj
Hospital during August 2017 to November 2017. Collected data was evaluated by at least 2 EMS medical directors
for appropriateness of EMS dispatch and prehospital care. e primary outcome was to determine the quality of
prehospital management among patients transported by EMS. Inter-rater variability in the evaluation of patient
care between EMS medical directors and medical providers in the emergency department (ED) was performed
using Cohen’s kappa coecient, with a value lower than 0.7 indicating signicant variability.
Results: Data was collected from 246 EMS providers that transported patients to our center. Evaluation by EMS
medical directors found EMS dispatch to be appropriate in 216 cases (87.8%), and patient management to be
appropriate in 198 cases (80.5%). Inappropriate prehospital management was found most oen in patients who
presented with out-of-hospital cardiac arrest (OHCA) (87.5%), and with chest pain (63.6%). Medical providers
in the ED rated prehospital management to be appropriate in 93.1% of cases. Cohen’s kappa coecient between
EMS medical directors and ED providers was 0.2, which indicates signicant variability between the two groups
of assessors.
Conclusion: Quality assessment of the ai EMS system revealed opportunities for improvement in prehospital
management of patients dispatched by ai EMS. Moreover, this study found variability in the evaluation of
prehospital care between medical providers at the ED and EMS medical directors. Information from this study will
help to inuence and guide improvement in prehospital patient care in ailand.
Keywords: Emergency medical services; quality assessment; prehospital management; emergency department
(Siriraj Med J 2020; 72: 287-295)
Corresponding author: Sattha Riyapan
E-mail: sattha.riy@mahidol.ac.th
Received 24 June 2019 Revised 11 February 2020 Accepted 20 February 2020
ORCID ID: http://orcid.org/0000-0003-1867-0080
http://dx.doi.org/10.33192/Smj.2020.39
INTRODUCTION
Emergency Medical Service (EMS) is a system that
provides emergency care for patients during transport
from incident sites to hospitals. An ecient EMS system
was proven to reduce mortality and morbidity in several
conditions.
1
erefore, continuous quality improvement
(CQI) in an EMS system is essential to accomplish desired
outcomes.
e majority of CQI systems in pre-hospital care
settings use the same concepts and methods of quality
measurement as those used in in-hospital settings.
2-7
Many studies in recent years were done to nd pre-
hospital care quality measurements; however, the majority
of studies focused on a specic disease, condition, or
scenario. For example, a study in out-of-hospital cardiac
arrest (OHCA) reported response time, presence of
Riyapan et al.
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bystander CPR, and presence of an AED as important
quality indicators that were selected to be part of a CQI
system.
3
Other studies that evaluated prehospital care
performance in an acute coronary syndrome setting
found use of a 12-lead EKG, providing initial treatment
with aspirin and/or nitroglycerine, and transporting
patients to appropriate hospitals to be indicators that
guarantee quality in prehospital care.
9-12
Thailand’s EMS system has been developing a
CQI system for 10 years. CQI-related projects have
ranged from a small quality improvement project in one
organization to the establishment of a national standard
for EMS providers, equipment, and ambulances. To
date, the national data used to evaluate EMS quality
in ailand has been data collected from Emergency
Department (ED) providers. However, sometimes
emergency department providers do not understand
what to evaluate in a prehospital care setting, and this
can make these assessments unreliable. To the best of
our knowledge, no previous study from ailand has
collected data directly from arriving EMS teams, aer
which that data was evaluated for appropriateness by both
ED providers and EMS medical directors at a national
tertiary emergency department. Accordingly, the aim
of this study was to evaluate the quality of pre-hospital
care given to patients transported to a ai university
hospital. e secondary objective was to compare the
assessments of prehospital care between ED providers
and EMS medical directors.
MATERIALS AND METHODS
is prospective observational study collecting
data from EMS teams who transported patients to the
Department of Emergency Medicine, Faculty of Medicine
Siriraj Hospital, Mahidol University, Bangkok, Hospital
during the August 2017 to November 2017 study period.
Siriraj Hospital is a 2,300-bed university-based national
tertiary center. We included EMS teams that transported
patients to the ED or the trauma unit. is study included
only EMS teams that were dispatched by the Bangkok
EMS Center. EMS teams that did not agree to sign the
informed consent document were excluded from the
study. e protocol for this study was approved by the
Siriraj Institutional Review Board (SIRB) (Si 375/2017).
Data collection
EMS teams dispatched by Bangkok EMS center came
through the triage area of Siriraj Hospital. e triage nurse
specied where the patient was to be sent according to
ED protocol. If the patient needed emergency care, they
were immediately transferred to the emergency room.
e nurse waited until the EMS team communicated
all appropriate information to the ED. e nurse then
approached the team and asked them for their written
informed consent to request, collect, and record data
relating to prehospital care given to the patient that they
just transported.
Outcome measurement
e record form was sent to 3 EMS medical directors
for a review of the quality of prehospital care that was
provided by the EMS team. e primary outcome was
the appropriateness of both dispatch decisions and pre-
hospital care. Appropriateness was determined based on
evidence-based management data and protocols in pre-
hospital care, and current resources available for use by
ai EMS teams. Appropriateness criteria were compiled
in a check list form, as demonstrated in the appendix.
A decision could be reached by agreement of two of
three EMS medical directors, and this was the primary
outcome. ED providers more broadly assessed prehospital
management according to the following 4 categories:
airway management, circulation management, bleeding
control, and immobilization. Appropriateness among ED
providers was dened as a judgment of appropriateness
in all 4 categories. Inter-rater reliability between EMS
medical directors and ED providers was the secondary
outcome.
Sample size calculation
is research aimed to evaluate the quality of EMS
prehospital patient care. Evaluation of EMS care in
ailand yielded a favorable prehospital care rate of over
90%. However, that evaluation was not performed by
experts in prehospital care. e assessment for quality
control was estimated using data from studies conducted
in other countries that included evaluation by EMS
medical directors that found only 80% adequacy of
prehospital patient care by EMS teams.
13
e degree
of accuracy required was 0.05 and the probability of
a type 1 error was 0.05. e calculated sample size was
246 with a standard normal deviation (Z=1.96).
Statistical analysis
Statistical analysis was performed using SPSS Statistics
(SPSS, Inc., Chicago, IL, USA). Demographic data were
summarized using descriptive statistics. Categorical data
are presented as number or number and percentage,
and continuous data are presented as mean ± standard
deviation. Inter-rater reliability was calculated by Cohen’s
kappa coecient, and a dierence in inter-rater agreement
of less than 0.7 was dened as signicant inter-rater
variability.
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Riyapan et al.
RESULTS
During the study period, 286 cases were transferred
by EMS to our center. Forty of those cases were excluded
due to various reasons (Fig 1). e remaining 246 cases
were included in our nal analysis. e mean age of
included patients was 67 years, and 43.1% were male.
Most cases received care from advanced life support
(ALS) EMS units (186 cases, 75.6%), and almost all cases
that arrived were non-trauma cases (240 cases, 97.9%).
Only 11 cases (4.5%) had physicians on scene, and 71
(29%) had pre-hospital notication. Table 1 describes
the demographic data of patients transported by EMS
to Siriraj Hospital.
In non-trauma cases, the chief complaint that
led to a call for an ambulance was dyspnea (73 cases,
30.4%), followed by alteration of consciousness (57
cases, 23.7%). Other reasons included seizures (21 cases,
8.8%), weakness (13 cases, 5.4%), and chest pain (11
cases, 4.6%). Provisional diagnosis by EMS was most
oen dyspnea (29 cases, 12%), followed by alteration of
consciousness (12 cases, 7%), hypoglycemia (19 cases,
7.9%), and seizure (18 cases, 7.5%). Regarding pre-
hospital interventions, 136 patients (57%) had airway
assistance, and most of those received oxygen cannula.
ree cases had endotracheal tube intubation attempts,
with successful intubation in all 3 cases. Intravenous
access was performed in 85 cases (37%), and normal
saline was the most oen given initial uid. Point-of-
care testing (POCT) for glucose was performed in 150
cases (62.5%), and EKG monitoring was performed in
54 cases (22.5%) (Table 2).
Evaluation of dispatch and prehospital management
by EMS medical directors demonstrated a Cohen’s kappa
coecient for inter-rater agreement of 0.83 and 0.71,
respectively. Final results showed appropriate dispatch
in 216 cases (87.8%), and appropriate prehospital care
in 198 cases (80.5%) (Table 3).
Fig 2 shows the proportion of inappropriate prehospital
management classied by chief complaint. OHCA had
the highest proportion of inappropriate treatment (7
out of 9 patients, 87.5%). is was due to no hospital
notication in 3 patients, and no initial rhythm noted in
2 patients. e second highest inappropriately managed
chief complaint was chest pain (63.3%), which was due
to no EKG monitoring and no aspirin administered in
ACS suspected patients. Presentation of weakness was
the third most inappropriately managed chief complain
(53.8%). All of those patients were suspected of having
a stroke, but the EMS responders did not notify the
hospital.
Only 131 cases (53%) had quality assessment
performed by ED providers. Of those, 122 cases (93.1%)
were judged to have received appropriate management
in all 4 categories (Table 4). A total of 102 cases (78%) in
this group had appropriate pre-hospital care evaluated
by EMS medical directors. Cohen’s kappa coecient
between EMS medical directors and ED providers was
0.2, which indicates signicant variability between the
two groups of assessors.
DISCUSSION
This prospective observational study collected
data from EMS providers who transported patients
to Siriraj Hospital. e objective was to evaluate the
quality of prehospital care and dispatch. e results
showed appropriate prehospital care and dispatch, as
evaluated by EMS medical directors, to be 80.5% and
87.8%, respectively.
Our results showed that 80.5% of patients had
appropriate care, which is lower than the recent report
on EMS care in ailand that reported appropriate care
of over 90% in all categories.
14
e reason that our study
found a lower result may be due to the following factors.
First, the EMS directors and the ED providers did not
use the same form to evaluate the patient. e research
form included information that is not regularly collected
from EMS providers, but it included key performance
indicators in patient care. For instance, prehospital
notication is essentially important in patients that are
likely to require immediate urgent care upon arrival, like
acute stroke patients and OHCA patients.
15
Secondly, our
EMS medical directors assessed quality using a specic
checklist classied by chief complaints. e checklist was
created using performance indicators that were more
specic and standardized. For example, POCT glucose
in alteration of consciousness or hypoglycemic patients,
bronchodilator in COPD/asthma exacerbation, EKG
monitoring and ASA in suspected ACS, and IV uids in
sepsis patients. In contrast, medical providers in the ED
evaluated cases using only primary survey assessment.
So, the observed assessment variability between ED
providers and EMS medical directors may be due to the
dierent forms and using key performance indicators
rather than primary survey assessments as an evaluation.
Out-of-hospital cardiac arrest had the highest
proportion of inappropriate care (87.5%). Excessively
long response time, no rhythm noted in the form, and
no hospital pre-notication were some of the reasons for
inappropriate care. Time documentation was noted in 5
patients, with a median response time of 7 minutes and
a median total CPR time of 15 minutes. Response time
is one of the key performance indicators in established
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Fig 1. Flow diagram of patient enrollment
Abbreviation: EMS = Emergency medical services
Fig 2. Proportion of inappropriate prehospital management of patients transported to Siriraj Hospital categorized by chief complaints
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Riyapan et al.
advanced EMS systems. In ailand, the response time
for OHCA should not be more than 10 minutes.
16,17
e
data collected in the present study showed a median
response time and call-to-arrival to the hospital time
that was shorter than data from Asian populations that
revealed a median response time of 11.8 minutes, and
call-to-arrival to the hospital time of 41.8 minutes.
16
Only
33.3% of OHCA patients in this study had prehospital
notication, which was lower than the rates reported
from other Asia-Pacic countries.
16
Eorts should be
made to improve EMS response or rst medical contact
time in cases with OHCA. Prehospital notication is also
an important issue that should be emphasized to EMS
teams.
Patients with chest pain that did not receive EKG
monitoring or that did not receive ASA were found to
have received inappropriate care. One or both of these
treatment omissions was observed in 63.6% of patients that
presented with chest pain. As stated in the guidelines
11
,
patients with suspected ACS should have an initial 12-
lead EKG and EKG monitoring to detect arrhythmia or
arrest. EKG monitoring was determined to be essential,
and was included as a key performance indicator.
9,10
It
is also recommended that patients with suspected ACS
receive aspirin in prehospital settings. ese are all key
indicators in current international guidelines. ai EMS
systems should also apply these treatment guidelines in
prehospital management to improve patient outcome.
Our results showed that half of the patients that presented
with weakness were prehospital diagnosed as acute stroke.
All of these cases were judged to be inappropriately
managed because the EMS provider did not notify the
ED. Prehospital notication was shown to reduce time-
to-CT and time-to-thrombolytic in patients with ischemic
stroke.
18,19
Hospital prenotication, therefore, reduces
morbidity and mortality in patients with suspected
stroke. Hospital prenotication was reported to be a key
performance indicator in an EMS CQI system.
20
Our result
showed that 28.9% of EMS providers notied our center
before arrival. Awareness of an incoming medical unit
facilitated improved preparedness in the ED, especially
in critical situations, such as trauma
21
, OHCA, stroke,
and myocardial infarction. Emphasis of the importance
of prehospital notication by EMS units and creating a
simple way to transmit patient information should be
a key development objective.
Dispatch appropriateness was 87.8%, with dispatch
inappropriateness dened as the patient being under-
TABLE 1. Patient and transport characteristics.Abbreviation: SD = Standard deviation.
Patients (N=246)
Numberofpatients(%)
Male gender 106 (43.1)
Age (years), mean + SD 67 + 17.8
Underlying diseases
Hypertension 123 (50)
Diabetes 94 (38.2)
Chronic obstructive pulmonary disease or asthma 19 (7.7)
Ischemic heart disease 34 (13.8)
Stroke(Ischemic/hemorrhagic) 34(13.8)
Epilepsy 7 (2.8)
Others 80 (32.7)
Transfer by advanced life support team 186 (75.6)
Doctor on scene 11 (4.5)
Prehospitalnotication 71(28.9)
Non-trauma patients 240 (97.9)
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triaged. Our number of under-triaged cases correlated
with the latest 11% gure reported from the National EMS
Registry.
14
e reason that patients were under-triaged
was multifactorial. e type of provider that was sent
depended on the decision of the dispatcher that relied
on the information given by the caller. Furthermore, the
availability or unavailability of ALS teams also inuenced
the type of ambulance sent. ese ndings highlight the
need for improved dispatcher skills and decision making,
and the need for more ALS units in our service area.
Limitations
is study has some limitations. First, this was
a single-center study, which limits the number and
demographics of the cases being transported to our
center. Second, the number of non-trauma cases was
signicantly greater than the number of included trauma
cases. e key reason for this dierence between groups
is likely that many (if not most) of the trauma cases that
are transported to our center arrive by emergency medical
responder, and this type of arrival was not included in
our study. is highlights the questions – what are the
conditions under which trauma patients are transported
to our hospital, and are ALS teams being appropriately
dispatched or not? ird, since the initiation of data
collection was dependent on the triage nurse who was
the rst person in the ED to make contact with the EMS
team, it is possible that some cases could have been missed.
Fourth, some data were collected from patient charts due
to the fact that patient data collection during real-time
emergency situations is impractical. at retrospective
factor means that some data could have been missing or
incomplete. Fih and last, the prospective data collected
from the EMS team had to be recalled by the members
of the EMS team. It is, therefore, possible that some data
could be adversely aected by recall bias.
CONCLUSION
is study found that the EMS system that dispatches
medical units to transport patients to the Emergency
Department of Siriraj Hospital has room for improvement
in several areas of prehospital patient care. Key areas of
improvement that were identied include improvements
in dispatcher decision making and increasing the number
of ALS providers in the service area. Improved prehospital
medical care provider knowledge, enhanced quality
assurance data collection methods, and the implementation
of a performance indicator-based system will improve
prehospital care and patient outcomes.
ACKNOWLEDGMENTS
e authors gratefully acknowledge the EMS units
that provided the data for this study, and Assist. Prof. Dr.
Chulaluk Komoltri of the Division of Clinical Epidemiology,
Department of Research, Faculty of Medicine Siriraj
Hospital, Mahidol University, Bangkok, ailand for
assistance with statistical analysis.
Conict of interest declaration: All authors declare no
personal or professional conicts of interest relating to
any aspect of this study.
Funding disclosure: e present research was supported
by the “Chalermphrakiat” Grant, Faculty of Medicine
Siriraj Hospital, Mahidol University.
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6. Al-Shaqsi SZK. Response time as a sole performance indicator
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8. Myers JB, Slovis CM, Eckstein M, Goodloe JM, Isaacs SM,
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9. Ting HH, Krumholz HM, Bradley EH, Cone DC, Curtis
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10. Canto JG, Rogers WJ, Bowlby LJ, French WJ, Pearce DJ, Weaver
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11. Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci
C, Bueno H, et al. 2017 ESC Guidelines for the management of
acute myocardial infarction in patients presenting with ST-
segment elevation. Eur Heart J 2017.p.1-66.
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12. Zedigh C, Alho A, Hammar E, Karlsson T, Kellerth T, Svensson
L, et al. Aspects on the intensity and the relief of pain in the
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WA. Physician medical direction and clinical performance
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Nonthaburi: National Institute for Emergency Medicine; 2017
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APPENDIX
Check list for EMS quality evaluation by EMS medical director
Check list for evaluator
Conditions Inappropriate due to
OHCA Dispatch
☐ Dispatch BLS team
Airway
☐ No BVM and no supraglottic airway device and no intubation
☐ Intubation more than 2 attempts (Only for ALS team)
Circulation
☐ No IV access if scene time more than 5 minutes
(only for ALS team)
CPR
☐ No note of initial rhythm
☐ No debrillation if shockable rhythm
Others
☐ Response time > 8 minutes
☐ No prehospital notication
☐ No EKG monitoring (only for ALS team)
Alteration of consciousness Dispatch
☐ Dispatch BLS team if GCS < 8
Airway
☐ O
2
sat < 94% and no airway intervention or oxygen therapy
☐ Intubation more than 2 attempts (Only for ALS team)
Circulation
☐ No IV given if pulse > 120 or hypotension in suspected sepsis case
(Only for ALS team)
Others
☐ No POCT glucose
☐ No prehospital notication in suspected acute stroke
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Dyspnea Dispatch
☐ Dispatch BLS team
Airway
☐ O
2
sat < 94% and no airway intervention or oxygen therapy
☐ Intubation more than 2 attempts (Only for ALS team)
☐ No bronchodilator given in suspected exacerbation of COPD
or asthmatic attack
Circulation
☐ No IV given if pulse > 120 or hypotension in suspected sepsis
case (Only for ALS team)
Chest pain Dispatch
☐ Dispatch BLS team
Airway
☐ O
2
sat < 94% and no airway intervention or oxygen therapy
Others
☐ No EKG monitoring
☐ No hospital notication in suspected ACS
☐ No aspirin if suspected ACS and no contraindication
(Only for ALS team)
Weakness Dispatch
☐ Dispatch BLS team if unilateral weakness
Airway
☐ O
2
sat < 94% and no airway intervention or oxygen therapy
☐ Intubation more than 2 attempts (Only for ALS team)
Circulation
☐ No IV given if pulse > 120 or hypotension in suspected sepsis case
(Only for ALS team)
Others
☐ No POCT glucose
☐ No prehospital notication in suspected stroke
Seizure Dispatch
☐ Dispatch BLS team if unilateral weakness
Airway
☐ O
2
sat < 94% and no airway intervention or oxygen therapy
☐ Intubation more than 2 attempts (Only for ALS team)
Circulation
☐ No IV given if pulse > 120 or hypotension in suspected sepsis case
(Only for ALS team)
Others
☐ No POCT glucose
Other conditions Airway
☐ O
2
sat < 94% and no airway intervention or oxygen therapy
☐ Intubation more than 2 attempts (Only for ALS team)
Circulation
☐ No IV given if pulse > 120 or hypotension in suspected sepsis case
(Only for ALS team)
Others
☐ No POCT glucose in suspected stroke
☐ No prehospital notication in suspected stroke
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Trauma Dispatch
☐ Dispatch BLS team if GCS < 8 or hypotension
Airway with C-spine
☐ No cervical collar in blunt mechanism with GCS < 15 or hypotension
Breathing
☐ O
2
sat < 94% and no airway intervention or oxygen therapy
☐ No needle thoracostomy in tension pneumothorax
(only for ALS team)
☐ No three side dressing in open pneumothorax (only for ALS team)
Circulation
☐ No IV uid given in SBP < 70 mmHg (only for ALS team)
☐ Give IV and prolong scene time > 10 min
☐ No bleeding control if active bleeding
Immobilization
☐ No spinal board in blunt mechanism with GCS < 15 or hypotension
Others
☐ Scene time > 10 min
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Sairung Nuanin, B.Sc. (Med Tech)*, Panutsaya Tientadakul, M.D.*, Kanit Reesukumal, M.D.*, Sudarat Piyophirapong,
M.D.*, Gerald J. Kost, M.D., Ph.D.**, Busadee Pratumvinit, M.D.*
*Department of Clinical Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, ailand, **Point-of-Care Testing Center for
Teaching and Research (POCT.CTR™), School of Medicine, University of California - Davis, Sacramento, California, USA.
AutovericationImprovedProcessEfciency,
ReducedStaffWorkload,andEnhancedStaff
SatisfactionUsingaCriticalPathforResultValidation
ABSTRACT
Objective: Continuous process improvements enhance accuracy and productivity in a clinical laboratory setting.
is study aimed to investigate the accuracy and eciency of a new autoverication (AV) system designed to
improve the consistency and uniformity of reported laboratory test results.
Methods: Limit checks, delta checks, and consistency checks were established, and then retrospective data from
500 requested tests were used to evaluate the accuracy of AV rules compared to manual verication, which was
performed by ve experienced medical technologists. Eciency was evaluated by comparing turnaround time
(TAT), error rates, workload, and sta satisfaction between before and aer AV implementation.
Results: AV had 100% sensitivity, 77.6% specicity, and a 22% false-positive rate. e AV passing rate was 95%,
85%, 42%, and 39% for chemistry, coagulation, microscopy, and hematology, respectively. e overall passing
rate was 65%. Aer implementation, the mean overall TAT decreased from 54.2±26.6 to 52.4±24.2 min (p<0.001).
However, TAT during peak hours increased (p<0.05). Incident reports decreased 8-fold (p<0.05), net workload
decreased by 0.76 full-time equivalent, and overall sta satisfaction increased (p<0.001).
Conclusion: Our laboratory’s new AV system demonstrated an overall passing rate of 65% with decreases in TAT,
incident reports, and workload, and an increase in sta satisfaction.
Keywords: Autoverication; critical path; delta check; full-time equivalent; laboratory information system; turnaround
time (Siriraj Med J 2020; 72: 296-306)
Corresponding author: Busadee Pratumvinit
E-mail: busadee.pra@mahidol.ac.th
Received 23 March 2020 Revised 26 May 2020 Accepted 28 May 2020
ORCID ID: http://orcid.org/0000-0002-5220-0552
http://dx.doi.org/10.33192/Smj.2020.40
INTRODUCTION
Autoverication (AV) uses predetermined rules
to direct the release of laboratory results, and veries
results by computer without sta review.
1,2
Previous
studies reported that AV improved turnaround time
(TAT)
3-7
, reduced manpower requirements
4, 5
, decreased
error rates
7
, and enhanced physician satisfaction.
3
AV
algorithms usually include instrument status ag, quality
control (QC) checks, interference indices (hemolysis,
icterus, lipemia), critical values, limit checks, delta checks,
and consistency checks to lter unusual data.
8-10
According to Clinical and Laboratory Standards
Institute (CLSI) guideline
1
, the criteria included in AV
algorithms can be simple or complex comprising multiple
data elements and multiple-step dened Boolean logic
to validate clinical laboratory results. Computer-based
actions could include immediate verication of a result,
repeat analysis, reexive testing, addition of comments,
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Nuanin et al.
or manual steps, including manual review of the results.
1
Previous studies described the use of AV in some sections
or specic test groups of laboratories, including clinical
chemistry
2,7,8,11-13
, arterial blood gas
14
, thyroid function
4,6
, sex
hormones
4
, hepatitis B serological markers
15
, urinalysis
7,16
,
hematology
17-20
, and coagulation.
18, 21-24
Our laboratory experiences a 3-9% annual increase
in testing volume each year; however, the number of
personnel that perform manual result verication has
not increased. In response and in order to improve
operational eciency, we designed and implemented
the AV system proled in this report to improve TAT,
improve the consistency of result verication, and to
reduce the workload of sta in our laboratory. Here,
we present a detailed description of the implementation
of AV in clinical chemistry, microscopy, hematology,
and coagulation. is study is the rst to describe the
implementation of an AV system that simultaneously
incorporates multiple disciplines using a critical path
concept.
25,26
is study aimed to investigate the accuracy
of the AV rules, and the eciency of a new AV system
designed to improve the consistency and uniformity
of reported laboratory test results. We evaluated the
AV passing rate, and determined the impact of the AV
system on laboratory personnel. We also compared TAT,
requisition sheets per hour, laboratory sta survey, and
error rates between before and aer the implementation
of the AV system.
MATERIALS AND METHODS
Setting and ethics
is study was conducted at the central laboratory
of Siriraj Hospital, which is a 2,300-bed national tertiary
referral center located in Bangkok, ailand. is laboratory
provides clinical chemistry, microscopy, hematology,
and coagulation testing for both outpatient and inpatient
services. Our laboratory performs approximately 6 million
tests per year using a cobas 8000 (Roche Diagnostics,
Mannheim, Germany) for clinical chemistry, a UX-2000
(Sysmex Corporation, Kobe, Japan) for urinalysis, an
XN-3000 (Sysmex Corporation) for hematology, and
the CA-1500 & CS-2100i systems (Sysmex Corporation)
for coagulation analysis. e HCLAB system (Sysmex
Corporation) is the laboratory information system (LIS)
used in our laboratory. e protocol for this study was
approved by the Siriraj Institutional Review Board of the
Faculty of Medicine Siriraj Hospital, Mahidol University
(Si 331/2015 EC2).
Study design
Fig 1 shows the study protocol for the design and
implementation of our AV system. First, we dened
the scope of the AV system, including selection of team
members, tests, and tools. e tool used in this study
was our laboratory information system (LIS). We then
collected the information needed to set the AV rules,
aer which the rules were decided by consensus among
the study team members. Next, we collected eciency
data before implementation of AV, and set up rules in
the computer system. e accuracy of the AV rules was
assessed before implementation into clinical service. Aer
implementation, we collected eciency data, surveyed
laboratory sta, and calculated AV passing rate and
full-time equivalent reduction (FTE).
Test selection
We selected tests that are performed on automated
analytical systems and that are released automatically via
the LIS, including 86 parameters in clinical chemistry (71
plasma/serum/blood parameters, and 15 urine parameters,
1 test in microscopy (urinalysis), 2 tests in hematology
(complete blood count [CBC], and automated hematocrit
[Hct]), and 5 tests in coagulation (Table 1).
Development of the autoverication algorithm
Fig 2 shows the multicomponent critical path for
autoverication. e algorithm for the clinical chemistry
and coagulation tests was developed according to the
CLSI AUTO10-A guideline.
1
For clinical chemistry, the
cobas® 8000 Data Manager was used to check instrument
status ags, quality control (QC) results, and interference
indices. If there were instrument ags or tests that failed
QC, the test results would not be released. If interference
indices exceeded the threshold for respective tests, the
results would be released with comments to the LIS. For
coagulation, the results would be released directly to the
LIS.
Aer entering the AV system, the order of verication
was limit checks, delta checks, and consistency checks. If
the analytes had critical values, the critical values were used
as their limit checks. If the results failed the limit checks,
the delta checks were used. Delta checks compared the
current data with previous data from the same patient to
determine the dierences. If the dierences were within
the range of delta check acceptability, consistency checks
were followed. If the test results passed all of the above
checks, they were reported by the AV system. If the test
results failed any of the above checks, they were reported
by manual verication (MV).
Criteria for hematology (complete blood count) and
microscopy (urinalysis) tests derived from our previous
studies were set in middleware before entering the LIS.
27,28
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Fig 1. Flow diagram describing the study protocol for the design and implementation of the autoverication system (AV).
