Volume 72, Number 3, May-June 2020

Siriraj Medical Journal

SMJ

ISSN 2629-995XE-ISSN 2228-8082

ORIGINAL ARTICLE

195 Comparison of the Oncologic Outcomes between

Exploratory Laparotomy and Laparoscopic Surgery for

Endometrial Cancer: Siriraj Experience

Pisutt Srichaikul, et al.

202 Characteristics and Clinical Presentations of Patients at

the Siriraj Snoring Clinic

Sarin Rungmanee, et al.

209 Incidence of Ocular Toxicity from Iron Chelating Agents at

Siriraj Hospital

Atiporn Thuangtong, et al.

214 Activity of Antimicrobial Combinations Against

Extensively Drug-Resistant Acinetobacter baumannii as

Determined by Checkerboard Method and E-test

Amornrut Leelaporn, et al.

219 Incidence and Pregnancy Outcomes of Primary

Postpartum Hemorrhage Following Implementation of

Postpartum Drape with a Calibrated Bag after Normal

Vaginal Delivery

Pattarawan Limsiri, et al.

226 Factors Related to the Clinical Outcomes of the Kasai

Procedure in Infants with Biliary Atresia

Niramol Tantemsapya, et al.

238 Stress and Coping Strategies among Thai Medical Students

in a Southern Medical School

Jarurin Pitanupong, et al.

245 The Relationship between Resilience Quotient, Social

Support and Spiritual Well-Being of Caregivers of Patients

with Hemiplegia

Panita Chavapattanakul, et al.

253 Evaluation of Combined Rapid Immunoglobulin M and

Immunoglobulin G Lateral Flow Assays for the Diagnosis

of Leptospirosis, Scrub Typhus, and Hantavirus Infection

Saowaluk Silpasakorn, et al.

REVIEW ARTICLE

259 Hepatitis E in Southeast Asia

Paul Wasuwanich, et al.

265 Immersive Technology for Medical Education: Technology

Enhance Immersive Learning Experiences

Mathuwan Srikong, et al.

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International Association of Surgeons

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By Paul Wasuwanich, et al.

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Seigo Kitano (Oita University, Japan)

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Masakazu Yamamoto (Tokyo Women’s Medical University, Japan)

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195

Original Article

SMJ

Pisutt Srichaikul, M.D.*, Jidapa Samrarn, M.D.**, Atthapon Jaishuen, M.D.*, Hideaki Yahata, M.D.***, Peerapong

Inthasorn, M.D.*, Korakot Sirimai, M.D.*, Pavit Sutchritpongsa, M.D .*, Amphan Chalermchockcharoenkit,

M.D.*, Prasong Tanmahasamut, M.D .*

*Department of Obstetrics and Gynecology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, ailand, **Woman Health Center,

Chulabhorn Hospital, HRH Princess Chulabhorn College of Medical Science, Chulabhorn Royal Academy, Bangkok 10210, ailand, ***Department

of Gynecology and Obstetrics, Graduate School of Medicine, Kyushu University, Fukuoka, 812-8582, Japan.

Comparison of the Oncologic Outcomes between

Exploratory Laparotomy and Laparoscopic Surgery

for Endometrial Cancer: Siriraj Experience

ABSTRACT

Objective: is study was undertaken to evaluate surgical and oncologic outcomes for patients with endometrial

cancer, compared between exploratory laparotomy and laparoscopic surgery.

Method: In total, 324 patients who diagnosed with endometrial cancer during January 2007 to December 2016

were enrolled. e comprehensive surgical staging procedures, including total hysterectomy, bilateral salpingo-

oophorectomy (BSO), pelvic lymphadenectomy (PL), and/or para-aortic lymphadenectomy (PAL) were undergone.

Demographic, clinical, treatment, operative, outcome, and survival outcome were recorded and evaluated.

Results: 81 patients performed laparoscopy without