Abbreviations: AV, autoverication; HIS, hospital information system; MV, manual verication; TAT, turnaround time
Development of AV rules
Hematology tests
For complete blood count analysis, the rst time test
results were held in the presence of hemoglobin <7 or >19
g/dL, mean corpuscular volume <70 or >110 fL, red cell
distribution width >22%, white blood cell (WBC) <1,500
or >30,000/μL, platelet <100,000/μL or >600,000/μL, no
dierential of WBC, absolute neutrophil counts <500/μL
or >25,000/μL, absolute lymphocyte counts >7,000/μL,
absolute monocyte counts >3,000/μL, absolute eosinophil
counts >2,000/μL, absolute basophil counts >500/μL,
absolute reticulocyte count >250/μL, or suspect ags.
27
In repeated samples, criteria included WBC <1,500 or
>30,000/μL and delta WBC ≥10,000/μL within 3 days,
platelet <100,000/μL and delta platelet >20,000/μL, and
the presence of suspect ags. All automated hematocrit
results were released by autoverication.
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Nuanin et al.
Plasma/serum/bloodinclinicalchemistry
25-hydroxyvitamin D Follicle stimulating hormone Placental growth factor
Alanine aminotransferase* Free calcium Potassium*
Albumin* Free thyroxine Potential of hydrogen (pH)
Alkaline phosphatase* Free triiodothyronine Prealbumin
Alpha-1 antitrypsin Gamma-glutamyltransferase Procalcitonin
Ammonia Glucose* Progesterone
Amylase Haptoglobin Prolactin
Anion gap Hemoglobin A1c* Sodium*
Aspartate aminotransferase* High-density lipoprotein cholesterol* Soluble fms-like tyrosine kinase-1
Beta-crosslaps High-sensitivity C-reactive protein Testosterone
Bicarbonate* Insulin Thyroid stimulating hormone
Carboxyhemoglobin Lactate Thyroxine
Ceruloplasmin Lactate dehydrogenase Total bilirubin*
Chloride* Lipase Total calcium
Cholesterol* Low-density lipoprotein cholesterol* Total procollagen type 1 amino-
terminal propeptide
Cortisol Luteinizing hormone Total protein*
C-reactive protein Magnesium Transferrin
Creatine kinase Methemoglobin Triglyceride*
Creatine kinase-MB (mass) N-mid osteocalcin Triiodothyronine
Creatinine* N-terminal pro-brain natriuretic peptide Troponin-T (high-sensitivity)
Direct bilirubin* Parathyroid hormone Urea nitrogen*
Estradiol Partial pressure of CO2 (pCO2) Uric acid*
Ferritin Partial pressure of O2 (pO2) Vitamin B12
Folate Phosphorus
Urineinclinicalchemistry
Albumin Creatinine Protein
Albumin/creatinine Glucose Protein/creatinine
Amylase Magnesium Sodium
Calcium Phosphorus Urea nitrogen
Chloride Potassium Uric
Coagulationtests
Activated partial thromboplastin time* Fibrinogen* Prothrombin time*
D-dimer International normalized ratio*
TABLE 1. List of tests in the autoverication system for clinical chemistry and coagulation.
*candidate tests incorporated during the trial of the autoverication system
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Microscopy tests
For urinalysis, the results were held in the presence
of red blood cells (RBC) >28.1/μL with negative blood
tests from chemical strip, RBC 17-59/μL with positive
blood tests, RBC >300/μL regardless the blood test results,
WBC 50-120/μL, epithelial cells 56-120/μL, small round
cells >10/μL, hyaline casts >3/μL, pathological casts >1.5/
μL, crystals >10/μL, yeast like cells, sperms >3/μL, or
ags.
Clinical chemistry and coagulation tests
The AV rules used in clinical chemistry and
coagulation tests included limit checks, delta checks,
and consistency checks. All D-dimer results were released
by autoverication. e methods for developing the AV
rules were, as follows:
1. Limit checks
Limit checks were developed using dierent methods,
as follows:
1.1 Critical values
Critical values are potentially life-threatening
laboratory results that require immediate medical
attention. e critical values were derived from the
literature
29,30
and discussed with clinicians. e analytes
for which critical values were used as a limit check were
free calcium, glucose, pCO
2
, pO
2
, potassium, pH, sodium,
and troponin-T (high-sensitivity).
1.2 Other sources
We used dierent sources to employ limit checks.
Limit checks were derived from a distribution interval
of patient data between the 2.5
th
and 97.5
th
percentiles
(modied from a previous study)
12
, a near-midpoint
between the median reference range value and the analyzer’s
linear analytical measurement limits
7
, and the analytical
measurement limits.
2. Delta checks
Delta check can be used to identify cases of patient
specimen misidentication, specimen integrity issues,
and analytical issues.
31
Our laboratory used this formula
to calculate delta check:
Delta check (%) = [(current result-previous result)/
previous result] *100
e acceptability limit of delta checks in this study
was obtained from:
2.1 Reference change value (RCV)
RCV denotes the amount of change that would
Fig 2. Flow diagram describing the critical path for autoverication (AV). Clinical chemistry tests were checked by middleware before
entering the AV system established in the laboratory information system (LIS). Coagulation tests entered the AV system directly. AV rules
were set in middleware for hematology and microscopy tests. For optimized criteria for smear review in rst-time samples and microscopic
review, please refer to the manuscript text.
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Nuanin et al.
indicate a signicant dierence between two sequential
results. e simplied formula for RCV calculation
includes variations associated with analytical variation
and intra-individual biological variation, as follows:
Reference change value (RCV) = 2
1/2
*Z*(CV
A
2
+CV
I
2
)
1/2
(Z = Z score, CV
A
= analytical variation, CV
I
=
intra-individual biological variation). In this study, a
bidirectional Z-score was used (1.96 for a 95% probability),
CV
A
was derived from analytical variation during a
1-month period in our laboratory, and CV
I
was obtained
from the literature.
32
2.2 Other sources
We applied delta checks from previous
autoverication study
2
, textbook
30
, and delta check rules
from another institute (Swedish Covenant Hospital,
courtesy of Susan Dawson). e duration of delta checks
was 120 days.
3. Consistency checks
The consistency checks were, as follows: (a) If
triglyceride was above 800 mg/dL (9 mmol/L) and sodium
was simultaneously requested, results would be held.
Sodium would be analyzed by direct ISE method instead
of indirect ISE method; (b) Direct bilirubin was more
than total bilirubin; (c) Albumin was more than total
protein; (d) T3 or FT3 or T4 or FT4 was more than the
upper limit check for each test, but TSH was not less than
the lower limit of the reference interval; and, (e) T3 or
FT3 or T4 or FT4 was less than the lower limit check for
each test, but TSH was not more than the upper limit of
the reference interval.
Implementation
Initially, limit checks, delta checks, and consistency
checks were applied to 24 candidate tests to test the
system and detect errors in AV settings (Table 1). We
then applied them to clinical chemistry and coagulation
tests without releasing the results to physicians. Results
that passed all AV rules would be labelled as auto-released,
and then they were subjected to MV before delivery to
clinicians. Results were checked retrospectively to detect
discrepancies and errors using simulation program. When
no errors occurred, we started to release the results to
clinicians without MV.
Accuracy of the AV rules
Before implementing AV into clinical service, we
validated the accuracy of AV rules and algorithms by
comparing 500 patient reports between AV using simulation
and MV by 5 experienced medical technologists (MT).
If the verication results were not in agreement with
at least 4 of the 5 MT, the decision would be made by
consensus among 4 clinical pathologists. If AV rules
were triggered and the results were held by MV, the
report was graded as true-positive [TP]. If the report
was released by both AV rules and MV, it was graded
as true-negative [TN]. False-positive [FP] was dened
as a report unvalidated by AV, but that was released
by MV, and false-negative [FN] was graded as a report
validated by AV, but that was held by MV.
33
Accuracy
was dened as [TP + TN]*100/[all results].
Eciency of the AV system
AV passing rates were obtained from each discipline
and per requisition sheet using data from 24 h of 5 working
days. Laboratory turnaround time (TAT) was dened as
the time from specimen receipt to result reporting. We
obtained laboratory TAT per hour for 20 days before
and 20 days aer implementation of the AV system.
Error rates were gathered from non-conformities (NC),
occurrence reports, and customer complaints during 1
month of each period.
A decrease in full-time equivalent (FTE) was
calculated using the following formula: Decrease in
FTE = (productive minutes/total work minutes) * the
overall AV passing proportion per requisition sheet.
Productive minutes = MV time per day (minutes)*
number of requisition sheets per day * 365 days.
MV time was obtained from the average time for
MV in triplicate among 13 experienced MT. e total
work minutes in our laboratory was calculated to be
96,600 minutes per year.
e questionnaire that we used in this study to
determine laboratory staff satisfaction comprised 5
questions that were scored 1 to 10, as follows: (a) How
would you describe your workload? (b) How much
condence do you have when reporting laboratory test
results? (c) How many incident reports do you think
the laboratory receives, either verbal communication or
written document? (d) Describe your level of satisfaction
with the speed with which laboratory results are reported.
(e) What is your overall level of satisfaction with the
laboratory reporting system?
Statistical analysis
AV passing rates from each discipline were compared
using Pearson’s chi-square test. Unpaired t-test was used
to compare mean laboratory TAT each hour from 20
days before and 20 days aer the implementation of AV.
Mann-Whitney U test was used to compare the total
number of requisition sheets per hour from 20 days
before and 20 days aer the implementation of the AV
system, and TAT for only AV results versus manually
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veried results aer the implementation of AV. Error
rates were compared using Fisher’s exact test. Data from
the survey of laboratory sta were compared using paired
t-test. Statistical analyses were performed using PASW
Statistics version 18.0 (SPSS, Inc., Chicago, IL, USA). A
p-value of <0.05 was considered statistically signicant.
RESULTS
Accuracy of autoverication rules
Using the data from a collection of 500 retrospective
laboratory test requests, the TP rate was 76.4% (382/500),
the TN rate was 1.6% (8/500), the FP rate was 22%
(110/500), and the FN rate was 0% (0/500). e accuracy
of AV rules was 78% (390/500), the diagnostic sensitivity
was 100% (8/8), and the specicity was 77.6% (382/492).
Eciency of the AV system
1. AV passing rate
To study the AV passing rate, 123,957 test results
derived from 13,342 requisition sheets were collected
from 5 working days. e highest AV passing rate was
found in clinical chemistry at 95% (95% condence
interval [CI]: 94.9-95.1%), whereas the lowest AV passing
rate was found in hematology at 39% (95% CI: 37.8-
40.0, p<0.001). e AV passing rates in microscopy
and coagulation were 42% (95% CI: 40.3-43.7) and
85% (95% CI: 83.7-86.2), respectively. e overall AV
passing proportion per requisition sheet was 65% (95%
CI: 64.2-65.8) (Fig 3).
2. Turnaround time (TAT)
Mean ± standard deviation (SD) laboratory TAT
was reduced by 1.8 minutes (54.2±26.6 vs. 52.4±24.2
minutes, p<0.001) between 20 days before (n=63,813)
and 20 days aer (n=68,947) implementation of the
AV system. e mean TAT aer implementation of
AV was signicantly lower than the mean TAT before
AV implementation at the 1
st
(p=0.03), 4
th
(p=0.002),
6
th
(p<0.001), 10
th
(p=0.001), 11
th
-21
st
(p<0.001), and
24
th
(p=0.004) hours. In contrast, the mean TAT before
implementation was signicantly lower than the mean
TAT aer implementation of AV at the 8
th
(59.4 vs. 61.9
minutes, p<0.001) and 9
th
(58.9 vs. 60.0 minutes, p=0.004)
hours (Fig 4). e total number of requisition sheets per
hour from 20 days was not dierent between before and
aer implementation of the AV process (n=24 hours,
median = 2,014 vs. 2,151 sheets, p=0.789).
3. Error rates
Before implementation of the AV system, errors
were found in 7 test results of 848,377 tests per month
(0.0008%). Aer the implementation of AV, errors were
detected in 1 of 870,511 tests per month (0.0001%)
(p=0.037).
4. Impact of AV on laboratory sta
e average time for MV in triplicate by 13 MT was
6.98 seconds per 1 requisition sheet. e average number
of requisition sheets per day (n=5 days, the same period
we used to determine the AV passing rate) was 2,669
sheets/day. erefore, the mean total time for MV was
310 minutes per day. e productive time (minutes)
= 310 mins * 365 days. Aer the implementation of
AV, the AV passing rate was 65%, which translates to
a reduction of 0.76 FTE medical technician personnel
needed for result verication.
5. Laboratory sta survey
From the perspective of laboratory sta (n=43),
mean±SD score for workload was reduced from 83±18%
to 52±21% (p<0.001). e condence to report laboratory
results was not dierent between before and aer AV
implementation (p=0.234). From a sta point of view,
incident reports decreased about 9% (p=0.045), and
the speed of the reporting of results improved by 31%
(p<0.001). Overall sta satisfaction increased from 65±17%
to 89±11% aer the implementation of AV (p<0.001)
(Fig 5).
DISCUSSION
e accuracy of AV rules and algorithms was 78%
when compared to MV. e FP rate was 22%, and the
FN rate was 0%. e sensitivity and specicity were
100% and 77.6%, respectively. Fuentes-Arderiu, et al.
compared the Validation Assistée aux Laboratoires
d'Analyses Biologiques (VALAB) Expert System to MV
by nine clinical biochemists among 500 clinical laboratory
reports. ey found the diagnostic sensitivity of the
VALAB Expert System to be 100%, and the diagnostic
specicity was 95.7%.
11
Our study had lower specicity
because we used thresholds of limit checks at 2.5
th
and
97.5
th
percentile of cumulative patient data so about 5%
of results would be held by AV. We plan to decrease
false-positive alerts through adjusting thresholds, and
by modifying non-specic rules.
Our overall passing rate, which included several
disciplines in the critical path, was 65%. For clinical
chemistry, the AV passing rate was 95% compared to
84.8% in the study by Fuentes-Arderiu, et al.
11
Krasowski,
et al. reported an increase in the passing rate for clinical
chemistry from 40% in 2000 using the rudimentary rules
set in the LIS to 99% in 2010 aer the implementation of
sophisticated rules in middleware
2
. For microscopy, the
AV passing rate in this study was 42%, which is nearly
the same as the 43% rate reported by Torke, et al.
7
, and the
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Nuanin et al.
Fig 3. Autoverication (AV) passing rates (95% condence interval). AV passing rates for chemistry, coagulation, microscopy, and hematology
obtained from 5 working days (*p<0.05, **p<0.001).
Fig 4. Turnaround time (TAT) before and aer the implementation of autoverication (AV). Mean hourly TAT compared between 63,813
requisition sheets obtained during 20 days before and 68,947 requisition sheets obtained during 20 days aer the implementation of AV
(*p<0.05).
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Fig 5. Laboratory sta survey. Mean ± standard deviation percentage of survey items (n=43) compared between before and aer the
implementation of the autoverication system (*p<0.05, **p<0.001).
47.6% rate reported by Palmieri, et al.
16
For hematology,
the passing rate in this study was 39%. Martinez-Niteo,
et al.
17
found a passing rate of 53.4% in pilot study, with
a subsequent increase to 60% 18 months later – both
of which were very high compared to our result. For
coagulation, our passing rate was 85%, which is similar
to the 82% result reported by Zhao, et al.
21
Our study found that the overall TAT decreased
from 54.2 to 52.4 minutes (3.3%) aer the implementation
of AV. However, the TAT during the peak hours (8
th
and 9
th
hours) was signicantly increased. A possible
explanation for this increase may be insucient capacity
of the computer server to manage the increased number
of processing requests during the peak period. A previous
study from a large, urban, tertiary acute care public hospital
and trauma center showed that the TAT, calculated from
time of specimen received to result released, was reduced
by 22% (142 min vs. 112 min) aer the implementation
of AV.
7
However, the baseline TAT in our laboratory was
about half of the baseline TAT in that study; therefore,
the percent reduction might not be comparable.
e error rate in our study decreased from 0.0008%
to 0.0001%. Previous study from John H. Stroger, Jr.
Hospital of Cook County (JHSHCC) showed that error
rates decreased from 0.06% to 0.009%.
7
We found that
aer implementation of AV, the number of laboratory
sta needed for MV was reduced by 0.76 FTE. e study
from JHSHCC found a much more dramatic reduction
from 14 FTEs to 8.5 FTEs (a reduction of 40%) aer
implementation of AV.
7
Our laboratory had a lower
reduction of FTE because criteria for manual review
of complete blood count and urinalysis were already in
place before the implementation of AV in all disciplines.
Aer implementation of the AV system in our central
laboratory, laboratory sta found the amount of workload
and defects to be decreased, and the speed of test result
reporting and overall satisfaction to be increased.
Although the AV system implemented at our center
has many advantages, it also has some limitations. e
soware that our laboratory used to design our system
was not specifically designed to build the rules and
algorithms for the AV system. Soware used to build AV
rules and algorithms according to CLSI guideline should
have the ability to use multiple data, to make changes to
algorithms, and to provide an easy to use and exible user
interface that provides laboratory dened information
in real time.
1
In some contrast, we were limited in our
ability to set rules due to the functional limitations of
our soware. Moreover, large volume trac during peak
hours caused processing delays, which resulted in delays
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Nuanin et al.
in the reporting of results. Lastly, our soware does not
currently have a feature that facilitates comparison of
result verication time between AV and MV.
CONCLUSION
Our new AV system demonstrated high sensitivity
for error detection. e overall AV passing proportion
per requisition sheet was 65%. is passing rate is similar
to previous studies in clinical chemistry, microscopy, and
coagulation tests. TAT time improved aer implementation
of the AV system, except during peak hours (8
th
and 9
th
hours), and this was likely due to a high trac-related
CPU slowdown. Overall sta satisfaction increased,
and incident reports and workload decreased aer the
implementation of AV.
AV has many advantages relative to the reporting
of test results; however, MV is still necessary to verify
results aer they fail AV. e improved eciency of AV
allows sta to spend more time on result verication.
We will continue to evaluate rules to decrease false-
positive alerts by modifying non-specic rules, and by
addressing rules that triggered alerts that had no further
action. If implemented broadly, this approach could
enhance laboratory understanding and performance
via successive critical path improvements.
ACKNOWLEDGMENTS
e authors gratefully acknowledge Sysmex (ailand)
Co., Ltd (especially itiyaporn Wanpiyarat), MED-ONE
Co., Ltd. (especially Surasit Techakasiwattana), Roche
Diagnostics (ailand) Co., Ltd., and Chatri Lerdmanee
of the Siriraj Information Technology Department for
providing data and/or establishing rules and algorithms
for our laboratory information system. We would also like
to thank Sorawit Kinko and Tanita aweethamcharoen
for assistance with the full-time equivalent analysis, and
Miss Julaporn Pooliam for assistance with statistical
analysis.
Authors’ contributions
All authors contributed suciently to this study
to be included as an author. All authors have read and
approved the nal version of this manuscript, and all
authors are in agreement with the decision to submit
this manuscript for journal publication.
Funding disclosure
PT, KR, SP, and BP each received a Chalermprakiat
Grant from the Faculty of Medicine Siriraj Hospital,
Mahidol University, Bangkok, ailand. e funding
organization played no role in the study design; in the
collection, analysis, and interpretation of data; in the
writing of the report; or, in the decision to submit this
report for publication.
Conict of interest declaration
All authors declare no personal or professional
conicts of interest, and no nancial support from the
companies that produce and/or distribute the drugs,
devices, or materials described in this report.
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307
irapath Chatlaong, M.D., Jarurin Pitanupong, M.D., Pakawat Wiwattanaworaset, M.D.
Department of Psychiatry, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla 90110, ailand.
SleepQualityandBurnoutSyndromeamong
ResidentsinTrainingattheFacultyofMedicine,
PrinceofSongklaUniversity
ABSTRACT
Objective: To assess sleep quality, burnout syndrome and associated factors among residents in training.
Methods: A cross-sectional study surveyed all residents in training at the Faculty of Medicine, Prince of Songkla
University; from August to October, 2019. e questionnaires were composed of 3 parts: 1) Personal and demographic
inquiry 2) e Pittsburgh Sleep Quality Index (PSQI), ai version 3) e Maslach Burnout Inventory (MBI), ai
version. All data were analyzed using descriptive statistics, and the results were showed as average, percentage,
frequency, and standard deviation. Associated factors of sleep quality were analyzed by chi-square and logistic
regression.
Results: ere were 217 respondents. e majority of residents were female (57.1%), with a mean age of; 26.8±1.6
years. e participants reported their mean working hours, per week, as 67.8±28.5, and 78.3% of them had poor
sleep quality. e problematic sleep subscales were subjective sleep quality, sleep duration, and daytime dysfunction.
In addition, the disturbed factors for sleep quality were sleep disruption while being on call at 02.00-04.00am,
temperature and noise in the bedroom while being on duty. e prevalence of burnout syndrome among residents
was 95.4%, with the highest score revealed to be emotional exhaustion. Logistic regression showed that the associated
factors of sleep quality were environmental problems in the bedroom while being on duty and emotional exhaustion.
Conclusion: Most residents had poor sleep quality; with associated factors of sleep quality being environmental
problems in the bedroom and burnout syndrome.
Keywords: Resident; sleep quality; burnout syndrome (Siriraj Med J 2020; 72: 307-314)
Corresponding author: Jarurin Pitanupong
E-mail: pjarurin@medicine.psu.ac.th
Received 23 July 2019 Revised 5 January 2020 Accepted 18 February2020
ORCID ID: http://orcid.org/0000-0001-9312-9775
http://dx.doi.org/10.33192/Smj.2020.41
INTRODUCTION
e number of doctors is proportionally much less
in comparison to the population unit, as listed by the
Ministry of Public Health. In 2018, data from the Ministry
of Public Health showed that the ratio between medical
personnel per population unit was 1:1,843. en some
doctors are required to practice for extended working
hours, which may have negative effects on sleeping
hours and quality; possibly leading to other undesired
consequences, including medical errors
1
, car accidents
2
,
job burnout
3
and depression.
1
Residents are doctors who have graduated from
their medical studies, and are attending specialization
practices. During such specialization practices, residents
are oen subjected to high stress periods.
4,5
ese stress
factors include extended working hours and a high level
of responsibility, with limited ability over the control of
their working environment.
6
Chatlaong et al.
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In the past, many studies have been conducted abroad
on the sleep quality of residents. e prior studies found
that most residents experienced sleep problems, which
in turn aected their decision-making ability, medical
procedures, increased the risks of car accidents
2
as well
as job burnout.
3
In ailand, there has been no study conducted
on the eects of poor sleep quality among doctors and
residents. ere were only two studies surveyed the eect
of sleep problems and job eciency among nurses.
7,8
However, a previous study was conducted on job burnout
syndrome among medical doctors and residents, in the
Regional Health District, that found the high prevalence
of burnout syndrome (99.6%). Moreover, the related
factors to emotional exhaustion were daily work hours,
awareness of stress from work and awareness of a lack of
sleep.
9
Furthermore, another previous study conducted
at Songklanakarin Hospital found the prevalence of
burnout syndrome among 244 residents was 100.0%,
and the related factors to emotional exhaustion were
daily work hours and the awareness of a lack of sleep.
10
As mentioned before, sleep disturbance or poor sleep
quality is associated to burnout syndrome. However,
there are currently few studies that explore the sleep
quality, and associated factors of sleep disturbance among
residents in training at Prince of Songkla University.
erefore, the objective of this survey was to determine
sleep quality and associated factors, so as to enhance
the focus of these sleep problems, including burnout
syndrome among residents.
Denition
Sleep quality is divided into two types; good sleep quality
is having e Pittsburgh Sleep Quality Index (PSQI)
score ≤ 5 and poor sleep quality is having e Pittsburgh
Sleep Quality Index (PSQI) score > 5.
Burnout syndrome, according e Maslach Burnout
Inventory (MBI) questionnaire, comprises of 3 parts 1)
emotional exhaustion 2) de-personalization 3) reduced
occupational accomplishment.
Major ward includes internal medicine, surgery, obstetrics
and gynecology, orthopedic surgery and physical medicine,
and pediatrics.
Minor ward includes anesthesiology, emergency,
otolaryngology head and neck surgery, ophthalmology,
radiology, family medicine and preventive medicine,
and psychiatry.
MATERIALS AND METHODS
e Ethics Committee of the Faculty of Medicine,
Prince of Songkla University approved this study (REC:
62-072-03-4). e study explored all residents that were
in training at the Faculty of Medicine, Prince of Songkla
University; from August to October, 2019. e inclusion
criterions were being a resident and able to complete all
of the questionnaires. Exclusion criterion was residents
on a leave of absence.
Methodology
e residents were approached by a researcher in
their classes beforehand. ey were invited to participate,
by introducing the rationale and given an overview on
the information contained of the research. In cases of
those who cooperated, the researcher distributed 3 self-
reporting questionnaires; these were explained to the
participants in detail. e participants were permitted to
take a few minutes to deliberate whether or not to join
the survey. So as to assure the participants’ identities
would be protected signatures of participants were not
desired, and all participants had the right to withdraw
from the study at any time.
All participants were allowed to nish, and return
the questionnaires immediately or at a later time. ey
could submit the questionnaires via two options: drop it
in the case at the front of the classroom, or return it and
place it in the case located at the Psychiatry Department.
erefore, protecting respondent condentiality was
retained.
Instruments
e questionnaires consisted of 3 parts:
1) Personal and general demographic information
comprising of: gender, age, training year, religion, income,
marriage status, caeine or alcohol drinking, substance
usage, underlying diseases and working information.
11-13
2) e Pittsburgh Sleep Quality Index (PSQI) ai version.
e PSQI is a self-rated questionnaire that evaluates
sleep quality, and disturbances within a month time
interval. Nineteen dimensions originate seven components:
subjective sleep quality, sleep duration, sleep latency,
sleep disturbances, habitual sleep eciency, use of sleep
medication and daytime dysfunction. Each component
score ranges from 0 to 3 points. A score of “0” represents
no diculty, whilst a score of “3” represents severe
diculty. e seven component scores are collected
to yield one “global” score, with a range from 0 to 21
points, total score >5 that means poor sleep quality.
11
3) e Maslach Burnout Inventory (MBI) ai version.
is questionnaire comprised of 3 parts:
1) Emotional exhaustion (EE) subscale, Cronbach’s alpha
coecient=0.9: never (score=0) to every day (score=6)
2) Depersonalization (DP) subscale, Cronbach’s alpha
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309
coecient=0.7: never (score=0) to every day (score=6)
3) Personal accomplishment (PA) subscale, Cronbach’s
alpha coecient=0.7): every day (score=0) to never
(score=6)
14-16
Statistical analysis
All data were analyzed, in order to describe the
participants’ behavior using descriptive statistics. e
results are showed as: average, percentage, frequency, and
standard deviation. e associated factors of sleep quality
were analyzed using chi-square and logistic regression.
RESULTS
Demographic data
During August to October, 2019, residents that
completed the questionnaires was 217 of 341; the response
rate was 63.6%. Of the participants, 124 were female
(57.1%) and 202 were unmarried (93.1%). Mean age
was 26.8±1.6 years and the median income (IQR) was
35,000 (30,000-40,000) baht, per month. In addition,
168 participants drank coffee or tea (77.4%), 30 of
them were drinkers (13.8%), and only 9 of them used
sedative medication (4.1%), such as benzodiazepines or
chlorpheniramine. Moreover, the majority of participants
had no psychiatric disorders (93.5%); however, 44 of
them had minor physical illness (20.3%), such as allergy,
dyspepsia or migraine. (Table 1) In their eld of work,
the participants reported the mean working hours per
week was 67.8±28.5.
Sleep data and quality
e majority of participants had poor sleep quality
(78.3%). e mean Global PSQI score was 7.1±2.4. Among
the sleep quality subscales, this study found sleep duration,
subjective sleep quality, and daytime dysfunction were
the problematic sleep subscale. (Table 2)
Among the participants, they reported the disturbed
time period of sleep while being on call that aected or
inuenced sleep quality, was 02.00-04.00 am and 00.00-
02.00 am (43.8% and 22.1%, respectively). (Table 3) In
addition, the majority determinants disturbing sleep
quality were environmental factors in the bedroom while
being on duty, such as temperature and noise (70.5%
and 64.5%, respectively). (Table 4)
Burnout syndrome
According to this survey, the prevalence of burnout
syndrome (BS) among residents was 95.4%, and 56.2%
of participants had a high level of EE, whereas 94.0% of
them had a high level of PA. e mean score of EE, DP
and PA were 26.9±13.1, 8.5±7.0, 15.8±10.2, respectively.
(Table 5)
e association between demographic characteristics,
burnout syndrome and sleep quality
Variables whose p-values from the univariate analysis
were lower than 0.2 were included in the chi-square test.
(Tables 1, 3, 5) From the multivariate analysis, emotional
exhaustion and environmental problems in the bedroom
were statistically signicant associated factors related to
sleep quality. (Table 6)
DISCUSSION
is survey showed the prevalence of poor sleep
quality among residents was 78.3%, this rate was lower
than the ndings among nurses in ailand.
8
However,
this rate was higher than the ndings in other countries
that found 54.3% of residents had poor sleep quality.
17
According to work dysfunction, from poor sleep quality,
the previous study reported the level of vigilance tasks
among medical nurses during a night-shi work period
was lower than other periods.
7
Among daytime work
ecacy, this study concurred with the previous study, in
that daytime dysfunction was subscale from poor sleep
quality.
In addition, the prevalence of burnout syndrome
among residents (95.4%) was agreeable to the previous
study, which found that residents in training at the Faculty
of Medicine, Prince of Songkla University had a high
level of EE.
8
From this useful information, the Faculty
of medicine should be aware of health-cover providers
work-loads and work-hour estimations, as they may be
signicant keys for quality of life, for both residents, and
inevitably ai patients. Additionally, it will be useful for
promoting residency health, and enhancing preventive
programs for dropout risk among residents.
According to the associated factors of sleep quality, this
study found the amount of working hours, environmental
problems in the bedroom while being on duty, emotional
exhaustion or burnout syndrome were signicantly
associated with poor sleep quality. Furthermore, most
residents worked more than 55 hours per week, these
prolonged working hours or exhaustion, caused by this
burden, may aect their sleep quality. As a previous
study found, working more than 55 hours per week was
related to abnormal sleep latency, sleep duration and
habitual sleep eciency.
18
In addition, prolonged daytime
work may produce stress, job burnout,
16,19
emotional
exhaustion
13,20
and poor sleep quality; as demonstrated
by a previous study conducted in India.
3
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TABLE 1. Association between general characteristics and sleep quality (n=217).
Number(%)
Chi2
Demographiccharacteristics Goodsleep Poorsleep Total
P-value
(n=47) (n=170) (n=217)
Gender 0.03
Male 27 (57.4) 65 (38.2) 92 (42.4)
Female 20 (42.6) 104 (61.2) 124 (57.1)
Not answered 0 (0.0) 1 (0.6) 1 (0.5)
Marriagestatus 0.01
a
Single 40 (85.1) 162 (95.3) 202 (93.1)
Couple 7 (14.9) 7 (4.1) 14 (6.5)
Not answered 0 (0.0) 1 (0.6) 1 (0.5)
Academictraining 0.55
1
st
17 (36.2) 51 (30.0) 68 (31.3)
2
nd
15 (31.9) 61 (35.9) 76 (35.0)
3
rd
12 (25.5) 34 (20.0) 46 (21.2)
4
th
3 (6.4) 20 (11.8) 23 (10.6)
Not answered 0 (0.0) 4 (2.3) 4 (1.8)
Coffeeorteadrinking(within1month) 0.12
Yes 32 (68.1) 136 (80.0) 168 (77.4)
No 15 (31.9) 34 (20.0) 49 (22.6)
Alcoholdrinking(within1month) 0.63
Yes 5 (10.6) 25 (14.7) 30 (13.8)
No 42 (89.4) 145 (85.3) 187 (86.2)
Substanceusage(within1month) 1
a
Yes (cigarette) 0 (0.0) 1 (0.6) 1 (0.5)
No 46 (97.9) 169 (99.4) 215 (99.1)
Not answered 1 (2.1) 0 (0.0) 1 (0.5)
Medicationforsedation(within1month) 1
a
Yes 2 (4.3) 7 (4.1) 9 (4.1)
No 45 (95.7) 163 (95.9) 208 (95.9)
Physical illness 0.21
Yes 6 (12.8) 38 (22.4) 44 (20.3)
No 41 (87.2) 132 (77.6) 173 (79.7)
Psychiatric illness 0.21
a
Yes 0 (0.0) 8 (4.7) 8 (3.7)
No 45 (95.7) 158 (92.9) 203 (93.5)
Not answered 2 (4.3) 4 (2.3) 6 (2.8)
a
Fisher’s exact test
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TABLE 2. e Pittsburgh Sleep Quality Index (PSQI) subscales (n=217).
TABLE 3. Association between working information and sleep quality (n=217).
PSQI subscales Mean ± S.D. (Min-Max)
Subjective sleep quality 1.4±0.7 (0-3)
Sleep latency 0.7±0.8 (0-3)
Sleep duration 2.1±0.2 (2-3)
HabitualSleepefcacy 0.3±0.7(0-3)
Sleep disturbance 0.8±0.5 (0-3)
Use of sleeping medication 0.1±0.5 (0-3)
Daytime Sleep dysfunction 1.8±0.9 (0-3)
Mean ± S.D. (Min-Max) 7.1±2.4 (0-15)
Number(%)
Workinginformation Goodsleep Poorsleep Total
Chi2
(n=47) (n=170) (n=217)
P-value
Department 0.59
Major ward 23 (48.9) 93 (54.7) 116 (53.5)
Minor ward 24 (51.1) 77 (45.3) 101 (46.5)
Amountofworkinghour/week 0.02
≤40 12(25.5) 26(15.3) 38(17.6)
41-55 10 (21.3) 19 (11.2) 29 (13.4)
>55 24 (51.1) 124 (72.9) 148 (68.2)
Not answered 1 (2.1) 1 (0.6) 2 (0.9)
Period of sleep cycle disruption 0.75
22.00-00.00 pm 7 (17.5) 20 (12.4) 27 (12.5)
00.00-02.00 am 10 (25.0) 38 (23.6) 48 (22.1)
02.00-04.00 am 16 (40.0) 79 (49.1) 95 (43.8)
04.00-06.00 am 5 (12.5) 22 (13.7) 27 (12.4)
Not answered 2 (5.0) 2 (1.2) 4 (1.8)
Environmentalproblemsinthebedroom <0.01
whilebeingonduty
Not disturb 14 (30.4) 21 (12.4) 35 (42.8)
Disturb 32 (69.6) 148 (87.6) 180 (157.2)
Note: ere were missing values for some variables.
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TABLE 4. Disturbing environmental factors in the bed room while being on duty (n=217).
TABLE 5. Burnout syndrome (n=217).
Disturbingenvironmentalfactors Disturb Notdisturb Notanswered
Bright light 105 (48.4) 107 (49.3) 5 (2.3)
Noise 140 (64.5) 75 (34.6) 2 (0.9)
Temperature 153 (70.5) 59 (27.2) 5 (2.3)
Inconvenience of bedding 118 (54.4) 91 (41.9) 8 (3.7)
Smell 115 (53.0) 93 (42.9) 9 (4.1)
Number(%)
Chi2
Burnout subscale Good sleep Poor sleep Total
P-value
(n=47) (n=170) (n=217)
Emotionalexhaustion < 0.001
Low (0-16) 15 (31.9) 23 (13.5) 38 (17.5)
Moderate (17-26) 13 (27.6) 34 (20.0) 47 (21.7)
High (≥27) 14 (29.8) 108 (63.5) 122 (56.2)
Not answered 5 (10.6) 5 (2.9) 10 (4.6)
Mean ± S.D. (Min-Max) 26.9±13.1 (0-51)
Depersonalization subscale 0.16
Low (0-6) 24 (51.1) 71 (41.8) 95 (43.8)
Moderate (7-12) 10 (21.3) 39 (22.9) 49 (22.6)
High (≥13) 8 (17.0) 55 (32.4) 63 (29.0)
Not answered 5 (10.6) 5 (2.9) 10 (4.6)
Mean ± S.D. (Min-Max) 8.5±7.0 (0-30)
Personalaccomplishment 0.04
a
Low (≥39) 2 (4.3) 0 (0.0) 2 (0.9)
Moderate (32-38) 0 (0.0) 1 (0.6) 1 (0.5)
High (0-31) 40 (85.1) 164 (96.5) 204 (94.0)
Not answered 5 (10.6) 5 (2.9) 10 (4.6)
Mean ± S.D. (Min-Max) 15.8±10.2 (0-48)
a
Fisher’s exact test
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TABLE 6. e association between demographic data, burnout syndrome and sleep quality (n=217).
Factors Crude odds ratio Adjusted odds ratio P-value
(95%Condenceinterval) (95%Condenceinterval) LRtest
Emotionalexhaustion <0.01
Low 1 1
Moderate 1.66 (0.66,4.13) 1.58 (0.62,4.02)
High 5.32 (2.23,12.68) 5.25 (2.17,12.72)
Havingdisturbingfactorsinthebedroom 0.02
No 1 1
Yes 2.78 (1.23,6.27) 2.8 (1.18,6.64)
is study showed environmental problems in the
bedroom while being on duty (temperature and noise) and
sleep disruption while being on call, especially between
02.00-04.00am, were signicant factors of poor sleep
quality. Because, in normal human circadian rhythm,
deep sleep or Non-REM periods commonly occur at this
time. en, the disruption during Non-REM periods
may produce confusion, amnesia, poor judgement,
21
dysfunctions,
22
which in turn aects sleep quality in
the next phase.
23
is point should be highlighted to
the Faculty of medicine, for awareness and focus on
residency quality of life or health promotion, because
it may be useful for preventing harmful patient care; as
well as decreasing the training risk from exhaustion or
burnout.
Limitations
is study was a cross-sectional survey, and employed
self-reporting questionnaire for individual evaluation.
Besides its response rate (63.6%), the information might
have led to bias in addition the study was quantitative,
and the sample size was restricted to only residents in
lower, southern ailand. us, it is too soon to generalize
nation-wide, or cannot be used for summing up all ai
residents.
Future recommendations and implications
Henceforward studies should include additional
Faculty of medicines, within ailand; in other words,
a multi-center study is introduced. Moreover, other
studies should retain a more qualitative method.
CONCLUSION
Most residents had poor sleep quality. e associated
factors of sleep quality were environmental problems in
the bedroom, emotional exhaustion or burnout syndrome.
ACKNOWLEDGMENTS
is study was full supported by the Faculty of
Medicine, Prince of Songkla University, ailand. e
reports are very appreciative for the data analysis provided
by Ms. Kruewan Jongborwanwiwat and Mrs. Nisan
Werachattawan. In addition, we would like to show our
gratitude to all residents who collaborated in this survey.
REFERENCES
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and short sleep as risk factors for depression and perceived
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4. Srikam S, Jiamjarasrangsi V, Lalitanantpong D. Job burnout
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5. Sargent M, Sotile W, Sotile M, Rubash H, Barrack R. Stress
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MJ, De la Cruz TJ, et al. Insomnia and sleep quality among
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11. Reangsing C. Quality of sleep and mental health of professional
nurses in government hospitals [dissertation]. Bangkok metropolis:
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12. Chanamanee P, Taboonpong S, Intanon T. Sleep quality and
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13. Lerthattasilp T. Burnout among psychiatrists in ailand:
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14. Sammawart S. Burnout among nurse in Ramathibodi hospital
[esis]. Bangkok: Mahidol University; 1989.
15. Maslach C, Jackson S. e measurement of experienced burnout.
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17. Murthy V, Nayak A, Assessment of sleep quality in post-
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21. Wood BD, Killion JB. Burnout among healthcare professionals.
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Chantanee Ninlerd, B.Sc., Sangarun Dungkong, B.Sc., Gonrada Phuangphay, B.Sc., Chutikarn Amornsupak,
B.Sc., Rapeepat Narkbunnam, M.D.
Department of Orthopaedic Surgery, Faculty of Medical Siriraj Hospital, Mahidol University, Bangkok 10700, ailand.
EffectofHome-BasedRehabilitationExercise
ProgramforElderlyPatientswithFemoralNeck
FractureafterBipolarHemiarthroplasty
ABSTRACT
Objective: is study aimed to investigate the eectiveness of a home-based rehabilitation program by examining
recovery time, the risk of falling, improvement in mobility, and improvement in quality of life.
Methods: is prospective cohort study included elderly patients who sustained a primary femoral neck fracture
that required cement less bipolar hemiarthroplasty using posterior approach at the Department of Orthopaedic
Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, ailand. Time to return to pre-injury
status was the primary outcome. Patient quality of life was evaluated using Short Physical Performance Battery
(SPPB) and EQ5D-5L at three and six months aer surgery.
Results: Forty-one patients were included in the nal analysis. All patients could return to pre-injury ambulatory
status within six months. e mean SPPB score at six months was signicantly higher than the mean score at three
months aer surgery. e results of EQ5D-5L showed that quality of life improved from three to six months aer
surgery. No postoperative complications were observed, including infections, secondary fractures, or hip dislocations.
Conclusion: e home-based rehabilitation program evaluated in this study was found to be safe and eective for
improving recovery, physical performance, and quality of life. All participating patients could return to their pre-
injury ambulatory status within six months.
Keywords: Femoral neck fracture; bipolar hemiarthroplasty; home-based rehabilitation exercise program; short
physical performance battery (SPPB); EQ5D-5L (Siriraj Med J 2020; 72: 315-320)
Corresponding author: Rapeepat Narkbunnam
E-mail: mai_parma@hotmail.com
Received 7 May 2019 Revised 30 September 2019 Accepted 30 October 2019
ORCID ID: http://orcid.org/0000-0002-3564-1700
http://dx.doi.org/10.33192/Smj.2020.42
INTRODUCTION
Since the proportion of elderly population continues
to increase, the issues that aect aging and aged societies are
attracting attention in many countries around the world.
In 2015, 15.8 percent of ai population were people aged
60 years and over. at number is projected to increase to
23.1% by 2025, and 37.1% by 2050.
1
Accordingly, ailand
has one of the fastest growing older adult populations in
Asia.
2
Health and healthcare are major concerns of older
people. Consistent with that, osteoporosis has been raised
as one of the most important diseases because it occurs
in most elderly people. Osteoporosis associates with a
decrease in muscle strength and an increase in fall risk,
which increases the risk of osteoporotic fractures.
3
e
literature shows that approximately 20 percent of elderly
people could experience a femoral neck fracture, which
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can cause serious health consequences with approximately
10 to 20% mortality within six months and signicant
loss of mobility.
4,5
A standard of treatment that is now
used to treat displaced osteoporotic femoral neck fracture
is bipolar hemiarthroplasty.
5
Aer undergoing this surgical procedure, patients
have to attend a rehabilitation program to improve their
ability to physically perform daily activities to the same
level they did prior to their fracture, and to minimize
their risk of falling and mortality.
6,7
General resistance
exercise and aerobic practice can improve patient mobility.
8
However, participation in a rehabilitation program may
be inconvenient for some patients for several possible
reasons. For instance, most rehabilitation programs require
a patient to travel to the hospital or rehabilitation center,
and this involves higher cost of rehabilitation, travel-
related expenses, the inconvenience of travel, and oen
the need for a caregiver. Home-based exercise programs
were established to reduce the cost of rehabilitation,
and to help patients regain physical functions.
9,10
Many
studies support the benet of having exercise at home
– particularly for patients with femoral neck fractures.
In ailand, various exercise programs have been
implemented. A few studies have evaluated the eectiveness
of home-based rehabilitation for stroke patients.
11,12
For patients with knee osteoarthrosis, Chaipinyo and
Karoonsupcharoen studied home-based strength and
balance training.
13
Our review of the literature revealed that
no studies have assessed the eectiveness of home-based
program for elderly patients with femoral neck fracture
who received bipolar hemiarthroplasty. Accordingly,
the aim of this study was to investigate the eectiveness
of a home-based rehabilitation program for elderly
patients with femoral neck fracture who received bipolar
hemiarthroplasty by examining recovery time, the risk
of falling, improvement in mobility, and improvement
in quality of life.
MATERIALS AND METHODS
This study was approved by Human Research
Protection Unit, Faculty of Medicine Siriraj Hospital,
Mahidol University (Si 400/2016). Patients aged from 60
to 85 years who required treatment for primary femoral
neck fracture and who underwent cementless bipolar
hemiarthroplasty using posterior approach were enrolled
starting in January 2016. Included patients had to have
had the ability to walk independently or walk with a gait
aid for at least 10 meters prior to sustaining their fracture.
Patients were excluded from this study if they had a
disease that aects exercise, such as severe cardiovascular
disease, severe respiratory disease, psychiatric disease,
dementia, or cognitive impairment. Patients with post-
operative complications that adversely aect the ability
to exercise were also excluded.
Before undergoing surgery, all patients were instructed
in how to perform a home-based rehabilitation program
for femoral neck fractures by a physiotherapist. e
program was designed to help patients recover and
to improve their mobility so they can return to their
pre-fracture status. Each patient had to perform the
postoperative exercise once a day for six months. e
rehabilitation program includes both lying and standing
exercises. Lying exercises consisted of hip abduction and
hip exion. Standing exercises included hip abduction,
hip extension, and hip exion.
14
Patients were advised
to perform each exercise 10-15 reps/set, 2 sets/time, 3
times per day (Table 1). Each patient received an exercise
booklet and daily record sheet. From six weeks to the
three month aer surgery, participants would receive a
phone call every week to encourage the rehabilitation
program and to assess their pain level and their ability
to walk. From the three months to the six months aer
surgery, patients would get a phone call once every two
weeks.
Data collection
Demographic and clinical data of recruited patients
were collected, including age, gender, side, number of
days before surgery, weight, height, and body mass index
(BMI). Patients were appointed for follow-up at six
weeks, three months, and six months aer receiving the
operation. At follow-ups, postoperative complications,
such as fracture, dislocation, and wound complication,
were investigated. Time to return to pre-injury ambulatory
status was measured as the primary outcome. Time to
return to pre-injury status was indicated as six weeks,
three months, or six months aer the operation date.
Physical performance and quality of life was assessed
using Short Physical Performance Battery (SPPB) and
EQ5D-5L, respectively. e SPPB test consists of three
sections, including the ability to rise from sitting on a
chair, standing balance test, and walking speed test, with
scores that range from 0 (worst performance) to 12 (best
performance).
15
e EQ5D-5L is a standardized tool used
for describing health-related quality of life. It consists
of two parts associated with health status: EQ5D and a
visual analogue scale (EQ-VAS), which range from 0
to 100. e maximum score indicates the best health
status.
16,17
is tool was proven to be reliable and valid
for assessing the health status of elderly patients with
femoral neck fractures.
18
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317
TABLE 1. e rehabilitation program for patients with femoral neck fracture aer bipolar hemiarthroplasty
Lying position
∙Repeat10-15reps/set,
2sets/time,
and 3 times per day
Standing position
∙Repeat10-15reps/set,
2sets/time,
and 3 times per day
Hip abduction exercise
Heel slide
Hipexionexercise
Hip abduction exercise
Hip extension exercise
Move your leg out to the side as far as you can and
then back to the starting position.
Bend your knee while keeping your heel on the bed. Do
notletyourkneerollinwardorbendover90˚.
Lift your operated leg toward your chest.
Do not lift your knee higher than your hip.
Keep your body straight and lift your leg out to the side.
Lift your operated leg backward slowly, keep your body
straight and then return your foot.
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Statistical analysis
Patient demographic and clinical characteristics
were summarized using descriptive statistics. Continuous
variables are expressed as mean ± standard deviation,
and categorical variables are presented as frequency and
percentage. Chi-square test was used to compare time
to return to pre-injury ambulatory status. Paired t-test
was used to compare the results of SPPB, EQ5D, and
EQ-VAS. All data was analyzed using SPSS Statistics
(SPSS, Inc., Chicago, IL, USA). A p-value less than 0.05
was considered statistically signicant.
RESULTS
ere were 53 patients with femoral neck fracture
who underwent cementless bipolar hemiarthroplasty,
as shown in Fig 1. e rst patient was recruited in
January 2016, and the last followed-up patient visited
our clinic in April 2018. Eleven patients were excluded
due to one of the following reasons: age over 85 years,
conservative treatment, or inability to walk more than
10 meters. One patient was withdrawn from the study
because two follow-up visits were missed.
Patient demographic and clinical characteristics are
shown in Table 2. e mean age of participants was 76.4
± 8.4 years, and 34 patients (82.9%) were women. Average
BMI was 22.2 ± 3.2 kg/m
2
. No patients had postoperative
complications, including infections, secondary fractures,
or hip dislocations.
After evaluating the outcome parameters, the
proportion of participants who returned to pre-injury
ambulatory status within six weeks, three months, and
six months aer surgery was 24.4%, 82.9%, and 99.9%,
respectively (Table 3). As a result of this rehabilitation
program, all included patients were able to return to
their pre-injury ambulatory status within six months.
As shown in Table 3, the mean SPPB scores was
6.7 ± 1.3 at three months, and 8.5 ± 1.9 at six months
(p < 0.000). According to the EQ5D questionnaires,
health-related quality of life was improved from the
three months to the six months. EQ-health state scores
were 0.9 ± 0.0 and 1.0 ± 0.0 at three and six months
(p < 0.000), respectively. For the pain scores, the average
of EQ-VAS was 69.4 ± 12.1 at three months, which was
improved to 85.9 ± 8.5 at six months (p < 0.000). At six
months, 39 patients (95.1%) had an EQ-VAS score of
zero on the prosthesis side. No patients experienced any
limitations of physical function aer six months.
DISCUSSION
Bipolar hemiarthroplasty is a conventional surgery
for treating elderly people with femoral neck fracture.
19
Aer undergoing this procedure, all patients need to
participate in a rehabilitation program to leverage their
recovery. Home-based exercise programs were developed to
reduce the cost of treatment and improve the eectiveness
of patient rehabilitation.
9,10
is prospective cohort study showed the recovery
of patient functions following bipolar hemiarthroplasty
to be improved aer performing the recommended
rehabilitation program for six months. Patient physical
functions, quality of life, and time to return to pre-
injury status were evaluated using SPPB and EQ5D-5L.
Similar to previous studies, we found the SPPB scores
at six months to be signicantly higher than the scores
at three months aer surgery.
10,20
Several studies have evaluated new rehabilitation
programs that associated with intensive supervision,
equipment, and progressive resistance exercises at hospitals.
ose programs were found to have improved the capacity
of conventional rehabilitation.
21-23
In contrast, the present
study evaluated a newly designed home-based rehabilitation
program that involved patients following a prescribed
program and three physical therapist follow-up visits
within six months. e advantages of this home-based
rehabilitation program are lower cost and no requirement
for the patient to travel to the hospital.
Although older patients with femoral neck fractures
had asymmetric strengths of lower extremities and impaired
postural balance
24,25
, the program evaluated in this study
included standing exercises to improve strength and
balance in elderly patients. e ecacy of this program
was demonstrated by improvement in SPPB scores.
The results obtained from the EQ5D-5L show
that quality of life was improved from three months
to six months. Moreover, 39 participants in this study
had an EQ-VAS score of zero at six months. Neither
recurrent fracture nor dislocation occurred during the
rehabilitation period. No evidence of falling case found
in this study. us, it can be concluded that this home-
based rehabilitation program could safely and eectively
promote health-related quality of life.
e key limitation of this study is that although
patients were instructed in the exercises to perform and
when and for how long, there is no way to know for
certain that the exercise program was strictly followed.
To enhance the likelihood of compliance, we provided
each patient with a logbook so they could record their
daily rehabilitation exercises and activities. e strengths
of this study are its prospective design, the six months
duration of rehabilitation, and the fact that validated
assessment tools were used to evaluate recovery.
In conclusion, the home-based rehabilitation program
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319
Characteristics Mean±SDor%(n)
Age, year 76.4 ± 8.4
Gender, % (n)
Male 17.1 (7)
Female 82.9 (34)
BMI,kg/m
2
22.2 ± 3.2
Affected side, % (n)
Right 43.9(18)
Left 56.1 (23)
ASA
2 56.1 (23)
3 43.9 (18)
Days before surgery, day 10.3 ± 11.3
TABLE 2. Patient demographic and clinical characteristics
Abbreviations: ASA = American Society of Anesthesia Score, BMI = body mass index
TABLE 3. Results of the rehabilitation program
Variables Mean±SDor%(n) P-value
Patientsreturnedtopre-injuryambulatorystatus,%(n)
Within 6 weeks 24.4 (10)
Within 3 months 58.4 (24)
Within 6 months 17.1 (7)
Mean SPPB scores
At 3 months 6.7 ± 1.3 <.000
At 6 months 8.5 ± 1.9
EQ-health state scores
At 3 months 0.9 ± 0.0 <.000
At 6 months 1.0 ± 0.0
EQ-VAS scores
At 3 months 69.4 ± 12.1 <.000
At 6 months 85.9 ± 8.5
p-value < 0.05 indicates statistical signicance
Abbreviations: SPPB = Short Physical Performance Battery; EQ5D-5L questionnaire = EQ-health state score and EQ-VAS score
Ninlerd et al.
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evaluated in this study was found to be safe and eective
for improving patient recovery, physical performance,
and quality of life. All participating patients were able to
return to their pre-injury ambulatory status within six
months. e results of this study suggest that exercise
program can be used as a standardized rehabilitation
protocol for elderly patients with femoral neck fracture
following bipolar hemiarthroplasty.
ACKNOWLEDGMENTS
is research study was support by the Routine
to Research Unit, Faculty of Medicine Siriraj Hospital,
Mahidol University (R2R: 15R00017/038/15). We
would like to thank Miss Nichakorn Khomawut for her
assistance with data collection in this study. We thank
Assist. Prof. Pakdee ipthavee, Assist. Prof. Vipawan
Chewachutirungruang and Mr. itipan Vichaiya for
consultation in research.
Conicts of interest: No conicts of interest
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Chawisa Nampoolsuksan, M.D.*, ammawat Parakonthun, M.D.*,**, ikhamporn Tawantanakorn, M.D.*,
Andres Mora, M.D., Ph.D.***, Jirawat Swangsri, M.D., Ph.D.*,**, awatchai Akaraviputh, M.D., Dr.Med*, Asada
Methasate, M.D., Ph.D.*,**, Anusak Yiengpruksawan, M.D.****, Vitoon Chinswangwatanakul, M.D., Ph.D.*
*Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, ailand, **Siriraj Upper Gastrointestinal Cancer
Center, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, ailand, ***Hospital of Specialties “Carlos Andrade Marin”, Quito,
Ecuador, ****Capital Health Cancer Center, Pennington, New Jersey, USA
Short-termPostoperativeOutcomesBeforeandAfter
theEstablishmentoftheSirirajUpperGastrointestinal
CancerCenter:APropensityScoreMatchedAnalysis
ABSTRACT
Objective: To evaluate short-term postoperative outcomes compared between before and 1 year aer the establishment
of the Siriraj Upper Gastrointestinal Cancer Center (UGICC).
Methods: Medical records of 211 adenocarcinoma of stomach (GC) and esophagogastric junction (AEG) patients
who underwent radical gastrectomy at Siriraj Hospital during January 2012-September 2018 were reviewed (before
UGICC; B-UGICC). Data of 40 patients operated upon during October 2018-September 2019 were prospectively
collected aer the establishment of UGICC (A-UGICC). Propensity score (PPS) matched analysis was conducted,
and short-term outcomes were compared. Enhanced Recovery Aer Surgery (ERAS) protocol was applied to some
patients in A-UGICC. Results of conventional care (CC) were compared with ERAS protocol.
Results: PPS matched 78 patients (13 AEG, 65 GC) in B-UGICC, and 40 patients (6 AEG, 34 GC) in A-UGICC.
Median postoperative length of stay (POS) was signicantly shorter in A-UGICC than in B-UGICC; however,
complications and time to oral diet tolerability were not signicantly dierent between groups. In A-UGICC,
median POS and time to toleration of oral diet were signicantly shorter among 15 ERAS patients than among 25 CC
patients. Intestinal recovery and time to ambulation trended to be earlier in ERAS. Regarding the ERAS outcomes,
103 CC and 15 ERAS patients were matched to 36 non-ERAS and 13 ERAS patients. Median time to toleration of
oral water, liquid diet, and solid diet was signicantly shorter in ERAS than in CC (all P<0.001). Median POS was
signicantly shorter in ERAS (P<0.001). Postoperative complications were non-signicantly dierent between
ERAS and CC. ere was no mortality in this study.
Conclusion: UGICC with multidisciplinary team approach and application of ERAS protocol contributed to
improvement of postoperative short-term outcomes.
Keywords: Gastric cancer; esophagogastric junction; gastrectomy; multidisciplinary team; centralization; Enhanced
Recovery Aer Surgery (ERAS) (Siriraj Med J 2020; 72: 321-329)
Corresponding author: ammawat Parakonthun
E-mail: t.parakonthun@gmail.com
Received 9 April 2020 Revised 21 April 2020 Accepted 22 April 2020
ORCID ID: http://orcid.org/0000-0002-2990-0649
http://dx.doi.org/10.33192/Smj.2020.43
INTRODUCTION
Gastric cancer is one of the cancers that is oen
diagnosed as late-stage at presentation. Radical surgical
resection with systemic chemotherapy is a mainstay of
treatment.
1-4
Radical surgical resection should be considered
among those regarded as being t for surgery.
5,6
An
Nampoolsuksan et al.
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experienced multidisciplinary team is needed from the
time of diagnosis to encourage, educate, and care for these
patients.
7-9
Previous meta-analysis demonstrated the eect
of a high volume center on postoperative mortality.
10
High
volume center appeared to associate with more radical
surgery and lymph node dissection, and this resulted in
better overall survival.
11,12
In ailand, the rst Upper
Gastrointestinal Cancer Center (UGICC) was established
at the Faculty of Medicine Siriraj Hospital, Mahidol
University in November 2017. e aim of the Siriraj
UGICC is to be a center of excellence in esophageal and
gastric cancer treatment and care. Our multidisciplinary
team, which includes surgeons, medical oncologists,
radiation oncologists, anesthesiologists, nutritionists,
physical therapists, nurses, and researchers, was organized
to provide intensive perioperative and surgical care. Since
October 2018, which is when surgical and perioperative
protocols were rened and fully implemented, esophageal
and gastric cancer patients at Siriraj Hospital have been
treated and cared for by this specialized multidisciplinary
team.
Several studies have recently published the results
of Enhanced Recovery Aer Surgery (ERAS) protocol
for perioperative care in gastric surgery.
13,14
Signicantly
earlier recovery of intestinal function and shorter hospital
length of stay were observed in ERAS patients.
15,16
A
reduction in total medical costs was also found in patients
that received ERAS protocol.
17
However, no statistically
signicant dierence in postoperative morbidities was
found in ERAS patients when compared to those who
received conventional treatment.
18-20
ese studies suggest
the safety and ecacy of ERAS when applied to gastric
cancer patients undergoing gastric surgery. Accordingly,
the ERAS protocol was adopted and integrated into the
Siriraj UGICC perioperative care protocol.
e primary aim of this study was to evaluate short-
term postoperative outcomes compared between before
and 1 year aer the establishment of the Siriraj UGICC.
e secondary objective was to compare short-term
postoperative outcomes between patients who received
ERAS and patients who received conventional care (CC).
MATERIALS AND METHODS
Patients
The medical records of 211 patients with adenocarcinoma
of stomach or esophagogastric junction (Siewert type II
and III) during January 2012 to September 2018 who
underwent curative gastrectomy according to Japanese
gastric cancer treatment guidelines
21,22
at Department of
Surgery, Faculty of Medicine Siriraj Hospital were reviewed
and classied as the before UGICC group (B-UGICC).
Data of 40 new patients who underwent surgery for the
same conditions during October 2018 to September
2019 were prospectively collected following the protocol
record form of the Siriraj UGICC, and those patients
were classied as the aer UGICC group (A-UGICC).
Propensity score matched analysis (approximately 2:1)
with a caliper width of 0.2 using gender, age, American
Society of Anesthesiology (ASA) grade, tumor location,
operative approach, and extent of operation was conducted
to compare between B-UGICC and A-UGICC groups,
and to reduce selection bias. Aer establishment of
the Siriraj UGICC, the ERAS protocol was applied in
some patients who underwent upper gastrointestinal
procedures whereas some patients received traditional
care. Perioperative ERAS or conventional care protocols
were applied depending on the patient-doctor discussion.
Postoperative recovery and complications were compared
between 25 patients who received conventional care and
15 patients who received ERAS protocol. Moreover, the
short-term outcomes were compared between those
in the B-UGICC and A-UGICC groups who received
conventional care (non-ERAS group) and patients who
received the ERAS protocol in the A-UGICC group (ERAS
group) aer propensity score matching (approximately
3:1) (Diagram 1).
Preoperative clinicopathological characteristics
of patients, including age, gender, ASA grade, tumor
location, operative approach and extent of resection
were reviewed and recorded. Extent of gastric resection
and lymphadenectomy were performed in accordance
with Japanese gastric cancer treatment guidelines.
21,22
In this study, extended gastrectomy was defined as
transabdominal gastrectomy with combined adjacent
organ resection. Esophagogastrectomy was dened as a
transthoracic esophagogastrectomy for adenocarcinoma
of esophagogastric junction.
Perioperative protocols included preoperative clinical
evaluation and laboratory investigations. Anesthesiologist
was consulted to evaluate for patients at high risk for
anesthesia. Nutritional status was assessed and improved to
achieve the energy and protein requirements. Smoking and
alcohol were strictly prohibited for at least 2-4 weeks before
surgery. For patients receiving the ERAS protocol, breathing
exercise and chest physical therapy were emphasized
before admission. Clear liquid oral diet was allowed until
3 hours before surgery. Risk of postoperative nausea and
vomiting was assessed and prevented. Postoperative pain
was controlled by multimodal strategies. Early removal
of all catheters and early ambulation were promoted.
Oral uid was started on the rst day aer surgery, and
then so diet was introduced on postoperative day 3
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323
Diagram 1. Patients and propensity score matching for comparison.
Abbreviations: UGICC, Upper Gastrointestinal Cancer Center; ERAS, Enhanced Recovery Aer Surgery group
Nampoolsuksan et al.
1
Retrospective cohort
Before UGICC (B-UGICC)
January 2012 - September 2018
(n= 211)
Propensity score matching 2:1
Prospective cohort
After UGICC (A-UGICC)
October 2018 – September 2019
(n= 40)
B-UGICC
(n= 78)
Non-ERAS
(n=103)
Propensity score matching 3:1
A-UGICC
(n= 40)
Non-ERAS
(n=36)
ERAS
(n=13)
Conventional care
(n=25)
ERAS
(n=15)
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if tolerable. Patients were discharged as soon as they
satised the discharge criteria.
is study was approved by the Institutional Review
Board of the Faculty of Medicine Siriraj Hospital, Mahidol
University, Bangkok, ailand (Si 119/2019).
Outcome measurements
e primary objective was to determine dierences
in short-term postoperative outcomes between before and
aer UGICC establishment. Study parameters were timing
of intestinal function recovery, timing of ability to tolerate
oral intake, postoperative complications and severity
classied by Clavien-Dindo classication
23
, postoperative
length of hospital stay (POS), and postoperative mortality.
In this study, we dened intestinal function recovery as
time to rst atus and defecation. Severe complication
was classied as a grade III and greater according to
Clavien-Dindo classication. e secondary objective was
to evaluate the benets of the ERAS protocol compared
to that of conventional care.
Statistical methods
All statistical analyses were performed using SPSS
statistical soware version 23.0 for Windows (SPSS, Inc.,
Chicago, IL, USA). Descriptive statistics were used to
characterize patients before and aer the establishment
of the Siriraj UGICC. Categorical variables were analyzed
using chi-square test or Fisher’s exact test, and continuous
variables were compared using Student’s t-test or Mann
Whitney U test. Data are presented as number or number
and percentage for categorical data, and as mean ± standard
deviation (SD) for normally distributed continuous data
(SD) or median and interquartile range for non-normally
distributed continuous data. Propensity score match
analysis was performed by PS matching for SPSS version
23.0. All statistical results were considered signicant
when the P-value was less than 0.05.
RESULTS
Demographic data
Two hundred and eleven patients in the B-UGICC
group underwent curative gastrectomy. In the A-UGICC
group, 40 new patients were prospectively recruited.
ere was no signicant dierence in age, gender, ASA
grade, tumor location, or operative approach between
groups. Most patients in the B-UGICC group underwent
radical extended gastrectomy (86 of 211 patients, 40.8%),
whereas radical total gastrectomy was the most common
procedure in the A-UGICC group (18 of 40 patients,
45.0%). e extent of gastric resection was signicantly
dierent between groups (P=0.005). Propensity score
matched 78 B-UGICC patients and 40 A-UGICC patients
(Table 1). Propensity score match analysis revealed
no statistically signicant dierences in any patient
clinical characteristics or surgical procedures between
groups. ere were 19 patients with adenocarcinoma
of the esophagogastric junction (13 in B-UGICC, 6 in
A-UGICC), and 99 gastric cancer (65 in B-UGICC, 34
in A-UGICC) patients.
erapeutic outcomes before and aer establishment
of the Siriraj UGICC
Of the 118 patients who underwent radical gastrectomy,
there was no in-hospital or 30-day postoperative mortality in
either group. e incidence of postoperative complications
was 30 of 78 patients (38.5%) in B-UGICC, and 19 of 40
patients (47.5%) in A-UGICC. e morbidity rate was
not signicantly dierent between groups (P=0.628).
Two patients (2.6%) in the B-UGICC group suered
from severe postoperative complications. In both cases,
intra-abdominal collections, classied as grade IIIa, were
successfully treated with non-operative management. In
the A-UGICC group, one patient (2.5%) had postoperative
bleeding at the esophagojejunostomy anastomosis, but this
bleeding was observed to have spontaneously stopped at
the time of endoscopy. is bleeding event was classied
as grade IIIa. ere was no signicant dierence between
groups relative to postoperative time to tolerate oral
intake. Median postoperative length of stay was longer
in the B-UGICC group than in A-UGICC group (10
days vs. 9 days, respectively; P=0.026) (Table 2).
Impact of the ERAS protocol
Analysis of short-term outcomes compared between
the conventional and ERAS protocols in the A-UGICC
group is shown in Table 3. Median time to toleration of
oral water, liquid diet, and solid diet was signicantly
shorter in ERAS patients than in CC patients (all P<0.001).
Recovery of intestinal functions and time to mobilization
and ambulation showed a non-signicant trend toward
being earlier in the ERAS group than in the CC group.
Postoperative length of hospital stay was signicantly
shorter in the ERAS group (5 days vs. 10 days, respectively;
P<0.001). e postoperative complication rate was not
signicantly dierent between ERAS and conventional
care (53.3% vs. 44.0%, respectively; P=0.570).
To assure the benet of the ERAS protocol beyond
conventional perioperative care, we rearranged previously
matched patients. Patients who received conventional care
(78 patients in the B-UGICC group, and 25 patients that
received the CC protocol in the A-UGICC group) were
grouped into the non-ERAS group, and 15 patients who
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325
TABLE 1. Demographic and clinical characteristics compared between groups before and aer propensity score
matching.
Characteristics Beforepropensityscorematching Afterpropensityscorematching
B-UGICC A-UGICC
P-value
B-UGICC A-UGICC
P-value
(n=211) (n=40) (n=78) (n=40)
Gender, n 0.387 0.847
Male 118 19 39 19
Female 93 21 39 21
Age,mean±SD 62.8±14.0 61.6±15.3 0.490 62.9±13.5 61.6±15.3 0.253
ASAgrade,n 0.709 0.673
0 – 2 149 27 56 27
3 – 5 62 13 22 13
Tumorlocation,n 0.821 1.000
AEG 38 6 13 6
GC 173 34 65 34
Operative approach, n 0.842 0.899
Transthoracic 10 1 4 1
Open 173 32 59 32
Laparoscopic 20 5 10 5
Robotic-assisted 8 2 5 2
Extent of operation, n 0.005 0.437
Proximal gastrectomy 2 0 2 0
Distal gastrectomy 72 14 32 14
Total gastrectomy 41 18 23 18
Extended gastrectomy 86 7 17 7
Esophagogastrectomy 10 1 4 1
CRS with HIPEC, n 7 3 0.201 4 3 0.688
A P-value<0.05 indicates statistical signicance
Abbreviations: AEG, adenocarcinoma of esophagogastric junction; ASA, American Society of Anesthesiologists physical status classication;
A-UGICC, aer establishment of the Upper Gastrointestinal Cancer Center; B-UGICC, before establishment of the Upper Gastrointestinal
Cancer Center; CRS with HIPEC, cytoreductive surgery with hyperthermic intraperitoneal chemotherapy; GC, gastric cancer; SD, standard
deviation
Nampoolsuksan et al.
received the ERAS protocol in the A-UGICC group were
assigned to the ERAS group. Propensity score analysis
(approximately 3:1) was performed and the patients were
matched. irty-six patients in the non-ERAS group and
13 patients in the ERAS group were matched (Table 4).
e results of that analysis were concordant with those
of the previous analysis of ERAS in A-UGICC group.
Specically, signicantly earlier time to toleration of oral
intake (all P<0.001) and shorter postoperative length
of stay (P<0.001) were observed in the ERAS group.
Incidence of postoperative complication in ERAS was
higher than in non-ERAS; however, the dierence was
not statistically signicant (61.5% vs. 36.1%, respectively;
P=0.124). No severe complication was observed in the
ERAS group.
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TABLE 2. Short-term postoperative outcomes compared between before and aer establishment of the Siriraj
UGICC.
TABLE 3. Outcomes of treatment compared between protocols aer establishment of the Siriraj UGICC.
Postoperativeoutcomes B-UGICC A-UGICC
(n=78) (n=40)
P-value
Oralintake(days),median(interquartilerange)
Water 4 (3-7) 4 (1.25-7) 0.825
Liquid 5 (4-9) 6 (2.5-8) 0.321
Solid 7 (5-10) 7 (4.25-9) 0.466
Complications,n(%) 0.628
No 48 (61.5) 21 (52.5)
Mild (grade I-II) 28 (35.9) 18 (45)
Severe (grade III-IV) 2 (2.6) 1 (2.5)
Mortality,n(%) 0 0 N/A
Lengthofstay(days),median(interquartilerange)
Total length of stay 12 (9-16.25) 10 (7-14) 0.023
Postoperative length of stay 10 (8-14) 9 (6.25-11) 0.026
A P-value<0.05 indicates statistical signicance
Abbreviations: A-UGICC, aer establishment of the Upper Gastrointestinal Cancer Center; B-UGICC, before establishment of the Upper
Gastrointestinal Cancer Center; N/A, not applicable
Postoperativeoutcomes Conventionalcare ERAS
P-value
(n=25) (n=15)
Oralintake(days),median(interquartilerange)
Water 7 (4.5-8) 1 (1-3) <0.001
Liquid 7 (6-8.5) 2 (2-4) <0.001
Solid 8 (7-10) 3 (3-5) <0.001
Intestinalrecovery(hours),median(interquartilerange)
Timetoatus 72(55-86.5) 60(24-86) 0.189
Time to defecation 96 (70-125.5) 88 (64-119) 0.401
Ambulation(hours),median(interquartilerange)
Time to in bed mobilization 28 (17-65.25) 22 (16-26) 0.442
Time to out of bed ambulation 63.5 (32.25-82.5) 44 (21-96) 0.682
Complications,n(%) 0.570
No 14 (56) 7 (46.7)
Mild (grade I-II) 10 (40) 8 (53.3)
Severe (grade III-IV) 1 (4) 0
Mortality,n(%) 0 0 N/A
Lengthofstay(days),median(interquartilerange)
Total length of stay 13 (10.5-15.5) 6 (6-8) <0.001
Postoperative length of stay 10 (9-12.5) 5 (5-7) <0.001
A P-value<0.05 indicates statistical signicance
Abbreviations: UGICC, Upper Gastrointestinal Cancer Center; ERAS, Enhanced Recovery Aer Surgery protocol; N/A, not applicable
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TABLE 4. Outcomes of treatment compared between patients that did and that did not receive ERAS protocol
aer propensity score matching (approximately 3:1).
Postoperativeoutcomes Non-ERAS ERAS
(n=36) (n=13)
P-value
Oralintake(days),median(interquartilerange)
Water 4 (3-7) 1 (1-2) <0.001
Liquid 5.5 (4-8.75) 2 (2-3) <0.001
Solid 7 (6-10) 3 (3-4.5) <0.001
Complications,n(%) 0.124
No 23 (63.9) 5 (38.5)
Mild (grade I-II) 11 (30.6) 8 (61.5)
Severe (grade III-IV) 2 (5.6) 0
Mortality,n(%) 0 0 N/A
Lengthofstay(days),median(interquartilerange)
Total length of stay 11.5 (9-14.75) 6 (6-7) <0.001
Postoperative length of stay 10 (8-13) 5 (5-6.5) <0.001
A P-value<0.05 indicates statistical signicance
Abbreviations: ERAS, Enhanced Recovery Aer Surgery protocol; N/A, not applicable
DISCUSSION
Centralization is now recognized as a factor that
improves postoperative mortality and treatment outcomes.
High-volume centers and centers of excellence that
specialize in certain types of cancer seem to have better
short- and long-term survival outcomes. Nimptsch U,
et al.
24
reported national hospital discharge data aer
complex gastric surgery in Germany. ey found surgery
in very high-volume hospitals (50 operations per year) to
be associated with lower in-hospital mortality compared
to treatment in very low-volume hospitals (5 surgeries
per year) (10.6% vs. 12.0%, respectively). For cancer
surgery, very high-volume hospitals (34 resections per
year) had lower in-hospital mortality than that in very low
volume hospitals (3 resections per year) (6.3% vs. 7.7%
respectively). Iwatsuki M, et al.
25
analyzed the results of
distal gastrectomy for gastric cancer from the National
Clinical Database of Japan. Operative mortality was
signicantly higher in low-volume hospitals (1-22 cases
per year) than in medium-volume (23-51 cases per year)
and high-volume (52-404 cases per year) hospitals (1.9%
vs. 1.0% vs. 0.5%, respectively; P<0.001). van Putten M,
et al.
11
reported the short-and long-term outcomes before
and aer centralization of gastric cancer surgery in the
Netherlands. e 30-day postoperative mortality rate
was 6.5% before, and 4.1% aer centralization (P=0.004).
e 2-year overall survival rate was also improved from
before to aer centralization (55.4% vs. 58.5%, respectively;
P=0.031). Hospital volume could have an impact on
postoperative outcomes, and that centralization was
associated with improved survival in the developed
countries. However, data specic to the development
and eectiveness of specialized esophageal and gastric
cancer centers in developing countries is scarce. To the
best of our knowledge, this is the rst data of postoperative
outcomes reported from the upper gastrointestinal cancer
center in ailand.
e Siriraj Upper Gastrointestinal Cancer Center
was established in November 2017. To the best of our
knowledge, this is the rst specialized upper gastrointestinal
cancer center organized by a multidisciplinary team in
ailand. e aim of the Siriraj UGICC is to be a center
of excellence in esophageal and gastric cancer services.
is center also aims to be a training center for medical
personnel in all aspects of patient care for these two
types of cancer. Research to identify ways to improve
treatment and patient care is also an important component
of the mission of the Siriraj UGICC. We arranged a
multidisciplinary discussion to decide upon a pattern
of perioperative and surgical care. Since this center’s
founding, management practices and clinical protocols
have become more systematic and ecient. In the initial
Nampoolsuksan et al.
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328
Original Article
SMJ
period, ERAS protocol could be completely implemented
for patients because of a strong multidisciplinary team. A
prospectively maintained database is regularly reviewed
and updated, and the quality of the documentation is
more reliable to study and analyze.
is study reports short-term postoperative outcomes
after radical gastrectomy compared between before
and aer the establishment of a UGICC. We applied
propensity score matched analysis to reduce selection
bias and improve the quality of comparison. Although
our patients were treated by the same group of surgeons
and the same surgical standard according to Japanese
gastric cancer treatment guidelines, perioperative care was
adjusted and rened by the multidisciplinary team aer
UGICC establishment. Patient recovery demonstrated a
non-signicant trend toward improvement in the A-UGICC
group compared to the B-UGICC group; however, length
of hospital stay was statistically signicantly improved
aer the establishment of the Siriraj UGICC. e ERAS
protocol is a strategy that can be applied during the
perioperative and intraoperative period. Since the ERAS
protocol is a new care strategy for esophageal and gastric
cancer patients at our center and its reported superior
postoperative results have never been proven at our
hospital, it was applied in only some selected patients.
Although the number of ERAS patients in our study
was comparatively low, the postoperative short-term
outcomes were promising. Signicant improvement in
patient recovery and length of hospital stay was clearly
shown. In contrast, severe postoperative morbidity and
mortality rates were not signicantly increased. e
identied safety and recovery benets of the ERAS protocol
suggest its benet in other types of surgical patients in
the future. Aer the Siriraj UGICC was established, the
incidence of postoperative complications and mortality
was not dierent from the pre-UGICC period. However
and importantly, it should be noted that there was no
postoperative mortality in this study. e high incidence
of minor postoperative complications might be the result
of better data collection.
Some limitations of this study have to be addressed.
First, our data was derived from a single super-tertiary
center in ailand, which makes this a single-center study.
Moreover, our center, which is a national super-tertiary
referral center, is routinely referred complex cases that
cannot be managed at a lower level center. is limitation
suggests that our ndings may not be generalizable to
all other care settings. Second, the size of our study
population was relatively small; however, the number
of patients that undergo radical gastrectomy is generally
quite low. In an attempt to mitigate this limitation and
improve the quality of our analysis, we employed the use
of propensity score matching to reduce selection bias
and improve the quality of our comparisons. Further
study is needed to compare the cost of treatment between
pre- and post-UGICC, and to investigate the long-term
outcomes of these patients.
In conclusion, Siriraj Upper Gastrointestinal Cancer
Center aims to improve the quality of esophageal and
gastric cancer care. is is the rst specialized center
organized by a multidisciplinary team in ailand. High
surgical standard and appropriate in-house perioperative
protocol had signicant positive impact on postoperative
short-term outcomes. Multidisciplinary team in UGICC
with the application of the ERAS protocol contributed to
signicant improvement in timing of ability to tolerate
oral intake and postoperative length of hospital stay.
ACKNOWLEDGMENTS
e authors gratefully acknowledge the patients
that generously agreed to participate in this study; Dr.
Saowalak Hunnangkul for her assistance with statistical
analysis; and, Miss Nongnard amnongdee for her
assistance with data collection.
Conict-of-interest statement: All authors declare no
personal or professional conicts of interest relating to
any aspect of this study.
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Nampoolsuksan et al.
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Original Article
SMJ
Charussri Leeyaphan, M.D., Ploypailin Tantrapornpong, M.D.
Department of Dermatology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, ailand.
Cutaneous Manifestations and Associated
SystemicFindingsofPatientswithZikaInfections
ABSTRACT
Objective: is retrospective study explored the clinical characteristics and laboratory results of ZIKV infections,
and compared them with those of other viral exanthems.
Methods: e medical records of patients presenting with maculopapular viral exanthems between January 2017
and December 2018 were reviewed. e patients were divided into 2 two groups: ZIKV infections (conrmed by
urine RT-PCR testing for ZIKV), and other viral exanthems. e clinical characteristics and laboratory results of
complete blood counts of the two groups were compared.
Results: In all, 104 viral-exanthem patients were reviewed, with 35 patients diagnosed with a ZIKV infection (33.7%)
and 69 with other viral exanthems (66.3%). e mean age of the ZIKV-infected patients was signicantly higher
than that of the other-viral-exanthem group (43.6 vs 36.2 years; p-value = 0.005). A multivariate analysis revealed
that the incidences of a family/close contact cluster, conjunctivitis, and myalgia were signicantly associated with
ZIKV infections. However, there were no signicant associations between the laboratory results of the ZIKV and
other-viral-exanthem groups.
Conclusion: e ZIKV infection exhibits a prominent pattern recognition, including a family/close contact cluster,
conjunctivitis, and myalgia, that can be used to distinguish it from other exanthematous viral diseases.
Keywords: Zika virus; viral exanthema; maculopapular rash (Siriraj Med J 2020; 72: 330-335)
Corresponding author: Charussri Leeyaphan
E-mail: charussrilee@gmail.com
Received 1 August 2019 Revised 25 November 2019 Accepted 27 November 2019
ORCID ID: http://orcid.org/0000-0001-8430-376X
http://dx.doi.org/10.33192/Smj.2020.44
INTRODUCTION
Maculopapular eruptions, or exanthems, are described
as non-specic, erythematous, at, and elevated lesions
on the skin. ey can develop on the face, trunk, and
upper and lower extremities. While exanthems could
be due to a variety of skin diseases, they are mostly the
result of viral or bacterial infections and drug reactions.
1
e manifestations of virally caused exanthems may be
non-specic, but they frequently involve fever, mucosal
involvement, lymphadenopathy, myalgia, arthralgia, or
arthritis. As the identication of the responsible viral
pathogens can be a diagnostic challenge, pattern recognition
and pathognomonic signs are needed to dierentiate the
various viral diseases.
2,3
e Zika virus (ZIKV), a mosquito-borne avivirus,
caused a major outbreak in the State of Yap, the Federated
States of Micronesia, in 2007. e ZIKV landed in the
Americas as a result of immigration, and a major outbreak
occurred throughout most of the Americas during 2015
and 2016.
4-6
ZIKV is transmitted by the bite of the
Aedes aegypti mosquito species, sexual intercourse, and
pregnancy, and it can cause serious complications such
as Guillain–Barré syndrome and birth defects, especially
microcephaly and other brain malformations (in the case
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331
Leeyaphan et al.
of maternal-fetal transmissions).
7-9
Patients with ZIKV
infections may have no symptoms or mild symptoms,
such as fever and maculopapular eruptions like other
viral exanthems.
10,11
is study aimed to dierentiate the
clinical manifestations, related factors, and laboratory
results associated with ZIKV infections and other viral
exanthems in order to diagnose ZIKV infections and
prevent their spread prior to receiving conrmation by
a specic laboratory investigation.
MATERIALS AND METHODS
Study population
Enrolled were adult patients (aged 18 years and above)
who had been diagnosed with, or were suspected of having,
a viral exanthem or ZIKV infection upon attending the
Dermatology Clinic, Siriraj Hospital, Bangkok, January
2017-December 2018. Viral exanthems were diagnosed
from the patients’ histories and clinical manifestations
(such as fever, skin eruptions, and lymphadenopathy),
with drug eruptions or other infectious/inammatory
diseases being ruled out. The information collected
on each included patient comprised (1) demographic
data; (2) clinical features (fever duration, rash duration,
family/close contact cluster, pattern of rash distribution,
conjunctivitis, myalgia, arthralgia/arthritis, oral ulceration,
genital ulceration, cough, coryza, pharyngitis, and
lymphadenopathy); and (3) laboratory ndings, with
at least one complete blood count. In the ZIKV-infection
group, urine RT-PCR testing for ZIKV was required as
a conrmatory laboratory diagnosis. e study protocol
was approved by the the Siriraj Institutional Review
Board (Si 083/2019).
Statistical analysis
e statistical soware, SPSS for Windows, version
18.0 (SPSS Inc., Chicago, IL, USA) was used for the data
analyses. All continuous data were presented as means
and standard deviations. e Chi-squared test was used
to compare dierences in the categorical data. A binary
logistic regression was performed in a multivariate analysis
to nd the factors associated with the ZIKV and other
viral exanthems. A probability value (p-value) of less
than 0.05 was considered statistically signicant.
RESULTS
Demographic data
Of the 104 enrolled patients, 35 had ZIKV infections
while 69 had other viral exanthems resulting from measles,
rubella, dengue infection, and nonspecic maculopapular
eruptions. All patients had maculopapular eruptions
as their chief complaint. e mean ages were 43.6 ±
14.5 years (ZIKV group) and 36.2 years (other-viral-
exanthem group; p-value, 0.05). Most of the ZIKV-
infected patients were female (n = 26; 74.5%). In the
other-viral-exanthem group, 30 (43.5%) were male, and
39 (56.5%) were female. e mean fever duration before
coming to hospital was shorter for the ZIKV-infection
group than the other-viral-exanthem group, with 2.1 ±
1.1 days and 4.8 ± 3.2 days, respectively. e mean rash
duration of the ZIKV-infection group (2.1 ± 1.1 days)
was also shorter than that of the other-viral-exanthem
group (3.9 ± 6.1 days).
Clinical manifestations
With a cut point of 35 years, the ZIKV infections
were signicantly associated with an age of more than
35 years (p = 0.007; OR, 3.3; 95% CI, 1.4–8.2). ere
were no signicant dierences in the sexual statuses
of the patients in the ZIKV-infection and other-viral-
exanthem groups. Of the 35 ZIKV-infected patients,
most had fever (n = 27; 77.1%); a family/close contact
cluster (n = 25; 71.4%); conjunctivitis (n = 22; 62.9%);
and myalgia (n = 27; 77.1%). From the univariate analysis,
the factors that were statistically signicantly related to
ZIKV infections rather than other viral exanthems were
a family/close contact cluster (p < 0.001; OR, 8.8; 95%
CI, 2.2–34.6); conjunctivitis (p < 0.001; OR, 6.1; 95% CI,
2.5–14.9); myalgia (p < 0.001; OR, 5.3; 95% CI, 2.1–13.2);
and arthralgia/arthritis (p < 0.001; OR, 5.0; 95% CI,
2.1–12.6). By contrast, the following clinical features
were not signicantly related to ZIKV infections or other
viral exanthems: fever, pattern of rash distribution, oral
ulceration, genital ulceration, cough, coryza, pharyngitis,
and lymphadenopathy (Table 1).
In a multivariate analysis adjusted for all related
factors, a family/close contact cluster (p = 0.018; OR,
6.7; 95% CI, 1.4–32.7), conjunctivitis (p = 0.012; OR, 3.9;
95% CI, 1.3–11.2), and myalgia (p = 0.015; OR, 4.0; 95%
CI, 1.3–12.5) were found to be statistically associated
with ZIKV infections rather than other viral exanthems
(Table 1).
Laboratory ndings
From an analysis of the complete blood counts,
hematocrits and platelets were not aected in most
patients (Table 2). Leukocytosis (2.9%) was noted in one
ZIKV-infected patient and 9 (13%) other-viral-exanthem
patients. In both groups, a lymphocyte predominance
was found in a small proportion of the patients. Atypical
lymphocytes were present in 11.4% (n = 4) of the ZIKV-
infected patients and 26.1% (n = 18) of the other-viral-
exanthem patients. None of the ZIKV-infected patients had
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TABLE 1. Clinical characteristics of patients with Zika and other-viral-exanthem infections.
Factors ZIKV Other-viral- Univariateanalysis Multivariateanalysis
infections exanthem Crudeodds Adjusted
n(%) infections ratio(λ
2
) P-value odds ratio P-value
n(%) (95%CI) (95%CI)
Age 3.3 (1.4–8.2) 0.007* 1.8 (0.6–5.0) 0.294
< 35 years 9 (25.7) 37 (53.6)
≥35years 26(74.3) 32(46.4)
Sexual status 0.5 (1.8–1.1) 0.077
Male 9 (25.7) 30 (43.5)
Female 26 (74.3) 39 (56.5)
Fever 1.2 (0.5–3.1) 0.719
Yes 27 (77.1) 51 (73.9)
No 8 (22.9) 18 (26.1)
Family/closecontactcluster 8.8(2.2–34.6) <0.001* 6.7(1.4–32.7) 0.018*
Yes 25 (71.4) 3 (4.3)
No 10 (28.6) 66 (95.7)
Pattern of rash distribution 0.369
Centripetal 10 (28.6) 12 (17.4)
Centrifugal 16 (45.7) 33 (47.8)
Generalized abruption 9 (25.7) 24 (34.8)
Conjunctivitis 6.1 (2.5–14.9) < 0.001* 3.9 (1.3–11.2) 0.012*
Yes 22 (62.9) 15 (21.7)
No 13 (37.1) 54 (78.3)
Myalgia 5.3 (2.1–13.2) < 0.001* 4.0 (1.3–12.5) 0.015*
Yes 27 (77.1) 27 (39.1)
No 8 (22.9) 42 (60.9)
Arthralgia/arthritis 5.0(2.0–12.6) <0.001* 1.1(0.3–3.8) 0.846
Yes 17 (48.6) 11 (15.9)
No 18 (51.4) 58 (84.1)
Oral ulceration 0.4 (0.0–3.4) 0.364
Yes 1 (2.9) 5 (7.2)
No 34 (97.1) 64 (64.0)
Genital ulceration 2 (0.1–33.0) 0.621
Yes 1 (2.9) 1 (1.4)
No 34 (97.1) 68 (98.6)
Cough 1.4 (0.5–3.5) 0.529
Yes 9 (25.7) 14 (20.3)
No 26 (74.3) 55 (79.7)
Coryza 1.3 (0.5–3.8) 0.605
Yes 7 (20.0) 11 (15.9)
No 28 (80.0) 58 (84.1)
Pharyngitis 1.8 (0.8–4.3) 0.183
Yes 13 (37.1) 17 (24.6)
No 22 (62.9) 52 (75.4)
Lymphadenopathy 0.5 (0.1–2.7) 0.448
Yes 2 (5.7) 7 (10.1)
No 33 (94.3) 62 (89.9)
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TABLE 2. Laboratory ndings of patients with Zika and other-viral-exanthem infections.
Factors ZIKV Other-viral- Univariateanalysis
infections exanthem Crudeoddsratio P-value
n(%) infectionsn(%) (λ
2
)(95%CI)
Anemia (Hct <35%) 0.5 (0.1–0.4) 0.508
Yes 1 (2.9) 4 (5.8)
No 34 (97.1) 65 (94.2)
Leukocytosis 0.2 (0.0–1.6) 0.096
WBC(>10,000/ul)
Yes 1 (2.9) 9 (13.0)
No 34 (97.1) 60 (87.0)
Lymphocyte predominance (>40%) 2.0 (0.7–5.7) 0.201
Yes 8 (22.9) 9 (13.0)
No 27 (77.1) 60 (87.0)
Presence of atypical lymphocytes 0.4 (0.1–1.2) 0.084
Yes 4 (11.4) 18 (26.1)
No 31 (88.6) 51 (73.9)
Eosinophils (>7.5%) 1.0 (0.9–1.0) 0.211
Yes 0 (0) 3 (4.3)
No 35 (100) 66 (95.7)
Platelets(<200,000/ul) 0.4(0.1–1.1) 0.082
Yes 6 (17.1) 23 (33.3)
No 29 (82.9) 46 (66.7)
eosinophilia, whereas a few in the other-viral-exanthem
group did. In addition, none of the laboratory ndings
were signicantly associated with the ZIKV-infection
or the other-viral-exanthem groups.
DISCUSSION
is retrospective cohort study evaluated factors related
to ZIKV infections and compared them with the factors
for other exanthematous viral diseases. e associated
factors were characterized by demographic data; a history
of a family/close contact cluster; signs and symptoms
of fever, rash, and other u-related symptoms (such as
conjunctivitis and upper respiratory tract symptoms);
arthralgia; arthritis; myalgia; and lymphadenopathy. We
found that the ZIKV infections occurred in one-third
(33.7%) of all of the viral-exanthem patients who presented
with maculopapular eruptions. e age and sexual-status
ndings of the ZIKV patients were consistent with the
patterns reported for other countries. For example, in
Puerto Rico, ZIKV infections were more common among
females than males.
12
In addition, the mean age of the
ZIKV group in the Puerto Rico research was 43.6 years,
which is in the same range as that of the present study
(>35 years).
Due to the extensive Zika global outbreak that
commenced in 2015, a clustering of cases among ZIKV-
infected patients is more likely to be detected in many
patterns, such as family, close contact, tour group, and
immigrant.
13-15
In the case of ailand, a number of
travelers returning from rural areas within the country
were found to have evidence of ZIKV infections.
16
Our
study demonstrated that there was a strong association
of cluster with ZIKV infection (an odds ratio of 6.7
compared with the other-viral-exanthem group). e
fever duration was also longer than the rash duration for
both the ZIKV-infection and the other-viral-exanthem
groups. However, both the fever and rash durations of
the ZIKV-infection group were shorter than those of
the other-viral-exanthem group.
e classic manifestations of ZIKV infections include
Abbreviations: n, number; CI, condence interval; Hct, hematocrit; WBC, white blood cell; ul, microliter
Leeyaphan et al.
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fever, rash, conjunctivitis, and arthralgia/arthritis.
17,18
e
outstanding feature that dierentiates ZIKV infections
from other-viral-exanthem infections is non-purulent
conjunctivitis.
19
Nevertheless, this feature may not be
reliably prominent in some populations, as was the
case in a Malaysian study.
20
As to Bangkok, ailand,
the current study conrmed a statistically signicant
association between conjunctivitis and the ZIKV, with a
3.9 odds ratio. Myalgia was an additional clinical feature
that the current study determined was significantly
associated with the ZIKV among the viral-exanthem
patients. This finding correlates with a study in the
Brazilian State of Piaui that focused on patients infected
with arboviruses (dengue virus, chikungunya virus, and
ZIKV). Myalgia is one of the signicantly associated
features of the arboviruses group.
21
On the other hand, the clinical manifestations
that were not signicantly dierent between the ZIKV-
infection and the other-viral-exanthems groups were
fever, the pattern of rash distribution, mucosal ulceration,
arthralgia/arthritis, and lymphadenopathy. Aside from
conrming a ZIKV-infection using a real-time RT-PCR
analysis, a complete blood count is likely to be normal
and show no dierences between the two groups.
is study has the intrinsic limitations of retrospective
studies. Moreover, ZIKV and other-viral-exanthem infections
generally produce a wide range of clinical manifestations,
from asymptomatic to viremic symptoms. e current
study, however, focused on viral-exanthem populations
presenting with a cutaneous sign (a maculopapular rash).
A prospective cohort study utilizing a larger sample size
with diverse clinical symptoms could be considered in
further research.
CONCLUSION
e clinical manifestations associated with ZIKV
infections were a family/close contact cluster, conjunctivitis,
and myalgia. Discriminating these clinical features might
be useful in dierentiating between ZIKV and other-
viral-exanthem infections.
ACKNOWLEDGMENTS
e authors gratefully acknowledge the Head and
other sta of the Department of Dermatology, Faculty
of Medicine Siriraj Hospital, Mahidol University.
Conflicts of interest: is study had no conicts of
interest.
REFERENCES
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Z, et al. Clinical features and etiology of adult patients with
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2. Keighley CL, Saunderson RB, Kok J, Dwyer DE. Viral exanthems.
Curr Opin Infect Dis 2015;28:139-50.
3. Biesbroeck L, Sidbury R. Viral exanthems: an update. Dermatol
er 2013;26:433-8.
4. MacDonald PDM, Holden EW. Zika and Public Health:
Understanding the Epidemiology and Information Environment.
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5. Baud D, Gubler DJ, Schaub B, Lanteri MC, Musso D. An update
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6. Chang C, Ortiz K, Ansari A, Gershwin ME. e Zika outbreak
of the 21
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7. Hussain A, Ali F, Latiwesh OB, Hussain S. A Comprehensive
Review of the Manifestations and Pathogenesis of Zika Virus
in Neonates and Adults. Cureus 2018;10:e3290.
8. Armstrong N, Hou W, Tang Q. Biological and historical
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9. Aziz H, Zia A, Anwer A, Aziz M, Fatima S, Faheem M. Zika
virus: Global health challenge, threat and current situation. J
Med Virol 2017;89:943-51.
10. Haby MM, Pinart M, Elias V, Reveiz L. Prevalence of asymptomatic
Zika virus infection: a systematic review. B World Health
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11. Agumadu VC, Ramphul K. Zika Virus: A Review of Literature.
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12. Adams L, Bello-Pagan M, Lozier M, Ry KR, Espinet C, Torres
J, et al. Update: Ongoing Zika Virus Transmission - Puerto
Rico, November 1, 2015-July 7, 2016. MMWR 2016;65:774-9.
13. Sun J, Fu T, Mao H, Wang Z, Pan J, Rutherford S, et al. A
cluster of Zika virus infection in a Chinese tour group returning
from Fiji and Samoa: Sci Rep 2017;7:43527.
14. Wang G, Zheng W, Wu Z, Qi R, Zhu S, Tong Y, et al. A cluster
of Zika virus infection among travellers returning to China
from Samoa: a case tracing study. J Travel Med. 2018;25(1).
doi: 10.1093/jtm/tay022.
Fig 1. Maculopapular eruption which is commonly found in patients
with zika infections.
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15. Wu D, Sun J, Zhong H, Guan D, Zhang H, Tan Q, et al. A
family cluster of imported ZIKV cases: Viremia period may
be longer than previously reported. J Infection 2016;73:300-3.
16. Buathong R, Hermann L, aisomboonsuk B, Rutvisuttinunt
W, Klungthong C, Chinnawirotpisan P, et al. Detection of
Zika Virus Infection in ailand, 2012-2014. Am J Trop Med
Hyg 2015;93:380-3.
17. Basarab M, Bowman C, Aarons EJ, Cropley I. Zika virus. BMJ
(Clinical research ed) 2016;352:i1049.
18. Ng DHL, Ho HJ, Chow A, Wong J, Kyaw WM, Tan A, et al.
Correlation of clinical illness with viremia in Zika virus disease
during an outbreak in Singapore. BMC Infect Dis 2018;18:301.
19. Benzekri R, Belfort R, Jr., Ventura CV, de Paula Freitas B, Maia
M, Leite M, et al. Ocular manifestations of Zika virus: What
we do and do not know. JFr Ophtalmol 2017;40:138-45.
20. Woon YL, Lim MF, Tg Abd Rashid TR, ayan R, Chidambaram
SK, Syed Abdul Rahim SS, et al. Zika virus infection in Malaysia:
an epidemiological, clinical and virological analysis. BMC
Infect Dis 2019;19:152.
21. Vieira M, Costa CHN, Linhares ADC, Borba AS, Henriques
DF, Silva E, et al. Potential role of dengue virus, chikungunya
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Cruz 2018;113:e170538.
Leeyaphan et al.
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Chananwat Manyanon, M.D., Sopa Pongpornsup, M.D., Aphinya Charoensak, M.D.
Department of Radiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, ailand.
DynamicContrast-EnhancedComputedTomography
FindingsthatmayPredictPoorly-Differentiated
HepatocellularCarcinomaPriortoTreatment
ABSTRACT
Objective: To identify CT ndings that predict poorly-dierentiated hepatocellular carcinoma (p-HCC).
Methods: is retrospective study included pathologically proven HCC patients during January 2010 to December
2017 who underwent dynamic contrast-enhanced computed tomography (CT) imaging within 12 weeks before the
pathological diagnosis. CT ndings were reviewed and graded by consensus opinion of two abdominal radiologists.
e relationship between imaging ndings and histological dierentiation of HCC was analyzed using chi-square
test. Sensitivity, specicity, positive predictive value (PPV), negative predictive value (NPV), and accuracy for
diagnosis of p-HCC were calculated.
Results: Of 200 HCCs during the study period, 18 were well-dierentiated, 170 were moderately-dierentiated, and 12
were poorly dierentiated. Irregular rim enhancement in arterial phase (p<0.001) and presence of lymphadenopathy
(p=0.003) were both statistically signicantly dierent among the three types of histological dierentiation of
HCC. Sensitivity, specicity, PPV, NPV, and accuracy for prediction of p-HCC by the presence of irregular rim
enhancement in arterial phase and lymphadenopathy were 58.3%, 97.3%, 58.3%, 97.3%, and 95%, and 50%, 88.8%,
22.2%, 96.5%, and 86.5% - all respectively.
Conclusion: e presence of irregular rim enhancement in arterial phase and lymphadenopathy are potentially
useful CT ndings for prediction of p-HCC prior to treatment.
Keywords: Computed tomography; histological dierentiation; poor dierentiation; hepatocellular carcinoma
(Siriraj Med J 2020; 72: 336-342)
Corresponding author: Aphinya Charoensak
E-mail: caphinya@gmail.com
Received 10 June 2019 Revised 16 December 2019 Accepted 20 December 2019
ORCID ID: http://orcid.org/0000-0001-5179-9279
http://dx.doi.org/10.33192/Smj.2020.45
INTRODUCTION
Hepatocellular carcinoma (HCC) is the most
common primary malignant hepatic tumor, and it is
a huge contributor to the world’s cancer burden.
1
e
treatment options for HCC include curative therapies
(hepatic resection, liver transplantation, and ablative
techniques such as radiofrequency/microwave ablation
(RFA), percutaneous ethanol injection therapy (PEIT)), and
noncurative therapies (transarterial chemoembolization
(TACE), radioembolization, stereotactic body radiation
therapy (SBRT) and molecularly targeted therapy).
2-4
e type of treatment depends on tumor staging, patient
performance status, and liver function reserve.
RFA has grown quickly during the last decade and
currently considered the treatment of choice for HCC
patients with Barcelona-Clinic Liver Cancer (BCLC)
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Manyanon et al.
stage 0-A who are not suitable for surgery. However,
small (<2.5 cm) single tumor that is easily located
may be treated by either resection or ablation.
4
Forner
et al.
5
suggested RFA instead of resection in patients
with early HCC (<2 cm.). Several studies
6-8
reported that
histological grading of HCC is an important prognostic
factor aer treatment, and that poorly-dierented lesions
have the worse prognosis. It has also been reported that
poor dierentiation is a risk factor for tumor seeding
aer RFA.
9,10
Fukuda et al.
11
suggested that even solitary
small HCC (up to 2 cm.), when hepatic function is well
preserved, hepatic resection should be the rst choice
especially in cases of moderately or poorly dierentiated
HCC due to high frequency of microscopic vascular
invasion. erefore, the prediction of poorly dierentiated
HCC before treatment has potential benet for treatment
planning and for safe RFA even in patients with small
HCC.
Currently, non-invasive diagnosis of HCC can be
made by imaging characteristics on dynamic contrast-
enhanced computed tomography (CT) or magnetic
resonance imaging (MRI).
2
Pathological diagnosis is
reserved for suspicious lesions without characteristic
imaging features. However, histological dierentiation
of HCC is not accurately obtained before surgery. Our
review of the literature revealed that only a few studies
12-16
have investigated the relationship between imaging
ndings and histological grading of HCC.
Accordingly, the aim of this study was to investigate
and identify dynamic contrast-enhanced CT ndings
that may predict poorly-dierentiated hepatocellular
carcinoma (p-HCC) prior to treatment.
MATERIALS AND METHODS
Study population
is retrospective single-center study was approved
by the Siriraj Institutional Review Board (SIRB) (Si
226/2016) of the Faculty of Medicine Siriraj Hospital,
Mahidol University, Bangkok, ailand. e requirement
to obtain written informed consent was waived. Patients
with pathologically proven diagnosis of HCC during
January 2010 to December 2017 were searched using
pathological electronic database diagnosis. Patients who
had no data relative to histological dierentiation, who
had not undergone dynamic CT within 12 weeks before
the pathological diagnosis, who had received any prior
treatment (e.g., RFA, TACE), and/or who had improper
phases of dynamic CT were excluded. A owchart showing
the patient enrollment process is given in Fig 1. Our
database search revealed 200 patients (151 males, and
49 females) with a pathologically proven diagnosis of
HCC. e mean age of patients was 60.3±11.3 years
(range: 30-93). e pathology diagnosis was obtained
from core needle biopsy in 49 patients (24.5%), and from
surgical resection in 151 patients (75.5%). e median
time interval between CT imaging and pathological
diagnosis was 31 days (range: 1-83).
Fig 1. Flowchart describing the patient enrollment process.
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CT technique and interpretation
Dynamic CT scans of the liver were performed with
a 16, 64, or 128 detector helical CT scanner (LightSpeed
VCT, Discovery CT 750 HD and Optimal CT660; GE
Healthcare, United States or SOMATOM Denition
Dual Source, Siemens, Germany). e slice thickness was
1.25-1.5 mm (reconstructed at 5.0-7.0 mm). Dynamic
contrast-enhanced CT scans were routinely performed
during breath hold, including non-contrast, arterial
dominant, and portovenous phases. Delayed phase
was added in some patients. e arterial dominant,
portovenous, and delayed phases were performed at 35
seconds, 80 seconds, and 5 minutes aer initiation of
contrast injection. Approximately 2 mL/kg of nonionic
iodinated contrast agent followed by 20 mL of water
was injected using a power injector at a rate of 2-3 mL/
second.
CT images were retrospectively reviewed and graded
by consensus opinion by two abdominal radiologists
with 16 years and 13 years of experience, respectively.
Types or levels of dierentiation of HCC included well-
dierentiated (w-HCC), moderately-dierentiated (m-HCC),
and poorly-dierentiated (p-HCC). Both readers were
blinded to pathological dierentiation data and other
clinical characteristics, and knew only that the patient
had been denitively diagnosed with HCC. For cases
with multiple tumors, the largest lesion at the location
of pathological diagnosis was assessed. CT ndings
were assessed, as follows: number of tumor(s) (single or
multiple), tumor size (measurement of maximal diameter,
including capsules), tumor margin (smooth, irregular, or
inltrative), tumor attenuation on pre-contrast images,
degree of tumor enhancement (arterial enhancement,
hypovascular enhancement), enhancement pattern on
arterial phase (homogenous, heterogenous (Fig 2)),
presence of non-enhanced area on arterial phase (Fig 2&3),
presence of irregular rim enhancement on arterial phase
(Fig 4), tumor stain washout on portovenous or delayed
phases (Fig 3), capsular enhancement, lymphadenopathy
(lymph node enlargement of >1 cm in short axis diameter),
and vascular invasion.
Statistical analysis
Descriptive statistics were used to summarize patient
characteristics. Normally distributed continuous data,
including age and tumor size, are presented as mean ±
standard deviation. Non-normally distributed continuous
data, such as time interval between CT imaging and
pathological diagnosis of HCC, are given as median
and range. Categorical data are shown as frequency
and percentage. e relationship of CT ndings among
the three types of histologic dierentiation of HCC was
analyzed using chi-square test. Sensitivity, specicity,
positive predictive value (PPV), negative predictive
value (NPV), and accuracy for diagnosis of p-HCC were
calculated according to signicant ndings on dynamic
contrast-enhanced CT. Statistical signicance was dened
as a p-value less than 0.05. All statistical analyses were
performed using SPSS Statistics version 18.0 (SPSS, Inc.,
Chicago, IL, USA).
A. Axial CT image of arterial phase showing homogenous arterial enhanced HCC in right hepatic lobe without non-enhanced area (arrow).
B. Axial CT image of arterial phase (dierent case) showing heterogenous arterial enhanced HCC in le hepatic lobe (arrow) with presence
of non-enhanced area (arrowhead).
Fig 2. Two dierent cases of arterial enhancement without non-enhanced area and arterial enhancement with non-enhanced area.
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RESULTS
Of 200 HCC cases, 120 cases (60%) had single lesion
and 80 cases (40%) had multiple lesions. e histological
classication was w-HCC in 18 cases (9%), m-HCC in
170 (85%) cases, and p-HCC in 12 cases (6%). ere
was no statistically signicant dierence in mean tumor
diameter, type of tumor margin, tumor attenuation on
pre-contrast image, pattern of tumor enhancement,
presence of non-enhanced area on arterial phase, tumor
stain washout, capsular enhancement, or vascular invasion
among the three types of histological dierentiation of
HCC, as shown in Table 1. Hypovascular enhancement
pattern was found in three cases (1.5%). All cases of
p-HCC in the present study showed hypoattenuation on
pre-contrast images, heterogenous arterial enhancement,
presence of non-enhanced area on arterial phase, and
tumor stain washout.
e present study found irregular rim enhancement
(p<0.001) and presence of lymphadenopathy (p=0.003)
to be statistically signicantly dierent among the three
types of histological dierentiation of HCC (Table 1).
e percentage of presence of irregular rim enhancement
was signicantly higher as the histological dierentiation
grade advanced. Lymphadenopathy was more commonly
observed in p-HCC (50%) than in w-HCC (11.1%) and
m-HCC (11.2%).
e sensitivity, specicity, PPV, NPV, and accuracy
for the prediction of p-HCC by irregular rim enhancement
and lymphadenopathy are shown in Table 2. Irregular rim
enhancement had higher specicity, NPV, and accuracy
(97.3%, 97.3%, and 95%, respectively) than lymphadenopathy
(88.8%, 96.5%, and 86.5%, respectively) for p-HCC. e
accuracy for prediction of p-HCC by combining these
two ndings did not signicantly improve diagnosis
compared to irregular rim enhancement alone, but the
sensitivity was decreased to 33.3%.
A. Axial CT image - arterial phase showing the presence of non-enhanced area on arterial phase (black arrow)
B. Axial CT image – portovenous phase showing tumor stain washout
C. Axial CT image – delayed phase showing tumor stain washout and the presence of capsular enhancement (white arrow)
Fig 3. Dynamic contrast-enhanced CT of a moderately-dierentiated HCC case (pathological diagnosis from surgical resection).
Axial CT images of arterial phase (A) and portovenous phase (B) showing the presence of irregular rim enhancement on arterial phase
(white arrow), and multiple abdominal lymphadenopathies (asterisk). Vascular invasion into portal vein and IVC was also demonstrated
(black arrow).
Fig 4. Dynamic contrast-enhanced CT of a poorly-dierentiated HCC case (pathological diagnosis from core needle biopsy).
Manyanon et al.
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TABLE 1. Correlation between CT ndings and histological dierentiation of HCC
CTndings Histologicallydifferentiation p-value
a
95%CI
w-HCC m-HCC p-HCC
(n=18) (n=170) (n=12)
Tumor size; mean diameter ± SD 6.5±4.4cm 5.3±3.9cm 6.3±3.4cm 0.524
Tumor margin 0.147
Irregular 16 (88.9%) 132 (77.6%) 11 (91.7%)
Smooth 1 (5.6%) 37 (21.8%) 1 (8.3%)
Inltrative 1(5.6%) 1(0.6%) 0(0.0%)
Tumor attenuation on pre-contrast images 0.232
Hypoattenuation 13 (72.2%) 152 (89.4%) 12 (100%)
Isoattenuation 2 (11.1%) 10 (5.9%) 0 (0.0%)
Hyperattenuation 3 (16.7%) 7 (4.1%) 0 (0.0%)
Fat content 0 (0.0%) 1 (0.6%) 0 (0.0%)
Degree of tumor enhancement 1.0
Arterial enhancement 18 (100%) 167 (98.2%) 12 (100%)
Hypovascular enhancement 0 (0.0%) 3 (1.8%) 0 (0.0%)
Enhancement pattern on arterial phase
b
0.232
Heterogeneous 17 (94.4%) 143 (85.6%) 12 (100%)
Homogeneous 1 (5.6%) 24 (14.4%) 0 (0.0%)
Non-enhanced area on arterial phase
b
0.077
Present 16 (88.9%) 125 (74.9%) 12 (100%)
Absent 2 (11.1%) 42 (25.1%) 0 (0.0%)
Irregular rim enhancement
b
<0.001
Present 0 (0.0%) 5 (3.0%) 7 (58.3%)
Absent 18 (100%) 162 (97%) 5 (41.7%)
Tumor stain washout
b
0.858
Present 17 (94.4%) 158 (94.6%) 12 (100%)
Absent 1 (5.6%) 9 (5.4%) 0 (0.0%)
Capsular enhancement 0.734
Present 7 (38.9%) 55 (32.4%) 3 (25.0%)
Absent 11 (61.1%) 115 (67.6%) 9 (75.0%)
Lymphadenopathy 0.003
Present 2 (11.1%) 19 (11.2%) 6 (50.0%)
Absent 16 (88.9%) 151 (88.8%) 6 (50.0%)
Vascular invasion 0.483
Present 3 (16.7%) 22 (12.9%) 3 (25.0%)
Absent 15 (83.3%) 148 (87.1%) 9 (75.0%)
a
Among the three dierent types of histologic dierentiation in HCC,
b
Does not included three cases of hypovascular enhancement
Abbreviations: CT, computed tomography; HCC, hepatocellular carcinoma; w-HCC, well-dierentiated HCC; m-HCC, moderately-
dierentiated HCC; p-HCC, poorly-dierentiated HCC; SD, standard deviation
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DISCUSSION
Histological grading of HCC is a relevant prognostic
factor aer treatment
6-8
, and some studies found that
poor dierentiation is a risk factor of tumor seeding
aer RFA.
9,10
However, pathological diagnosis of HCC
is not usually obtained before surgery, and needle biopsy
is not routinely performed because of the risk of tumor
seeding and the probability of diagnostic error due to
tumor heterogeneity. erefore, investigation into the
correlation between imaging ndings and histological
grading of HCC might have some potential benet for
management of HCC patients.
Our study found that irregular rim enhancement on
arterial phase had high specicity (97.3%) for prediction
of p-HCC. is is similar to the ndings of Kawamura,
et al.
15
who found heterogeneous enhancement with
irregular ring-like structures in the arterial phase to be
an independent predictor of p-HCC. e explanation of
this enhancement pattern may be combination of tumor
necrosis and other factors, such as type II vessels
15
; however,
the exact mechanism remains unknown. Nakachi, et al.
13
reported that arterial enhancement with non-enhanced
areas, which included irregular rim enhancement pattern,
was associated with p-HCC. Non-enhanced area on arterial
phase and irregular rim enhancement on arterial phase
were separately investigated in our study. Although non-
enhanced area on arterial phase was present in all p-HCC
in our study, this nding was not signicantly dierence
among the three types of histological dierentiation of
HCC. is dierence compared to prior study might be
due to the small number of p-HCC and the relatively
larger mean tumor size (5.5±3.9 cm. for all HCC cases)
in our study. Tumor size is a factor that may aect
enhancement pattern of HCC. Yoon SH, et al.
16
reported
that tumor size <2 cm and w-HCC frequently had atypical
enhancement patterns.
Irregular rim arterial enhancement pattern can also be
found in other hepatic tumors, such as cholangiocarcinoma
and brolamellar HCC. However, cholangiocarcinoma
is rare in chronic hepatitis or cirrhotic patients when
compared with HCC. Some imaging features can help in
dierentiating intrahepatic cholangiocarcinoma (ICC)
from HCC.
17
ICC exhibits rim-like peripheral arterial
enhancement with progressive centripetal enhancement,
and it usually associates with peripheral biliary dilatation
or capsular retraction. On the other hand, presence of
intralesional fat and enhanced capsule are more suggestive
of HCC than ICC. Fibrolamellar HCC, which is a rare
primary liver tumor, has clinicopathologic features
dierent from conventional HCC. It predominantly
occurs in young patients without underlying hepatitis
or cirrhosis, and serum alfa-fetoproteins are not elevated
in most cases.
18
Calcication and central stellate scar
are commonly seen in brolamellar HCC.
18
Presence
of intralesional fat is more suggestive of conventional
HCC than of brolamellar HCC.
18
Abdominal lymph node is one of three most common
sites of extrahepatic metastatic HCC.
19
In our study,
lymphadenopathy was more commonly present in p-HCC
(50%) than in w-HCC or m-HCC, and it had a specicity
of 88.8% for prediction of p-HCC. is nding is similar
to that reported by Lee, et al.
20
who found HCC with
lymph node metastasis to be signicantly associated with
worse histological grade. However, the use of lymph node
size criteria did not improve the accuracy of detection of
metastatic nodes in our study. Enlarged lymph nodes can
be either benign or metastatic nodes, and lymph node
metastasis can be found in normal sized nodes. Further
non-invasive imaging study for accurate evaluation of
metastatic nodes is needed.
Tumor stain washout in the portovenous phase was
reported to be associated with p-HCC in prior study.
13
TABLE 2. Sensitivity, specicity, positive predictive value (PPV), negative predictive value (NPV), and accuracy
for prediction of p-HCC using CT ndings.
CTndings Sensitivity Specicity PPV NPV Accuracy
Irregular rim enhancement 58.3% 97.3% 58.3% 97.3% 95%
Lymphadenopathy 50.0% 88.8% 22.2% 96.5% 86.5%
Coexisting irregular rim enhancement 33.3% 98.4% 57.1% 95.8% 94.4%
and lymphadenopathy
Abbreviations: p-HCC, poorly-dierentiated hepatocellular carcinoma; CT, computed tomography
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Lee, et al.
12
reported that early washout favored m-HCC
and p-HCC more than w-HCC, and the presence of
intratumoral aneurysm was highly specic nding for
p-HCC. However, tumor stain washout was not found
to be signicant dierent among the three histological
grades of HCC in our study.
Limitations
Our study has some limitations. First, this was a
retrospective study and there was selection bias related to
the inclusion criteria that only patients with pathological
proof and CT images obtained within 12 weeks were
selected. Second, the pathological diagnosis included
patients with needle biopsy samples which can lead to
diagnostic error due to heterogeneity of HCC tumors.
ird, the small numbers of w-HCC (18 cases) and p-HCC
(12 cases) in our study may reduce the reliability of the
analysis. In the future, a larger scale cohort investigation
should be conducted.
CONCLUSION
ere is potential benet of dynamic contrast-
enhanced CT for prediction of p-HCC. e presence
of irregular rim enhancement in arterial phase and
lymphadenopathy are potentially useful CT ndings
for prediction of p-HCC prior to treatment.
ACKNOWLEDGMENTS
e authors gratefully acknowledge Ms. Julaporn
Pooliam, MSc. of the Division of Clinical Epidemiology,
Department of Research, Faculty of Medicine Siriraj
Hospital, Mahidol University for assistance with statistical
analysis.
Conict of interest declaration: Both authors declare
no personal or professional conicts of interest, and no
nancial support from the companies that produce and/
or distribute the drugs, devices, or materials described
in this report.
Funding disclosure: AC and SP were supported by a
Chalermphrakiat Grant from the Faculty of Medicine
Siriraj Hospital, Mahidol University, Bangkok, ailand.
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Taketomi A, et al. Arterial blood supply of hepatocellular
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Bedavanija et al.
Anan Bedavanija, M.D.*, Pongsakorn Tantilipikorn, M.D, Ph.D.*, Pichit Suksaranjit, M.D.***, Tawatchai
Pongpruttipan, M.D.**, Pawin Keskool, M.D.*, Cheerasook Chongkolwatana, M.D.*, Choakchai Metheetrairut,
M.D.*, Jate Lumyongsatien, M.D.*, Triphoom Suwanwech, M.D.*
*Department of Otolaryngology, **Department of Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, ***Diamond Clinic,
Bangkok 10240, ailand.
FactorsAffectingUnfavourableResultsfrom
aSinonasalInvertedPapillomaSurgery
ABSTRACT
Objective: Sinonasal inverted papilloma (SNIP) is the most common nasal benign tumor, but locally invasive.
e standard treatment is to identify origins of the tumor and total removal. Unfavourable results are nding
postoperative residual or recurrent tumors. e aim of this study is to determine factors aecting postoperative
residual or recurrent tumors and a rate of getting postoperative residual or recurrent tumors from SNIP surgeries.
Methods: A retrospective study in patients with SNIPs was conducted. Relationships between demographic data, tumor sites,
tumor stages by Krouse classication, surgical approaches, surgeons’ experience, using microdebrider assisted surgery, operative
time, intraoperative blood loss, histopathology, Epstein Barr virus (EBV), human papillomavirus (HPV) infection, time to
detect tumor aer surgery and unfavourable results were evaluated. HPV and EBV were detected by in situ hybridization.
Results: 73 patients were included in this study. Unfavourable results were found in 27 patients (36.99%). 50% of patients
received unfavourable results aer postoperative duration of 115 months. 5 years of a disease-free survival rate was 64.3%
(95% CI: 51.9% to 76.7%). e patients with external surgical approaches got worse results than those with endoscopic
sinus surgery (p = 0.01, a hazard ratio of 3.88, 95% CI: 1.39 to 10.87). e patients operated without using microdebrider
assisted surgery got worse results than those with using the device (p < 0.001, an adjusted hazard ratio of 5.09, 95%
CI: 2.08 to 12.45). e patients with abnormal pathological changes (tissue dysplasia and malignant transformation)
had worse results than those without changes (p = 0.02, an adjusted hazard ratio of 3.42, 95% CI: 1.24 to 9.38).
Conclusion: Non-endoscopic nasal surgery, non-using microdebrider assisted surgery, and abnormal pathological
changes may be some of the causes of unfavourable results from SNIP surgeries. Long postsurgical surveillance
should be done, because of 36.99% of patients received unfavourable results from SNIP surgeries.
Keywords: Sinonasal inverted papilloma; unfavourable results; relationship; sinus surgery (Siriraj Med J 2020; 72:
343-351)
Corresponding author: Pongsakorn Tantilipikorn
E-mail: ptantili@yahoo.com
Received 17 February 2020 Revised 20 April 2020 Accepted 22 April 2020
ORCID ID: http://orcid.org/0000-0003-1995-4798
http://dx.doi.org/10.33192/Smj.2020.46
INTRODUCTION
Sinonasal papillomas are nasal benign tumors
developing from Schneiderian membranes, which are
ectodermal remnants at boundary between nasal and
sinus mucosa. ey are classied into sinonasal inverted
papilloma (SNIP), exophytic (fungiform) papilloma,
and oncocytic (cylindrical cell) papilloma. e most
common type of sinonasal papilloma is SNIP. SNIPs,
which are found 0.2-1.5 cases per 100,000 populations
1,2
,
are the most common benign tumor of the nose and
paranasal sinuses
13
, but they are locally aggressive and
usually recurrent. e tumors usually erode adjacent
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344
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SMJ
bones, extend to the orbit and intracranium. ey have
5-15% risks of malignant transformation, and 5-15%
risks of recurrence.
3-9
e main treatment is to identify
all sites of tumor attachments, remove all tumors with
aected mucosa, and drill out underlying bone in order
to prevent tumor recurrence.
10
e standard treatment is
an external approach with a medial maxillectomy via a
lateral rhinotomy, or a midfacial degloving procedure.
11,41
Nowadays, an endoscopic surgery is usually performed,
because it can reduce the morbidity of an external approach.
An endoscope can help surgeons to visualize in the
surgical eld, even hidden sites such as an anterior wall
of the maxillary sinus e.g., endoscopic Denker approach
(anteromedial maxillectomy).
9,41
erefore, some surgeons
use an endoscope to assist an external approach to
obtain complete tumor removal. A microdebrider is a
powered rotary shaving device. It provides atraumatic
dissection by resecting tissue precisely, minimizing
unintended mucosal trauma. e using microdebrider
assisted surgeries showed minimal bleeding, decreased
surgical time, faster postoperative healing
19,22
, and should
reduce postoperative recurrences of SNIP surgeries.
Postoperative recurrent rate of SNIP surgeries is lower
in primary resections than secondary resections
10,12
, so
the patients with SNIPs should be operated as primary
resections. Meta-analysis studies suggest HPV and EBV
infection maybe potential causes of recurrence
2, 21,40
, but
no study in ailand.
e risk factors aecting unfavourable results from
SNIP surgeries, in literary reviews, are ages, genders, surgical
approaches, tumor sites, tumor stages, histopathology,
virus infection, and smoking
2,11-13
; however, they are still
controversial. e purpose of this study is to determine
the factors aecting postoperative residual or recurrent
tumors and a rate of getting postoperative residual or
recurrent tumors from SNIP surgeries.
MATERIALS AND METHODS
A retrospective study was conducted on patients,
selected from 289 cases of SNIP surgeries, at Siriraj
Hospital between January 2004 and December 2012. All
patients, presenting as primary SNIPs, are more than 18
years old, postoperative tumor surveillance to December
2019. Exclusion criteria included partial or incomplete
resection, revision surgery, and incomplete patient data.
Demographic data, tumor sites, tumor stages by Krouse
classication
14
, surgical approaches, surgeons’ experience,
using microdebrider assisted surgery, operative time,
intraoperative blood loss, histopathology, EBV, HPV
infection, and a date of nding postoperative tumors
were evaluated. e criteria of unfavourable result are
nding postoperative residual or recurrent tumor by nasal
endoscopic examination and pathological conrmation.
e recurrent cases were dened as nding postoperative
tumor aer postoperative duration of 3 months. A total
of 73 patients were selected in this study (Fig 1).
Hematoxylin and eosin-stained pathological slides
were reviewed, and the diagnosis was conrmed by one
pathologist (T.P.). Paran-embedded tissue blocks were
selected for tissue microarray. e tissue microarray
sections were hybridized separately with a target probe
of Ventana Inform HPV II Family® 6 Probes, for low-
risk HPV genotypes 6,11, then Ventana Inform HPV III
Family® 16 Probes, for high-risk HPV genotypes 16, 18,
31, 33, 35 45, 51, 52, 56, 58, 66, and Epstein Barr virus
encoding RNA (EBER).
is study protocol was approved by the Institutional
Review Board Committee of the Siriraj Hospital. e
sample size calculation was based on the study of Busquets
et al.
8
, found 15 % of postoperative SNIP recurrences.
Sixty-one patients were required to get 95% condence
level with a type I error at 0.05.
Fig 1. Flowchart of this study
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345
Statistical analysis
e data was presented as numbers and percentages. If
quantitative variables were normally distributed, the results
were expressed as mean values and standard deviation,
otherwise as median. A dierence between two groups
was analyzed by using t-test, or Mann-Whitney U test.
Qualitative data are reported as counts and frequencies,
and dierences between two groups were analyzed by
using Pearson Chi-Square test or Fisher’s exact test,
and receiver operating characteristic (ROC) curve. Cox
regression was used to analyze the association of factors
of unfavorable results. Kaplan-Meier curve and log
rank test were used to analyze a disease-free survival. A
p value of 0.05 was considered as a statistical signicance.
All calculation was performed by using SPSS, PASW
statistics for windows, version 18.0.
RESULTS
General data
e age of the 73 patients ranged from 24 to 87
years, with a mean of 54.90 ± 13.27 years. ere were
37 males and 36 females. e most common presenting
symptom was nasal obstruction (71.60%). Other presenting
symptoms were rhinorrhea/postnasal drip (11.24%),
epistaxis (6.51%), smell dysfunction (2.96%), facial pain
(2.96%), headache (1.78%), blocked ear (1.18%), toothache
(1.18%), and oropharyngeal pain (0.49%).
Sixty-three patients had multiple tumor sites (86.30%).
All SNIPs were unilateral sites, found 37 right-sided
tumors, and 36 le-sided tumors. Tumors were located
at lateral nasal wall (34.72%), maxillary sinus (23.83%),
ethmoid sinus (19.17%), sphenoid sinus (5.70%), frontal
sinus (7.25%), middle turbinate (4.66%), superior turbinate
(2.07%), nasal septum (1.55%), and inferior turbinate
(1.04%). Tumor stages by Krouse classication
14
revealed
4 groups as T1 (5.48%), 20 patients as T2 (27.40%), 47
patients as T3 (64.38%), and 2 patients as T4 (2.74%).
Endoscopic sinus surgeries were performed in
49 patients (67.12%). 6 patients (8.22%) underwent
external surgical procedures and 18 patients (24.66%)
were operated by combined approaches. Microdebriders
were used in 28 of all cases (61.64%). SNIPs with tissue
dysplasia without malignant change were found in 3
patients (4.11%). All of them were gotten postsurgical
recurrences. Malignant transformations to squamous
cell carcinoma occurred in 3 patients (4.11%). All of
them were synchronous malignancy, no regional or
distant metastasis, and recurrent tumors were found in
2 patients. All patients with malignant transformations
were received postoperative radiation therapy, and 2
patients were received concurrent chemotherapy. A
surgical margin was not free in one patient; however,
all patients with malignant changes had survived.
Analysis of unfavorable results
e unfavourable results were found in 27 patients
(36.99%) (7 residual cases, and 20 recurrent cases) and 50%
of patients received unfavourable results aer postoperative
duration of 115 months. 5 years of a disease-free survival
rate was 64.3% (95% CI: 51.9% to 76.7%). A mean time
of unfavourable results was 30.23 months (ranging from
0.82 to 115.31 months).
Genders, ages, and onset of disease
An average age of the patients with unfavourable
results was 50.82 years old, which is lower than a mean
age of 57.30 years old in the successful group. ere
was a statistically signicant dierence between the two
groups (p = 0.04). However, no relationship was found
between genders, onset of disease and unfavourable
results (p = 0.52, 0.27, respectively) (Table 1).
Tumor sites and stages
No statistical signicances were found between each
of the tumor sites (lateral nasal walls, ethmoid sinuses
maxillary sinuses, sphenoid sinuses, frontal sinuses,
superior turbinates, middle turbinates, inferior turbinates,
and nasal septums), multiple tumor sites, tumor stages
and unfavourable results (p = 0.19, 0.52, 0.61, 0.52,
0.61, 0.14, 0.28, 1.00, 0.55, 0.74, and 0.82, respectively)
(Table 1).
Surgical approaches, intraoperative time, techniques,
and blood loss
A signicantly dierence was found between three
surgical approaches (p = 0.04) (Table 1). Both an endoscopic
sinus surgery and an endoscopic assisted external surgical
procedure oered better outcome than an external surgical
procedure (p = 0.007, 0.04, respectively). However, no
dierent in treatment outcome was found between the
two groups using endoscope (p = 0.60). e patients
with external surgical approaches had worse results than
those with endoscopic sinus surgery (p = 0.01, a hazard
ratio of 3.88, 95% CI: 1.39 to 10.87) (Fig 2).
No dierence in surgical treatments was found
between experienced and training surgeons (resident
and/or fellow under supervision) (p = 0.45) and no
relationships between intraoperative time, blood loss
and unfavourable results were found (p = 0.16, 0.39,
respectively) (Table 1).
Microdebrider is an assisted surgical device in
nasal surgery and can be used for cutting and removing
Bedavanija et al.
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TABLE 1. Factors aecting unfavourable results from SNIP surgeries in univariate analysis.
Factors Successfultreatments Unfavorabletreatments P-value
(n = 46) (n = 27)
Genders 0.52
Male 22 15
Female 24 12
Meanofages (years) 57.30 50.82 0.04***
Median of disease onset (months) 7.5 (3,12) 12 (3,24) 0.27
Tumorsites:
Lateral nasal walls 0.19
No 2 4
Yes 44 23
Ethmoidsinuses 0.52
No 24 12
Yes 22 15
Maxillary sinuses 0.61
No 16 11
Yes 30 16
Sphenoid sinuses 0.52
No 40 22
Yes 6 5
Frontal sinuses 0.61
No 38 21
Yes 8 6
Superior turbinates 0.14
No 45 24
Yes 1 3
Middle turbinates 0.28
No 42 22
Yes 4 5
Inferior turbinates 1.00
No 45 26
Yes 1 1
Nasalseptums 0.55
No 45 25
Yes 1 2
Multiple sites 0.74
No 7 3
Yes 39 24
Tumorstages 0.82
T1 3 1
T2 12 8
T3 30 17
T4 1 1
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347
TABLE 1. Factors aecting unfavourable results from SNIP surgeries in univariate analysis. (continued)
Factors Successfultreatments Unfavorabletreatments P-value
(n = 46) (n = 27)
Surgicalapproaches 0.04***
Endoscopic sinus surgery 34 15
External surgical procedure 1 5
Endoscopic assisted external 11 7
surgical procedure
Medianofintraoperativetime (minutes) 120 (90,150) 140 (100,180) 0.16
Median of intraoperative blood loss (ml) 225 (80,450) 300 (100,550) 0.39
Usingmicrodebrider assistedsurgery 0.005***
Non-using 12 16
Using 34 11
Surgeons’experience 0.45
Experience 36 19
Training 10 8
Tissuedyplasiaandmalignant 0.05***
transformation
No dysplasia and malignant 45 22
transformation
Dysplasia and malignant transformation 1 5
HPV infection 0.37
No HPV infection 46 26
HPV infection 0 1
Fig 2. Disease free survival and surgical approaches
Bedavanija et al.
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tissues, together. e patients with using microdebrider
assisted surgery got better surgical outcomes than those
without using the device (p =0.005) (Table 1).e patients
operated without using microdebrider assisted surgery
got worse results than those with using the device (p =
0.001, a hazard ratio of 4.51, 95% CI: 1.88 to 10.81, and
p < 0.001, an adjusted hazard ratio of 5.09, 95% CI: 2.08
to 12.45, in multivariate backward cox regression analysis
with abnormal pathological changes (tissue dysplasia
and malignant transformation) (Fig 3).
Histopathology
The relationship was found between abnormal
pathological changes (tissue dysplasia and malignant
transformation) and unfavorable results (p = 0.05)
(Table 1). The patients with the changes got worse
unfavourable results than those with no pathological
change (p = 0.05, a hazard ratio of 2.59, 95% CI: 0.97 to
6.90, and p = 0.02, an adjusted hazard ratio of 3.42, 95%
CI: 1.24 to 9.38, in multivariate backward cox regression
analysis with using microdebrider assisted surgery) (Fig 4).
Virus infection
Only one patient in the unfavourable group was
positive for HPV type 6 by in situ hybridization and no
EBV was detected in all patients. No relationship was
found between HPV infection and unfavorable results
(p = 0.37) (Table 1).
Fig 4. Disease free survival and abnormal pathological changes
Fig 3. Disease free survival and using microdebrider assisted surgery
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349
DISCUSSION
Factors aecting unfavourable results from SNIP
surgeries could be surgical approaches, using microdebrider
assisted surgeries, and abnormal pathological changes.
An average age of the patients with unfavourable
results was 50.82 years old, which is lower than a mean
age of 57.30 years old in the successful group. e patients
with unfavourable results of SNIP surgeries were younger
than those with good results as other studies
20,36,39
, because
they might get more risks of exposure with chronic
inammatory conditions, such as chronic infection,
smoking, pollution
15,16
, which could induce normal tissues
developing to SNIPs. However, it might be no clinical
signicance in surgical decisions between age groups.
e surgical approaches, which depended on surgeons’
experience, tumor sites, were selected in each patient. e
patients with external surgical approaches had a hazard
ratio of 3.88 to get failed results. e groups of using
endoscope had better outcomes, as other studies
8,9,18
,
because endoscope can help surgeons to visualize in
all surgical elds, even hidden sites such as an anterior
wall of maxillary sinus, a lateral wall of frontal sinus.
erefore, we should use endoscope to assist in SNIP
surgeries, especially in high Krouse classication.
e patients operated without using microdebrider
assisted surgery had an adjusted hazard ratio of 5.09 to get
unfavourable results. e group with using microdebrider,
which can cut together with tissue suction, got better
results, because surgeon could see clearly operative eld
and got completely tumor removal.
8,19,22
Unfortunately,
the device is a special instrument which is not included in
the standard instruments in SNIP surgeries. According
to our study, surgeons should use this device to get good
outcomes in all cases of SNIP surgeries.
e study by Lisan et al.
2
found that the tumor
attachment sites were related to tumor recurrences,
especially in the frontal sinus, and in cases with
multiple tumor origins. ere were not found in our
and others study
36,42
, because of few patients included in
some tumor sites. No relationship was found between
Krouse classication, and unfavourable results as other
studies
10,12-13,17,38-39
, because of also few patients in T1
and T4.
Long intraoperative time and high intraoperative
blood loss might be factors of poor surgical outcomes such
as delayed wound healing, incomplete tumor removal, but
no relationship between those and unfavourable results
were found in our study. Experienced surgeons should be
better in surgical outcomes than training surgeons. No
dierence in curative eects in surgical experience was
found, because Siriraj Hospital is a tertiary care and an
otolaryngological training center. Even though, patients
were in training cases, our stas had to supervise our
training surgeons and completely examine those patients
before nishing operations.
In this study, a statistical signicance was found
between the patients with abnormal pathological changes
(tissue dysplasia and malignant transformation) and
unfavourable results. e patients with that changes got an
adjusted hazard ratio of 3.42 to get unfavourable results as
previous studies that found features of atypia, enhanced
hyperkeratosis, presence of squamous hyperplasia
12,42
may predispose to recurrence. us, we should pay
more attention to those and frequently postoperative
surveillance with the changes that could be a factor of
tumor recurrences.
EBV was not detected in all patients as same as other
studies
15
and could not be a factor of unfavorable results.
One patient with an unfavourable result was positive for
HPV type 6 by in situ hybridization. Our study is the
rst study of HPV in nasal tumors in ailand, so there
is no study in that for comparison. e HPV studies,
which were found low HPV detection, in head neck
tumors in ailand
25-29
, might be used as comparison.
HPV was low detected in our study, which contrasted
with previous studies
21-24
because HPV might rarely be
found in these regions in ailand, and Ventana Inform
HPV Family® cannot detect all HPV types. Our negative
results could be true negative, because Ventana Inform
HPV Family® can be usually used in paran-embbed
tissues as other studies and in situ hybridization can
detect HPV as same as other molecular techniques.
30-35
e study by Holte et al.
36
found a decreasing ratio of
HPV-positive SNIPs with advanced tumor stages as T3,4
of Krouse classication. e positive case in our study
was in T2 of Krouse classication and other negative
results were usually found in T3 of Krouse classication.
Accordingly, HPV infection may not be a risk factor of
unfavourable results in SINP surgeries in ailand.
e unsuccessful treatment rate of 36.99%, in our
study, was nearly the recurrent rate of 30.51% in the
past study by Jareoncharsri et al.
37
and 37% in the other
study in ailand by Fooanant et al.
18
e recently meta-
analysis study by Peng et al.
9
found the recurrence rate
was 12.8%. In our study, the unsuccessful treatment rate
was higher than that study, because our study included
residual and recurrent tumors, was long terms postsurgical
surveillance, and microdebrides were not used in all
surgical cases. SNIPs in our country may tend to recur.
e 115 months of 50 % nding postoperative tumor
were suggested postoperative surveillance should be at
least 10 years.
Bedavanija et al.
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Malignant transformation (4.11%) was lower than
other studies of 5 to 15 % of malignant transformation.
11-12,38
is nding may indicate that SNIPs in ailand are
non-violent, but frequently recurrent.
e drawback of this study is not included some
factors, which might be factors of unfavourable results,
such as smoking, pollution, revision surgery, sending an
intraoperative tumor margin and few patients in some
Krouse classication.
e prominence of this study is a retrospective
study, which is no bias in surgical outcomes, and long
postsurgical surveillance. From our and other studies in
ailand
18,37
, SNIPs may tend to recur, low malignant
changes and need long postsurgical surveillance. e
future study should include a medical genetic study
in patients with SNIPs and malignant changes, and a
benet of using microdebrider assisted surgery.
CONCLUSION
Non-endoscopic nasal surgery, non-using microdebrider
assisted surgery, and abnormal pathological changes
were possible risk factors of unfavourable results in
SNIP surgeries. Because of the patients, with using nasal
endoscopes and microdebriders assisted SNIP surgeries,
gotten better surgical results, both devices should be the
standard equipments in SNIP surgeries. e patients with
abnormal pathological changes should be frequently
surveilled, because they had a risk of postoperative
recurrences. Long postsurgical surveillance should be
done, because of 36.99% of patients received unfavourable
results from SNIP surgeries.
ACKNOWLEDGMENTS
is study was supported by a grant from Faculty
of Medicine Siriraj Hospital, Bangkok, ailand. e
authors would like to thank Mr. Suthipol Udompunturak
for his help with statistical analysis and Ms. Ngamrat
Treerassapanich for her help with complete data.
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Original Article
SMJ
awatchai Lukseng, Vorasith Siripornpanich, Nuanchan Chutabhakdikul, Ph.D.
Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Nakornpathom 73170, ailand.
Long-TermVipassanaMeditationEnhances
Executive Function in Adult Meditators
ABSTRACT
Objective: Vipassana meditation (VM) is a traditional Buddhist meditation practice that focuses on monitoring of
clear awareness of oneself exactly what is happening as it happens, without judging. Executive functions (EF) are
the high-level cognitive processes that facilitate goal-directed behaviors. It is well known that VM has signicant
eects on various aective states of the mind, such as relaxation, reduce stress and anxiety; however, less is known
about the eect of VM on the executive function. is study aims to examine the eects of VM practice on the
performance of the executive function in the adult meditators.
Methods: Forty adult participants, age range between 25-50 year-olds, were recruited to this study. ey were
divided into three groups; the control group (N=20, mean age = 40.5 ± 5.8 years), Short-term VM group (N=6,
mean age = 38.0±9.1 years), and Long-term VM group (N=14, mean age = 37.7±7.3 years). All participants were
examined by 1) State-trait anxiety inventory (STAI); 2) Philadelphia mindfulness scale (PHLMS); 3) Digit span task
of WAIS-IV, 4) Tower of Hanoi (ToH), and 5) Wisconsin Card Sorting Test (WCST-CV4). e mean scores of all
task performance were statistically analyzed and compared between groups. Alpha values of .05 were considered
signicant throughout.
Results: Both short-term and long-term VM has common benets to decreased anxiety and increased mindfulness
score as compared with the non-meditator group. Although short-term VM shows some benets to the performance
of several EF tasks, the discrepancy was not signicant when compared with the control group. In contrast, long-
term VM had a signicant benet to the performance of working memory, planning, and shi/cognitive exibility,
when compared with the non-meditator group. Our results indicated that long-term VM practice not only reduces
anxiety and improves mindfulness, but the benet also extends to improve the performance of the executive function
in adult practitioners.
Conclusion: In conclusion, our results suggest that continued practice of VM is highly eective for enhancing EF
in healthy individuals. Long-term VM practice not only reduce stress and improve mindfulness but also enhance
the performance of EF tasks of the practitioners.
Keywords: Vipassana meditation; executive function; Philadelphia Mindfulness Scale; Wisconsin Card Sorting
Test; Digit Span; Tower of Hanoi (Siriraj Med J 2020; 72: 352-360)
Corresponding author: Nuanchan Chutabhakdikul
E-mail: nuanchan.chu@mahidol.edu
Received 23 July 2019 Revised 5 January 2020 Accepted 18 February 2020
ORCID ID: http://orcid.org/0000-0001-7338-4824
http://dx.doi.org/10.33192/Smj.2020.47
INTRODUCTION
Meditation is the method of body and mind training
for promoting relaxation, improving focus attention,
and concentration.
1,2
Previous studies demonstrate
various benets of meditation practice on body and
mind, such as; reduced anxiety and stress,
3-5
improve
emotional stability,
6
improve concentration and enhance
personal well-being,
7
and produce long-term increases
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353
in efficiency of the attentional network.
8
Moreover,
the clinical eectiveness of meditation has been reported for
the treatment of various physical and mental illnesses.
9-11
Buddhist meditation can be classied into two main
methods according to the mental skills that exercise during
meditation practice as follows; 1) Focused Attention (FA)
in which the practitioner requires to attend or focus onto
the selected object, such as breathing or candlelight, and to
avoid mind wandering for a period of practice,
12,13
and 2)
Open Monitoring (OM)in which the practitioner requires
to maintain awareness of their mental, interoceptive,
and exteroceptive experiences, and without any object to
focusing on.
14-16
ese two types of meditation have been
reported to aect brain function dierently. For example,
FA improves sustained attention associated with increased
activity in the dorsolateral PFC (DLPFC).
17
In contrast,
OM improves sustaining internalized attention associated
with increased activity in the posterior insular cortex.
18
e previous study reported that one of the OM-like
meditation called Mindfulness-based stress reduction
(MBSR), not only has a signicant benet on emotional
well-being but also improved cognitive inhibition in the
school-aged students as examined by various cognitive
tasks.
19
Importantly, a study in the healthy individuals
shows that MBSR increased brain activity in the insular
cortex (the brain area involved with self-awareness and
interoceptive awareness) but no signicant eect on the
DLPFC activity.
20
In contrast, FA that focuses on the
concentration training alone might have less benet on
cognitive abilities since the previous study reported that
FA meditators perform various cognitive tasks as equal
to the non-meditator group.
19
Another type of Buddhist meditation that combines
both FA and OM together is the so-called Vipassana
meditation or VM. VM is the meditation practice that
focuses on the monitoring of clear awareness of oneself
exactly what is happening as it happens.
15,16
Usually, the
VM starts by focusing attention (FA) on to the selected
object (such as the breath) and then broadens the focus
to the sensory or mental stimuli (OM). erefore, VM
practice uses both FA and OM in order to stay in the
monitoring state to any experiences that may arise without
selecting, judging, or avoiding the aective responses to
that stimuli. In this way, the VM practice could enhance
concentration, bare attention, and cultivate a non-reactive
form of sensory awareness.
Executive function (EF) is an umbrella term representing
higher cognitive processes that are essential for goal-
directed behaviors.
21-24
ere are 3 main components of
EF which compose of; 1) working memory-the ability
to updating and monitoring information; 2) Inhibitory
control-the ability to inhibit the pre-potent responses and
inhibit at the level of attention or inhibit distraction; and
3) Shi/cognitive exibility-ability to shiing of mental set
and exible thinking.
23
EF gradually develops from early
childhood to adulthood, correlate with the maturation
of the neural networks that linking the prefrontal cortex
with other brain regions.
25
In healthy adults, EF serves
as a predictor of everyday functioning since intact is
required for daily functions including; setting goals,
planning, and prioritizing the complex tasks, initiating,
sustaining attention despite distraction. People with proper
EF skills show better in managing their life and work
performance in the challenge situations, as compared
to the one with poor EF.
21
Although many studies consistently reported the
common benet of meditation on body and mind,
3,5,26,27
however, dierential eects of short-term and long-term
VM on the performance of EF tasks have yet to be fully
elucidated. Interestingly, a recent study showed that
amygdala activity response dierently in the short-term
or long term meditators in response to the negative
emotional stimuli.
28
e present study employed various
neuropsychological tests to investigate the eects of
short-term and long-term VM on executive function in
adult practitioners. We hypothesized that long-term VM
practice associated with higher mindfulness scale and
lower anxiety level that could enhance the performance
of EF as compared to the non-meditator group.
MATERIALS AND METHODS
Participants
Participants are healthy adults, aged between 25-50
years, n=40. Vipassana meditators were recruited from
the meditation centers in Bangkok metropolitan areas,
whereas the control subjects were recruited from the
communities in the same area. A demographic questionnaire
was completed before any measurements, which included
information about age, sex, general health information,
and years of education. Participants were asked for
information about their meditation background such
as; duration, frequency, and average hours of lifetime
VM practice, then, they were divided into three groups;
1) Control group, is the participants who had no prior
experience of any meditation practice (n =20; mean
age = 40.5±5.8 years), 2) Short-term VM group, is the
beginner who had average VM practice around 3.5 years
(n=6; mean age 38.0±9.1 years), and 3) Long-term VM
group is the meditator who had average VM practice
for 10 years (n=14; mean age=37.7±7.3 years). ere
were no signicant dierences in the mean ages and
average years of education of the participants from all
Lukseng et al.
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Original Article
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groups (Table 1). e meditation background of the
participant in the short-term and long-term VM group
was shown in Table 2. Informed consents were obtained
from all participants before any measurements, and the
experimental protocol was strictly followed the ethical
standards outlined of the Declaration of Helsinki in
1975 and has been approved by the Institutional Review
Board (COA.No. 2014/146.2011). All participants had
no history of neurological illness.
Measures
e State-Trait Anxiety Inventory (STAI-Adult)
e State-Anxiety scale (S-Anxiety) consists of
twenty statements that evaluate how participants feel right
now or at this moment.
29
e S-anxiety scale represents
the feelings of apprehension, tension, nervousness, and
worry of the participant at that time. Whereas the Trait-
Anxiety scale (T-Anxiety) consists of twenty statements
that assess how participants generally feel. e T-anxiety
scale has been used for identifying persons with high
levels of anxiety. e total questions are 40 items; each
item was weighted score from 1 to 4. e raw scores were
converted into the standard scores and the percentile
rank. e higher means score indicated more anxiety
in that section.
Philadelphia Mindfulness Scale (PHLMS-ai)
Philadelphia Mindfulness Scale (ai version) from
the Department of Mental Health, Ministry of Public
Health, ailand, was used to assess the mindfulness level
of the participants.
30,31
e PHLMS has high reliability, and
high validity with Pearson’s correlation for the awareness
and acceptance scale is 0.88 and 0.89, respectively; and
the Cronbach’s alpha coecient of the awareness and
acceptance scale are 0.87 and 0.88, respectively.
30
It
contains 20 items for measurement of awareness and
acceptance level of the participants. e awareness and
acceptance subscales were obtained from the sum of
scores in all odd or even-numbered items, respectively.
e score ranged from 10-50 points in each subscale
or 20-100 points in the total score. e higher PHLMS
score indicates more mindful than lower PHLMS scores.
Participantsbackground Non-meditation Short-termVM Long-termVM
Age (years) 40.5 ± 5.8 38.0±9.1 37.7±7.3
Gender (M:F) 18:2 4:2 11:3
N 20 6 14
Years of Education 15.6 ± 2.5 15.6±1.9 16.8±1.0
TABLE 1. Demographic characteristics of the participants. Data represents means±SD.
TABLE 2. Meditation background of the participants of the Vipassana meditation (VM) group. Data represents
means±SD.
Meditationbackground
Short-termVM Long-termVM
Average Max Min Average Max Min
Years of practice 3.6±1.1 5.0 2.0 10.0±6.6 18.0 5.0
Durationofpractice(hours/day) 0.5±0.1 0.5 0.3 1.2±0.6 3.0 0.5
Frequencyofpractice(days/week) 4.3±2.1 7.0 2.0 6.1±1.5 7.0 4.0
Total hours of practice 366±198 650 89 3,462±2,654 8,736 728
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Working Memory Scale (WAIS-IV)
e working memory part of the Wechsler Adult
Intelligence Scale (WAIS-IV) was used to evaluating the
working memory (WM) capacity of the participants.
32
Two categories of WM tasks were used; the digit span
forward and the digit span backward. In the forward
session, the researcher read a series of number sequences
to the subject, and then subjects had to repeat them
immediately in the same order. Aer nish the forward
session, the examiner began the digit span backward
session by reading a series of number sequences, and
subjects had to repeat the number sequences in the
reversed order. There are eight blocks of digit span
forward, and seven blocks of digit span backward. Each
block contains two sets of questions. In both tasks, the
length of the most extended number lists that the subject
could recall was recorded. e scaled score by the age-
and gender-matched was used to compare between the
two groups.
Tower of Hanoi (ToH)
e Tower of Hanoi was used for evaluating a higher
level of EF, especially the planning process (http://www.
coolmath-games.com/0-tower-of-hanoi). It composes
of 3 pieces of the rod with several discs. e discs are
dierent in their size and can be moved among the
rods. Subjects are required to move the disc from the
start point until they reach the goal position. ere were
three to ve discs that represent levels of task diculties.
e numbers of moves and the total time to complete
the task were recorded. Lower numbers of moves and
shorter response times indicate the better performance
of the ToH task.
Wisconsin Card Sorting Test (WCST-CV4)
e Wisconsin Card Sorting Test®: Computer Version
4 (WCST:CV4) (PAR, Inc.) was used for measurement of
various EF domains, including; mental shiing, planning,
and working memory.
33
For the task, the stimulus cards
were presented on the monitor, and the participants
were asked to match the stimulus cards with one of the
four category cards by trial and error. Subjects were
given by the feedback on the screen (“right” or “wrong”)
immediately aer each sorted. e following data were used
for analysis: (1) trials administered, (2) total correct, (3)
total errors, (4) perseverative responses, (5) perseverative
errors, (6) non-perseverative errors, (7) % conceptual
level responses, (8) number of Categories Completed,
(9) trials to complete the 1st Category, and (10) failure
to maintain set.
Data and statistical analysis
Data were analyzed using the SPSS soware version
18.0, and the values were reported as mean ± SD. Group
dierences in the demographic variables were examined with
non-parametric chi-square or independent samples t-tests.
e normality of standardized residuals for the dependent
variables was tested using the Kolmogorov-Smirnov (K-S)
test. e data form all groups were found to be normally
distributed with all variables demonstrating skewness
and kurtosis within standard limits. To investigate the
dierence among the short-term-, long-term meditators
and the control group, the statistical analysis for the mean
scores of the state-trait anxiety inventory (STAI), tower
of Hanoi (ToH), and the Philadelphia mindfulness scale
(PHLMS); scale scores of the WAIS working memory
index, and the standard scores of the Wisconsin card
sorting test (WCST), were performed using the one-
way analysis of variance (ANOVA) and following up a
signicant result with Tukey’s multiple comparisons test.
Pearson’s correlation examined the correlation between
the acceptance scale of PHLMS and the time to complete
the 3-discs ToH task. e statistical signicance was set
at a p-value of less than 0.05.
RESULTS
State-Trait Anxiety Inventory (STAI)
e mean scores of S-Anxiety and T-Anxiety were
compared between the three groups. Short-term VM had
a signicant lower in the mean score of the S-Anxiety as
compared to the control group (p<.05) (Table 3). Long-
term VM had a signicant lower in the mean score of
both the S- and T-Anxiety as compared to the control
group (p<.05). Regarding the experience of VM practice,
our results indicated that both short-term and long-term
VM generally lead to a decrease in stress and anxiety as
compared to the non-meditator control group.
Philadelphia Mindfulness Scale (PHLMS)
The mean score of the PHLMS awareness and
acceptance subscale were compared between the three
groups. Both short-term and long-term VM had a
signicantly higher mean score of the total mindfulness
score of the PHLMS (p<.01 and p<.001, respectively). For
the mean scores of each subscale, short-term VM had a
signicantly higher in the mean score of the awareness
subscale (p<.001) as compared to the control group.
While long-term VM had a signicantly higher in the
mean score of both awareness (p<.001) and acceptance
subscale (p<.01), as compared to the control group
(Table 3). Results indicate that both short-term and
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long-term VM practices had a similar benet on the
mindfulness scale as compared to the non-meditator
control group.
Digit Span
Raw scores of the total digit span (digit forward
plus digit backward) were converted into the standard
score. e standard scores were then compared between
the three groups. e result demonstrated that only the
long-term VM group had a signicantly higher mean
standard score of the total digit span as compared to the
control group (p<.001) (Table 4). Although the short-term
VM group show a small increase in the mean, standard
score of the total digit span, however, the discrepancy was
not signicant when compared with the non-meditator
control group. Results indicated that long-term VM had
a signicantly better performance on working memory
tasks as compared to the non-meditator group.
Tower of Hanoi
For the ToH 3-Discs level, only long-term VM group
signicantly use less number of moves as compared to
the control group (p<.05). For the times to complete
the task, both short-term and long-term VM groups
signicantly perform faster when compared with the
control group (p<.05 and p<.01, respectively) (Table 5).
Results indicated that long-term and short-term VM had
a signicantly better performance on the plan/organize
domain of EF than the non-meditator control group.
Wisconsin Card Sorting Test – Computer Version 4
(WCST-CV4)
Although there is no signicant dierence between
the three groups in the Total correct of WCST test, long-
term VM had a signicantly higher standard score, which
means better performance in overall WCST performance,
as compared to the control (Table 6). For examples, long-
term VM had a signicant lower in total error (p<.001),
perseverative responses (p<.05), perseverative errors
(p<.01), and non-perseverative errors (p<.001), and a
signicant higher in % conceptual level response (p<.001),
as compared to the control. Long-term VM also had a
signicant lower in the number of trials administered
(p<.001), number of trials to completed the 1
st
Category
(p<.05), and a signicantly higher in number of categories
completed (p<.05), as compared to the control. For the
short-term VM, although they show a trend of better
in the overall performance of WCST, however, most
of the discrepancy was not signicant when compared
with the non-meditator or the long-term VM group.
Short-term VM had a signicantly lower only in the non-
perseverative errors (p<.05), and a signicantly higher in
% conceptual level response (p<.05), as compared with
the control. Our results indicated that long-term VM
practice had a better performance on WCST that focuses
on the set-shiing domain of EF, especially cognitive
exibility, as compared to the non-meditator group.
Correlation between PHLMS acceptance scale and the
time to complete ToH task
Pearson’s correlation analysis found the negative
correlation between the acceptance scale of the PHLMS
and the time to complete the ToH task (3-Discs) within
the subjects of the VM group (both short-term and
long-term) with r = -0.52, p<0.05 (Fig 1). e results
indicated that the meditator who has a higher PHLMS
acceptance score tends to use less time to complete
the 3-Discs of ToH task (better performance) than the
meditator who has a lower PHLMS acceptance score.
TABLE 3. Table compares the mean standard scores of the STAI and the PHLMS scale scores between the control,
short-term, and long-term VM groups. Data represents means±SD.
Tasks Control Short-termVM Long-termVM
State-trait anxiety inventory (STAI)
State-anxiety 50.1 ± 6.3 43.0±6.5* 44.8±4.5*
Trait-anxiety 54.9 ± 7.6 50.8±8.5 47.2±7.9*
Philadelphia mindfulness scale (PHLMS)
Awareness 33.8 ± 3.0 40.1±4.1** 42.2±4.4***
Acceptance 29.0 ± 6.2 34.0±5.1 37.2±7.9**
Total scores 62.9 ± 6.1 75.1±7.5** 77.4±9.7***
*p<.05, **p<.01 and ***p<.001, as compared to the control group.
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TABLE 4. Table compares the mean standard scores of the digit span total between the control, short-term, and
long-term VM groups. Data represents means±SD.
TABLE 5. Table compares the performance of Tower of Hanoi (ToH) between the control, short-term, and long-
term Vipassana group. Data represents means±SD.
TABLE 6. e performance of WCST-CV4 compared between the control group, short-term and long-term VM
group. Data represents means±SD.
Workingmemorytask Control Short-termVM Long-termVM
Digit span total 9.5±1.9 12.2±1.7 15±3.7***
***p<.001, as compared to the control group.
TowerofHanoi(3discs) Controlgroup Short-termVM Long-termVM
Number of moves 10.0±4.4 7.0±0.0 7.0±0.0*
Moving time (sec) 41.8±29.9 16.6±6.9* 15.0±4.0**
*p<.05 and **p<.01, as compared to the control group.
WCST-CV4 Controlgroup Short-termVM Long-termVM
WCST-CV4Standardscores
Total Errors 82.5±16.5 96.2±11.1 99.6±4.9***
PerseverativeResponses 86.3±23.8 95.0±10.9 97.1±4.9*
Perseverative Errors 85.8±23.3 94.0±11.2 97.1±4.7**
Non-perseverative Errors 85.2±23.0 97.2±11.2* 99.8±5.7***
%ConceptualLevelResponses 82.5±16.1 97.3±12.8* 100.0±6.0***
WCST-CV4Rawscores
Trials Administered 108.1±21.7 92.3±22.7 77.4±7.5***
Trials to Complete 1
st
Category 30.4±30.3 13.3±5.2 11.6±2.1*
Total Correct 70.1±12.9 73.8±12.3 76.2±4.8
Categories Completed 4.5±2.2 6.0±0.0 6.0±0.0*
Failure to Maintain Set 0.8±1.6 1.0±1.5 0.3±0.4
*p<.05, **p<.01 and ***p<.001, as compared to the control group.
Lukseng et al.
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DISCUSSION
is study examined the long-term eects of Vipassana
meditation on executive function in adult practitioners.
e main ndings are; 1) Both short-term and long-term
VM groups had a signicantly higher PHLMS mindfulness
score and a signicantly lower state- anxiety score as
compared to the non-meditator group. 2) Although
short-term VM shows a trend of improving performance
on various EF tasks; however, the discrepancy was not
significant when compared with the non-meditator
group. 3) Only long-term VM shows signicantly better
performance on various EF tasks that require working
memory, shi/ cognitive exibility and planning, as
compared to the non-meditator group. Furthermore,
4) e PHLMS acceptance scale signicantly correlates
with the performance on the EF task (ToH-3 discs).
Traditional Vipassana meditation combines both
FA and OM together. VM usually begins with focus
attention (FA) and followed by an open monitoring
(OM) session. Aer practicing of VM for many years,
the meditator could gradually cultivate both the narrow
or focus attention (during FA) and the broader attention
skill (during OM).
16
e previous study found that VM
practice could enhance attention and reduce the distracting
thoughts and behaviors, indicated that systematic
attention training through VM practice has a benet
on the brain plasticity underlying a better cognitive
inhibition or focus attention.
27,34
In opposite ways, the
neural circuit for cognitive inhibition is required when
the meditators monitoring own emotions or inhibit
inappropriate behaviors. Importantly, cognitive inhibition
is a fundamental requirement for executive function and
self-regulation.
19,35
In this study, we found that both short- and long-
term VM group had signicantly better performance on
planning, as examined by the Tower of Hanoi (ToH) task,
than the non-meditator group. Besides, the performance
on ToH correlates with the PHLMS acceptance scale. e
previous study revealed that during the ToH task, there is
an increased activity in the dorsolateral PFC (DLPFC)
36
which is the brain area associated with planning and
prediction of the sequence of actions, as well as sustaining
focus and monitoring of attention.
37,38
erefore, the VM
practice could enhance the planning domain of EF via
increased activity in the DLPFC, especially during the
FA session.
Fig 1. Scatter plot between acceptance scale of Philadelphia mindfulness scale (PHLMS) and 3-D time of tower of Hanoi (toH).
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Although short-term VM shows a trend of better
in the overall performance of WCST, however, most
of the discrepancy was not signicant when compared
with the non-meditator or the long-term VM group. In
contrast, long term VM practice signicantly improves
performance in various executive function tasks. It is
possible that during each VM practice, it requires the
inhibitory control aspect of EF, either during FA or OM
sessions. e inhibitory control composed of; 1) Response
inhibition -which means the behavioral inhibition or self-
control and 2) Interference control- or the inhibition of
the wandering thought at the level of attention (similarly
to inhibit distraction).
21
e inhibitory control (includes
both response inhibition and interference control) could
enhance attentional control, which in turn supports the
working memory performance as well. erefore, the
interaction among these factors could explain how long
term VM practice could enhance the executive function
of the practitioners.
Results from the present study indicated that long
term VM practice could improve the overall performance
of various EF tasks, which required working memory,
plan/organize, and cognitive exibility. Moreover, the
strong correlation between the mindfulness acceptance
scale and the performance of EF tasks indicate the benet
of VM on the mindfulness acceptance that might support
a better performance of EF tasks as well.
In conclusion, our results suggest that continued
practice of VM is highly eective for enhancing EF in
healthy individuals. Long-term VM practice not only
reduce stress and improve mindfulness but also enhance
the performance of EF tasks of the practitioners. Our
results suggest that the benet of VM practice on the
performance of EF might need several hours of lifetime
practice, therefore, the application of meditation to
improve EF in patients with physical and mental problems,
should consider both the types of meditation and the
duration of practice. Long-term VM practice extends
the benet beyond stress reduction to improve higher
cognitive executive function.
ACKNOWLEDGMENTS
e authors thank the ailand Research Fund for
nancial support for this project. Also, we would like to
thank Mr. Supakij Patthanapitoon to help us collect the
data. Finally, we would like to give a sincere thanks to
all participants who agree to participate in this study.
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361
Sutasinee Boonsopon, M.D.*, Pitipol Choopong, M.D.*, Wisakorn Wongwijitsook, M.D.**, Wanchana
Sopitviriyaporn, M.D.*, Nattaporn Tesavibul, M.D.*
*Department of Ophthalmology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, **Debaratana Nakhon Ratchasima Hospital,
Nakhon Ratchasima 30280, ailand.
Non-InfectiousScleritisandSystemicCollagen
Vascular Disease Association
ABSTRACT
Objective: To evaluate the dierences between scleritis in association with a systemic collagen vascular disease and
idiopathic scleritis and to describe the clinical characteristics of patients presenting with non-infectious scleritis.
Methods: A retrospective cohort study of 95 patients who presented with non-infectious scleritis was conducted.
A comparison of the clinical dierences between patients who had an associated systemic collagen vascular disease
and idiopathic scleritis was performed.
Results: Of the 95 patients (123 eyes), 72.6% was female with mean age of 47 years. Diuse anterior scleritis was
the most predominant type (57.9%). e rst and the second most frequent complications were anterior uveitis
and scleral thinning. Almost twenty percent of the patients had a systemic collagen vascular disease involvement;
rheumatoid arthritis and non-specic anti-neutrophil cytoplasmic antibodies-related scleritis were the two most
common (4.2% each). Most of the patients who had a concurrent systemic collagen vascular disease presented with
diuse anterior scleritis, but it was not statistically signicant compared with the idiopathic group. e presence of
scleral thinning during follow-up periods showed a statistically signicant dierence between the groups with and
without systemic collagen vascular disease at p value 0.038.
Conclusion: Diuse anterior scleritis was the most common type of scleritis found. Patients who had collagen vascular
disease and scleritis commonly developed scleral thinning during follow up visits. Aggressive treatment for scleritis
in immune-mediated systemic collagen vascular disease may be considered to prevent progressive scleral thinning.
Keywords: Scleritis; immune; rheumatology; inammation (Siriraj Med J 2020; 72: 361-367)
Corresponding author: Sutasinee Boonsopon
E-mail: sutasinee.boo@mahidol.edu
Received 18 August 2019 Revised 4 April 2020 Accepted ……………….
ORCID ID: http://orcid.org/0000-0002-6556-0215
http://dx.doi.org/10.33192/Smj.2020.48
INTRODUCTION
Scleritis is a considerably rare ocular disorder which
can be characterized by an inammation of the sclera.
Most scleral inammation is non-infectious in origin and
is commonly associated with a systemic collagen vascular
disease.
1,2
Previous studies established that approximately
25% to 50% of scleritis cases were associated with an
underlying systemic inammatory condition, including
rheumatoid arthritis (RA), granulomatosis with polyangiitis
(GPA), seronegative spondyloarthropathies, and systemic
lupus erythematosus.
2,3
RA and GPA were reported to
have the highest associations.
2,4-6
Patients presenting
with anterior scleritis typically complain of an eye pain
with globe tenderness and progressive ocular redness,
whereas patients presenting with posterior scleritis may
present with a reduced vision without ocular pain.
4,7
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Complications of scleritis can be mild, such as limited
adjacent structural inammation, or serious, such as
scleral melting and perforation. e treatment decision
between non-steroidal anti-inammatory drugs (NSAIDs),
corticosteroids, or immunomodulatory therapy (IMT)
usually depends on disease severity and patient safety.
e incidence of overall scleritis varies; in Northern
California, it was reported as 3.4 cases per 100,000 person-
years
8
; in a Pacic islander (Hawaiian) population, it was
approximately 4.1 cases per 100,000 person-years
9
; and
in the general population, it was claimed to be 6 cases per
100,000 person-years.
5
Scleritis occurs most frequently
among women and the elderly.
10,11
We conducted this
study to evaluate the clinical features of non-infectious
scleritis in ailand and the patterns of association of
the scleritis with a systemic collagen vascular disease.
MATERIALS AND METHODS
is study was designed as a descriptive retrospective
cohort study. A retrospective chart review of 95 patients
with non-infectious scleritis presenting at Siriraj Hospital,
Mahidol University, ailand, between January 2013 and
December 2015 was performed. e study was conducted
in accordance with the declaration of Helsinki, and
approved by the Ethics Committee of Siriraj Hospital,
Mahidol University. Scleritis was dened as a presentation
of edematous episcleral and scleral tissue with deep
episcleral and scleral vessels engorgement. Application of
10% phenylephrine revealed no blanching of deep scleral
vascular plexus. Scleritis classication was based on site of
anatomical inammation, which was anterior and posterior
scleritis. For anterior scleritis, it could present as diused
scleral inammation, localized nodular inammation
or necrotizing sclera. For posterior scleritis, fundus
examination might reveal edematous optic disc and/or
retinal striae or subretinal uid. B-scan ultrasonography
showed positivity of T-sign as a result of posterior scleral
inammation and adjacent swollen tenon. Patients with
infectious related scleritis including bacteria, mycobacteria,
spirochete, fungus, and parasite were excluded from the
study. Mantoux test was done in some selected cases.
Only patients who had been exposed to tuberculosis,
was considered for the skin test. Treponemal and non-
treponemal test was performed in most of the patients
to rule out syphilitic infection. We documented the
demographic data, the scleritis type (namely, diuse
anterior scleritis, nodular anterior scleritis, necrotizing
scleritis with and without inammation [also known
as scleromalacia perforans], and posterior scleritis),
and the associated systemic collagen vascular disease.
e details documented were the ocular ndings of a
slit-lamp examination, the best-corrected visual acuity
at the baseline visit and subsequent follow-ups, the
number of recurrences, and the treatment (including
any necessity for immunomodulatory therapy). As to the
ocular complications, we collected details on associated
peripheral ulcerative keratitis (PUK), anterior uveitis,
scleral thinning, secondary ocular hypertension (OHT),
vitritis, papillitis, cystoid macular edema (CME), and
exudative retinal detachment (ERD). For scleral thinning,
we normally documented it when sclera appeared blue on
a slit lamp examination. Once non-infectious scleritis was
suspected, we routinely perform laboratory investigations
to evaluate possibility of systemic immune-related diseases.
Not only basic laboratory investigations (complete
blood count, liver and renal function test, urinalysis,
chest radiogram) but also specic investigations such as
rheumatoid factor, anti-citrullinated protein antibody,
antinuclear antibodies, anticytoplasmic antibodies,
erythrocyte sedimentation rate, C-reactive protein were
performed. Some patients with symptoms specic to
autoimmune diseases would be further investigated
with some of the following tests: anti-double stranded
DNA, anti-Smith, urine protein and urine protein to
creatinine ratio, paranasal sinus radiogram, and may be
sent for a rheumatologist consultation to evaluate cause
of inammation. For the subgroup analysis, we divided
our patients into two groups: an idiopathic group, and a
scleritis with associated systemic collagen vascular disease
group. Patients with incomplete investigations were
excluded from the subgroup analysis. For patients who
had bilateral eye involvement, only the right eyes were
used for analysis. e clinical features were described
as descriptive statistics. Pearson’s chi-squared test was
used to compare categorical data, and Student’s t-test was
used to compare continuous data. To determine which
variables were associated with systemic collagen vascular
disease, a multivariate model was developed using variables
significantly associated (p < 0.1) with systemic collagen
vascular disease from univariate analysis. Variables
found not to be significant or variables for which 95%
confidence limits crossed the line of unity were excluded
by backwards elimination, unless they improved the fit
of the model. All statistical analyses were performed
using SPSS Statistics version 18.0 (SPSS, Inc., Chicago,
IL, USA). Ethical approval for this study was provided
by the Ethical Committee of Siriraj Hospital, Mahidol
University, Bangkok, ailand (Si 703/2015(EC2). Clinical
Trials Registration: TCTR2017318001.
Boonsopon et al.
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363
RESULTS
There were 95 non-infectious scleritis patients
(123 eyes) during the study period; their mean age was
47 years (range: 12-88 years), and 69 patients were
female (69/95,72.6%). Of the cohort, 67 presented with
unilateral eye involvement (67/95, 70.5%), and 16 had
recurrent inammation (16/95, 16.8%). e numbers of
the patients who had diuse anterior scleritis, nodular
anterior scleritis, posterior scleritis, and combined
nodular anterior scleritis with posterior scleritis were
55/95 (57.9%), 29/95 (30.5%), 8/95 (8.4%), and 1/95
(1.1%), respectively. Scleritis type was not documented
in 2 patients. None of our patients were diagnosed with
necrotizing anterior scleritis. e most common associated
nding reported in this study was anterior uveitis (39/95,
41.05%), with the second most common being scleral
thinning (21/95, 22.11%). e other associated ocular
ndings were PUK (13/95, 13.7%); secondary OHT
(13/95, 13.7%); papillitis (7, 7.37%); vitritis; CME; and
ERD (the last three being found in equal numbers: 3/95,
or 3.16% each). rough laboratory investigation, 18
patients had an associated systemic collagen vascular
disease (18/95, 19%). RA and nonspecic antineutrophil
cytoplasmic antibody (ANCA)-associated scleritis were
the two most common systemic diseases (4/95, or 4.2%
each), followed by systemic lupus erythematosus (3/95,
3.2%) and GPA (2/95, 2.1%). Unfortunately, 27.4% of
our cases lacked thorough laboratory investigations to
identify a possible associated systemic collagen vascular
disease. From a subgroup analysis, aer excluded patients
with incomplete investigations, the mean age of the
idiopathic group was 45.06 years, whereas it was 48.22
years for the scleritis with associated systemic collagen
vascular disease group. Both groups were predominantly
female, with 40/51 (78.4%) and 10/18 (55.6%) females,
respectively. Interestingly, most of the patients in the
scleritis with associated systemic collagen vascular disease
group (24/27 eyes [88.9%]) presented with diuse anterior
scleritis; on the other hand, only about half of the patients
in the idiopathic group (40/70 eyes [58.8%]) did so,
which was statistically signicant at p-value 0.054 in
univariate analysis. e cause of inammation of all
eleven patients who presented with posterior scleritis
was not found; thus, all of them were diagnosed with
idiopathic posterior scleritis (16.2% versus 0%, p 0.026). As
many as 9/27 eyes (33.3%) in the scleritis with associated
systemic collagen vascular disease group had subsequent
scleral thinning at their follow-up visits, compared to
8/70 eyes (11.4%) in the idiopathic group (p 0.038). No
statistical signicance was found for the other factors
used to compare the dierences between the two groups
(namely, the best-corrected visual acuity on patients’
rst and last visits; laterality; the number of recurrences;
scleral thinning on the rst visit; and OHT, PUK, anterior
uveitis, vitritis, CME, ERD, and papillitis on the rst
and follow-up visits); these are summarized in Table 1.
Almost all of our patients received topical, regional, and/
or systemic corticosteroids as their mainstay therapy.
Some of them were treated with oral NSAIDs. Fieen
patients (29.4%) in the idiopathic group were treated
with systemic IMT, whereas 10/18 patients (55.6%) in
the scleritis with associated systemic collagen vascular
disease group received IMT (p 0.047). Multivariate linear
regression analysis between systemic collagen vascular
disease association group and idiopathic group is shown
in Table 2.
DISCUSSION
Although scleritis is scarcely seen in general
ophthalmology practice, its serious complications and
its possible association with a systemic inammatory
disease have captured our attention. A delayed diagnosis
of an associated systemic rheumatologic disease might
result in lethal complications. From previous reports
worldwide, approximately 25% - 50% of non-infectious
scleritis is related to systemic collagen vascular disease
2,3
;
therefore, screening laboratory tests for rheumatoid
factors, antinuclear antibodies, and ANCA have been
recommended. In our study, 20% of our patients were
diagnosed with scleritis as a presenting feature of systemic
collagen vascular diseases. is is consistent with the
nding of a report from the Ocular Autoimmune Systemic
Inammatory Infectious Study that scleritis occured in
conjunction with a systemic collagen vascular disease might
be lower in the Asian population.
6
Some of the 27.4% of
our patients who lacked a laboratory investigation might
have had an undiagnosed systemic rheumatologic disease,
which would have aected the study results. RA has been
reported to be by far the most common rheumatologic
disease related to scleritis
2,4,6
, although some other studies
found that GPA was far and away the most prevalence.
5
We believe that ethnicity might play an important role in
the dierences in these results. Certain systemic diseases
related to scleritis were found to have an association
with the ocular prognosis; GPA had the worst visual
outcomes, whereas RA and relapsing polychondritis had
intermediate visual outcomes.
12
e two most common
rheumatologic diseases found to be related to scleritis in
this study were RA and non-specic ANCA associated
disease. Our data demonstrated that diuse anterior
scleritis was the main type of scleral inammation found
with a systemic collagen vascular disease; this form of
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TABLE 1. Demographics and characteristics of non-infectious scleritis patients.
Subgroupanalysis
Factors Non-infectious Idiopathicgroup Systemiccollagen P-value
scleritis (N=51 cases, vascular disease
(N=95cases, 70eyes) associationgroup
123 eyes) (N=18 cases, 27 eyes)
Age(years);(mean+/-SD) 46.60 45.06(+/-12.1) 48.22(+/-15.45) 0.379
Female 69 (72.6%) 40 (78.4%) 10 (55.6%) 0.074
Unilateral 67 (70.5%) 33 (47.1%) 9 (33.3%) 0.219
Recurrence 16(16.8%) 19(27.1%) 3(11.1%) 0.085
BCVA(LogMAR)(median,range)
First visit 0.1 (0-3) 0.1 (0-1) 0.1 (0-3) 0.041
Last visit 0.1 (0-2) 0.1 (0-2) 0.1 (0-2) 0.375
Scleritis type (eyes)
Diffuse anterior 75 (60.98%) 40 (58.8%) 24 (88.9%) 0.005
Nodular anterior 34 (27.64%) 18 (26.5%) 3 (11.1%) 0.104
Posterior 11 (8.94%) 11 (16.2%) 0 0.026
Associatedndings(eyes)
PUK
First visit 9 (7.32%) 9 (12.9%) 0 (0.0%) 0.058
Other visits 11 (8.94%) 10 (14.3%) 1 (3.7%) 0.281
Anterior uveitis
First visit 38 (30.89%) 26 (37.1%) 10 (37%) 0.992
Other visits 14 (11.38) 11 (15.7%) 2 (7.4%) 0.343
Secondary OHT
First visit 9 (7.32%) 5 (7.1%) 4 (14.8%) 0.259
Other visits 13 (10.57%) 7 (10%) 4 (21.1%) 0.180
Scleral thinning
First visit 12 (9.76%) 8 (11.4%) 2 (7.4%) 0.722
Other visits 19 (15.48%) 8 (11.4%) 9 (33.3%) 0.017
Vitritis
First visit 4 (3.25%) 3 (4.3%) 1 (3.7%) 0.815
Other visits 1 (0.81%) 1 (1.4%) 0 (0.0%) 1.0
CME
First visit 3 (2.44%) 3 (4.3%) 0 (0.0%) 0.447
Other visits 2 (1.63%) 1 (1.4%) 0 (0.0%) 0.674
ExudativeRD
First visit 1 (0.81%) 1 (1.4%) 0 (0.0%) 0.674
Other visits 2 (1.63%) 2 (2.9%) 0 (0.0%) 0.550
Papillitis
First visit 7 (5.69%) 7 (10%) 0 (0.0%) 0.186
Other visits 3 (2.44%) 3 (4.3%) 0 (0.0%) 0.992
Treatment
Immunosuppressive therapy 25 (26.32%) 15 (29.4%) 10 (55.6%) 0.047
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TABLE 2. Multivariate linear regression analysis between systemic collagen vascular disease association group
and idiopathic group.
Parameters Univariateanalysis Multivariateanalysis
Odd ratio CI P value Odd ratio CI P value
Female 0.31 0.096 to 0.97 0.044 NS NS NS
Age 1.02 0.98 to 1.06 0.36
Bilateral 1.68 0.57 to 4.98 0.99
VA(LogMAR)
First visit 4.0 1.05 to 15.3 0.43
0.74 to 5.73
Last visit 2.06 1.66
Recurrence 0.37 0.08to1.73 0.21
Associatedndings
PUK
First visit 0.000001 0.000001 to 0.99
0.0000002
0.25 to 20.2
Other visits 2.27 0.46
AU
First visit 0.93 0.31 to 2.8 0.90
0.29 to 7.77
Other visits 1.49 0.64
IOP > 21
First visit 0.33 0.04 to 2.5 0.28
0.62 to 11.1
Other visits 2.63 0.19
Scleral thinning
First visit 0.87 0.15 to 4.93 0.88
1.2 to 17.7
Other visits 4.6 0.03 4.38 1.1 to 17.6 0.038
Vitritis
First visit 1.44 0.12 to 16.9 0.77
NA
Other visits NA NA
CME
First visit 0.0001 0.000001 to 0.99
0.000002
0.000001 to
0.00003
Other visits 0.00001 1.0
ERD
First visit 0.0001 0.00001 to 1.0
0.00001
0.0001 to 0.002
Other visits 0.001 0.99
Papillitis
First visit 0.001 0.0001 to 0.003 0.99
0.00001 to 0.0003
Other visits 0.0001 0.99
Scleritis type
Diffuse 3.79 0.98 to 14.7 0.054 NS NS NS
0.16 to 2.6
Nodular 0.65 0.00002 to 0.55
0.0002
Posterior 0.0001 0.99
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Original Article
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scleritis is universally the most common.
13
None of
our patients were diagnosed with necrotizing scleritis,
but as high as 15.48% of them developed subsequent
scleral thinning without scleral melting or perforation.
Most of them had a systemic rheumatologic disease
association. Necrotizing scleritis was dened by Galor
and orne as an area of scleral infarction and necrosis
with or without typical signs of anterior scleritis (which
depend on the type of necrotizing scleritis).
5
Given that
denition, none of our patients had necrotizing scleritis
even though they had scleral discoloration either in
conjunction with, or without, signs of anterior scleritis at
any time point. Galor and orne also explained that the
bluish grey hue following anterior scleritis was not scleral
thinning but instead a development of scleral collagen
ber rearrangement aer inammation.
5
e mechanism
for the subsequent bluish discoloration of the sclera is
unclear since there have been few studies on the scleral
structure following an inammation. A study by Kuroda et
al., which described the optical coherence tomography of
active anterior scleritis, reported that there was a swelling
of the conjunctival stroma and episcleral layer without
scleral thickening.
14
In contrast, Watson et al. reported
that there was scleral edema with collagen ber separation
and inltration of the inammatory cells in the active
stage of diuse anterior scleritis.
15
Neither study reported
any structural changes during the quiescence period.
Further investigations to evaluate the pathophysiology of
the subsequent scleral discoloration during the inactive
stage of the scleral inammation need to be considered
in the future. Since there is a possibility of developing
scleral thinning following a scleral inammation and as
the association is signicantly higher among patients with
concurrent systemic collagen vascular disease, we believe
that aggressive treatment to halt disease progression is
warranted. is is especially the case for patients who
have a systemic collagen vascular disease, even if they
do not initially present with necrotizing scleritis. A
multidisciplinary approach is recommended to ensure
the provision of a systematic assessment and sucient
treatments. We found that diuse anterior scleritis had
the highest association with systemic collagen vascular
disease, which differs from some other reports that
necrotizing scleritis had the highest association.
5,6
Based
on our study ndings, we urge clinicians to be aware of
the high proportion of diuse anterior scleritis found in
patients who had a systemic collagen vascular disease,
and of the chance of patients developing scleral thinning
in cases of non-necrotizing anterior scleritis.
Limitations
As this was a retrospective study, incomplete data
might have distorted its results. A sizeable proportion
of our patients had not had a thorough investigation
to rule out the possibility of there being an associated
systemic inammatory disease; thus, the percentage of
patients who had scleritis in association with a systemic
disease was probably underreported. Follow up duration
of each patient was not reported and analyzed, which
might also interfere with the study result. A further study
with a larger number of patients would make the data
analysis more reliable.
CONCLUSION
Scleritis can be a presenting sign of some systemic
collagen vascular diseases. e pattern of scleral inammation
can be an indicator of the need to investigate for the
presence of a more serious systemic disease. From this
study, diuse anterior scleritis was more likely to occur
in conjunction with a systemic collagen vascular disease.
Scleral thinning was found more frequently among patients
who had a related systemic inammatory disease; thus,
an aggressive treatment should be considered in these
patients.
ACKNOWLEDGMENT
We would like to acknowledge and thank Miss
Wilawan Sanpan for assisting with the manuscript
preparation.
Conicts of Interest: None declared.
REFERENCES
1. Ahn SJ,Oh JY,Kim MK,Lee JH,Wee WR. Clinical features,
predisposing factors, and treatment outcomes of scleritis in
the Korean population. Korean J Ophthalmol 2010;24(6):331-5.
2. Akpek EK,orne JE,Qazi FA,Do DV,Jabs DA. Evaluation
of patients with scleritis for systemic disease. Ophthalmology
2004;111(3):501-6.
3. Smith JR
1
,Mackensen F,RosenbaumJT. erapy insight:
scleritis and its relationship to systemic autoimmune disease.
Nat Clin Pract Rheumatol2007 ;3(4):219-26.
4. Al Barqi M,Behrens A,Alfawaz AM. Clinical features and
visual outcomes of scleritis patients presented to tertiary care
eye centers in Saudi Arabia. Int J Ophthalmol 2015;8(6):1215-9.
5. Galor A,orne JE. Scleritis and peripheral ulcerative keratitis.
Rheum Dis Clin North Am 2007;33(4):835-54, vii.
6. Bin Ismail MA,Lim RHF,Fang HM,Wong EPY,Ling HS,Lim
WK,et al. Ocular Autoimmune Systemic Inammatory Infectious
Study (OASIS)-report 4: analysis and outcome of scleritis in
an East Asian population. J Ophthalmic Inamm Infect 2017;
7(1):6.
Boonsopon et al.
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367
7. Gonzalez-Gonzalez LA,Molina-Prat N,Doctor P,Tauber
J,Sainz de la Maza M,Foster CS. Clinical features and presentation
of posterior scleritis: a report of 31 cases. Ocul Immunol
Inamm 2014;22(3):203-7.
8. Honik G,Wong IG,Gritz DC. Incidencec and prevalence of
episcleritis and scleritis in Northern California. Cornea
2013;32(12):1562-6.
9. Homayounfar G,Nardone N,Borkar DS,am VM,Porco
TC,Enanoria WT,et al. Incidence of scleritis and episcleritis:
results from the Pacic Ocular Inammation Study. Am J
Ophthalmol 2013;156(4):752-8.
10. Chen YW,Poon YC,Yu HJ,Kuo MT,Fan PC. Experience
of scleritis and episcleritis at a tertiary center in Southern
Taiwan. Taiwan J Ophthalmol 2015 ;5(1):19-22.
11. Lane J,Nyugen E,Morrison J,Lim L,Stawell R,Hodgson L,
et al. Clinical Features of Scleritis Across the Asia-Pacic
Region. Ocul Immunol Inamm 2019;27(6):920-6.
12. Sainz de la Maza M,Foster CS,Jabbur NS. Scleritis associated
with systemic vasculitic diseases. Ophthalmology 1995;102(4):687-
92.
13. Sainz de la Maza M,Molina N,Gonzalez-Gonzalez LA,Doctor
PP,Tauber J,Foster CS. Clinical characteristics of a large
cohort of patients with scleritis and episcleritis. Ophthalmology
2012;119(1):43-50.
14. Kuroda Y,Uji A,Morooka S,Nishijima K,Yoshimura N.
Morphological features in anterior scleral inammation using
swept-source optical coherence tomography with multiple
B-scan averaging. Br J Ophthalmol2017;101(4):411-7.
15. Watson P,Romano A. e impact of new methods of investigation
and treatment on the understanding of the pathology of scleral
inammation. Eye (Lond) 2014;28(8):915-30.
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Letter to the Editor
SMJ
EmergenceofInuenzaPandemicinBangkokin
1918:HistoricalReview
To the editor:
Inuenza pandemic in 1918 was known as the worst
pandemic in human history; it is now well documented to
be caused by Inuenza A, H1N1 virus. e information
regarding this pandemic has been mostly published from
the Western countries but only a small number of pieces of
information published from Asian countries, even though
the origin of this pandemic was speculated to be in China.
1
Unfortunately, only one article regarding this pandemic
in ailand was published in ai language in 1967 by
the late Prof. Dr. Samran Wangspa, an ophthalmologist
and a member of the Royal Institute (nowadays, Oce
of the Royal Society), in Siriraj Hospital Gazette,
2
a local
medical journal prior to the transformation to international
journal standard level as Siriraj Medical Journal. In his
article, based on the Interior Ministry announcement on
July 14, 1919 by the Minister of Interior Ministry that
was published in the Royal ai Government Gazette
on July 27, 1919,
3
the total ai population was nearly
9 million people (8,478,566 outside Bangkok + 500,000
in Bangkok), approximately 2.5 million people (27.8%)
got the infection and 81,370 people died (0.9%).
Regarding the 1918 influenza pandemic in
ailand, the article by Prof. Wangspa mentioned that
the pandemic occurred shortly aer the end of World
War I, presumably the spreading was introduced by the
soldiers who returned to their homes. e late Emeritus
Prof. Dr. Prasert ongcharoen, a well-known senior
virologist in ailand, concurred with this speculation
as shown in the excerption of his presentation on “a
chronological outbreak of inuenza in ailand, 1918-
2010” at the panel talk in the 9
th
Training Programs in
Epidemiology and Public Health Interventions Network
(TEPHINET) Global Scientic Conference which was
held on 7-11 August 2017 in Chiang Mai, ailand,
as follow: “e outbreak of inuenza in ailand was
brought by troops aer the World War I (WWI) as
ailand sent the Royal ai Army Forces to join the
Allied Forces in France and returned later when the
WWI ended. e troops arrived back with the inuenza
virus, which was spreading over the frontline. In October
1918, inuenza was reported to spread from the harbour
city in the southern of ailand. By November 1918,
the infection had been spread throughout the whole
country and it was aerwards subsided in March 1919.”
4
But, upon the historical review, the ai troops that
joined the WWI could not be blamed for the outbreak
of inuenza pandemic in ailand because the 2 ai
troops le ailand and arrived in France on July 30,
1917 and August 6, 1917, respectively.
5
en, aer the
end of the WWI, the troops arrived in Bangkok with the
“welcome back home” ceremony taken place on May 1,
1919
6
while the inuenza pandemic had already swept
throughout Bangkok and the whole country in 2 waves,
the rst one during October and November, 1918 and
the second one during January and February, 1919 as
documented in the Royal ai Government Gazette
during 1918.
Historical review brought out the interesting event
that might be the cause of the emergence of 1918 inuenza
pandemic in ailand. On September 12, 1918, e Siam
Red Cross posted the donation of 1,554.30 Bahts collected
from the tickets (5,181 people attended, if the ticket cost
0.30 Baht) to watch the charity football match between
ai Royal Navy team and British Royal Navy team
taken place at the football eld at Suankularb College in
Bangkok.
7
e football players of the British Royal Navy
team were selected from the crew of the HMS Whiting, a
C-class destroyer,
8
that visited Bangkok during that very
month of September 1918. is football match brought
joyfulness to everyone in this event as mentioned in
the book entitled “Chaiyo! King Vajiravudh and the
development of ai nationalism” written by Walter F.
Vella in 1978 as follow:
e match, held on September 12, was attended
by “a huge crowd.” e game, aer “a hard, ding dong
struggle,” ended in a tie; the crowd was not displeased,
and the match was called “one of the happiest and most
successful events in the present naval visit.”
9
Note: Certainly, the huge crowd with elation in this
particular football match is worrisome in term of spreading
germs because social distancing, an important measure
used to contain COVID-19 at present, cannot be applied!
Historical search in the internet also helps to nd
out the log book of this British Royal warship.
10
She had
been atomized by a spray of a 2% solution of zinc sulphate
Sukpanichnant et al.
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Sukpanichnant et al.
from May 2 to 4, 1918 at the Royal Navy’s shore base,
HMS Tamar, in Hong Kong as a preventative measure
against inuenza pandemic before departure on May 6,
1918 to Singapore. e warship received 60 tons of coal in
Saigon on May 10, 1918. When she arrived in Singapore
on May 14, 1918, one petty ocer was sent to hospital
one hour aer docking – 7 days aer departure from
Hong Kong. en, 12 days later, on May 26, 1918, the log
book recorded “One sick rating le for Tanglin Hospital
(returned to ship aer a 29-day-long admission),” 8 days
aer that, on June 3, 1918, “Mr. Ellis discharged to hospital
(returned to ship aer a 9-day-long admission),” another
8 days later, on June 11, 1918, “One AB le for hospital
(AB = Able Seaman).” Look like the crew experienced
the rst wave of Inuenza pandemic as described in the
literature.
1
en, on August 7, 1918, the log book recorded
“One Stoker le for hospital,” 15 days later, on August 22,
1918, “One AB sent to hospital,” 4 days later, on August
26, 1918, “One Stoker discharged to hospital,” and 1 day
later, on August 27, 1918, “Leading Signalman le for
hospital,” then, 5 days later, on September 1, 1918, the
warship le Singapore for Bangkok where she arrived on
September 5, 1918. e crew spent time in Bangkok for
10 days before departing on September 15, 1918. e log
book, however, did not mention any activity in Bangkok
at all. During that period of HMS Whiting warship
visiting Bangkok, there was not any report of inuenza
epidemic in Bangkok even though King Rama VI had
been ill for 10 days, possibly inuenza with pneumonia
at right lower lobe, from July 27, 1918 to August 5, 1918.
On August 17, 1918, the King did not have any abnormal
lung sign and he was advised to leave Bangkok for a 4 to
5-week-long vacation so that the next day he moved to
Bang Pa-in Palace in Ayudhaya Province. According to
the Royal ai Government Gazette regarding the news
of death, mostly the royal family members, government
services, army ocers, and priests, on July 26, 1918,
an army ocer died of fever. On August 30, 1918, a
government service in Nakhon Sri ammarat in the
South died of fever. On September 28 and 30, an army
ocer and a government service were reported as died
of fever, respectively. Since October 6, 1918, 20 cases
were reported as died of fever in October and 12 more
cases in November, presumably corresponding to the
second wave of inuenza pandemic reported all over
the world.
e HMS Whiting warship returned back to Singapore
and arrived there on September 19, 1918 and on that very
day, 2 ratings were discharged to hospital (4 days aer
leaving Bangkok). en, 11 days later, on September 30,
1918, “One Signal rating discharged to hospital.” And the
log for October 1918 recorded “Singapore dry dock and
in harbor during ‘u epidemic” and it started to record
sick list during October 1 (sick list of 5) and November
16 (sick list of 8). e peak of sick list was 19 for 3 days
during October 12 and 14. ere was a note – presumably
“Spanish inuenza” – recorded on October 8. Even the
commander of the ship was recorded to be sent to the
hospital on November 13 and he returned on duty 8
days later. No sick list appeared in the log book during
November 17 and December 31, 1918 but on January
1, 1919, another sick list of 4 appeared for the very last
time and no more! HMS Whiting warship resumed her
duty on January 13, 1919. In this log book, no record of
death among the crew members is found at all.
However, based on the search of “Royal Navy Service
Records” from “e National Archives” website
11
for
more than 2,000 records, one ordinary seaman year II,
aged 25, on service of the HMS Whiting warship, was
recorded as “DD October 4, 1918; inuenza and bronchial
pneumonia. (Note: DD = died of disease)” Nevertheless,
the log book of the warship on this particular date recorded
only “One AB discharged to hospital.” about the illness
of the crew members. But, on October 7, the log book
recorded “Medical inspection of seven men who were
sick.” while the sick list was 6.
At this point, based on the above historical review,
it is possible that the emergence of inuenza pandemic
in Bangkok in 1918 was the result of this charity football
match between the ai Royal Navy team and the British
Royal Navy team on September 12, 1918. Due to the
limitation of time, even aer the scrutiny of more than
2,000 records of the “Royal Navy Service Records” from
“e National Archives” website above (time spent on
1 entry, approximately 1 minute), another death record
(like the one above on HMS Whiting) cannot be retrieved
to show whether at least one of the 60 ocers and men
on this warship had died of inuenza prior to their visit
to Bangkok. Certainly, there are approximately 35,748
more records during the year 1918 awaiting further
scrutiny.
REFERENCES
1. Taubenberger JK,Hultin JV,Morens DM. Discovery and
characterization of the 1918 pandemic influenza virus in
historical context. Antivir er.2007;12(4 Pt B):581-91.
2. Samran Wangspa. Inuenza in the reign of King Rama VI
[ai]. Siriraj Hospital Gazette. 1967;19:615-20.
3. Ratchakitchanubeksa (Royal ai Government Gazette). July
27, 1919 Vol. 36 Page: 1193-1202 [ai]. [Internet]. [cited 2020
Apr 2]. Available from: http://www.ratchakitcha.soc.go.th/
DATA/PDF/2462/D/1193.PDF
4. ongcharoen P. A chronological outbreak of inuenza in
ailand, 1918-2010. Outbreak, Surveillance and Investigation
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PB
Letter to the Editor
SMJ
Sukpanichnant et al.
Reports (OSIR). 2017;10(4):22-6. [excerpted from the panel
talk of Emeritus Prof. Dr. Parsert ongcharoen in the 9
th
Training Programs in Epidemiology and Public Health Interventions
Network (TEPHINET) Global Scientic Conference, 7-11 Aug
2017, Chaing Mai, ailand] [Internet]. [cited 2020 Apr 2].
Available from: http://www.osirjournal.net/index.php/osir/
article/view/112
5. Kumlertsakul P. Centenary of Siam Joining the World War I:
Review of the decision for survival [ai] [Internet]. [cited 2020
Apr 2]. Available from: https://www.bbc.com/thai/thailand-40670894
6. Ratchakitchanubeksa (Royal ai Government Gazette). May 11,
1919 Vol. 36 Page: 331 [ai]. [Internet]. [cited 2020 Apr 2].
Available from: http://www.ratchakitcha.soc.go.th/DATA/
PDF/2462/D/331.PDF
7. Ratchakitchanubeksa (Royal Thai Government Gazette).
October 6, 1918 Vol. 35 Page: 1601-5 [ai]. [Internet]. [cited
2020 Mar 29]. Available from: http://www.ratchakitcha.soc.
go.th/DATA/PDF/2461/D/1601.PDF
8. HMS Whiting (1986) [Internet]. [cited 2020 Mar 29]. Available
from: https://en.wikipedia.org/wiki/HMS_Whiting_(1896)
9. Vella WF. Chaiyo! King Vajiravudh and the development of ai
nationalism. Honolulu, USA: University Press of Hawaii, 1978,
p. 156. [Internet]. [cited 2020 Apr 2]. Available from: https://
scholarspace.manoa.hawaii.edu/bitstream/10125/62864/
9780824880309.pdf
10. Paul Money. Royal Navy Log Books of the World War 1 Era.
HMS Whiting – August 1916 to July 1919, China Station
[Internet]. [cited 2020 Apr 2]. Available from: https://www.
naval-history.net/OWShips-WW1-10-HMS_Whiting.htm
11. e National Archives [Internet]. [cited 2020 Apr 2]. Available
from: https://www.nationalarchives.gov.uk/
Sanya Sukpanichnant, M.D., FRCPath (ailand)
Department of Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, ailand.
Corresponding author: Sanya Sukpanichnant
E-mail: sanya.suk@mahidol.ac.th
Received 10 April 2020 Revised 5 May 2020 Accepted 6 May 2020
ORCID ID: http://orcid.org/ 0000-0002-9724-2692
http://dx.doi.org/10.33192/Smj.2020.49
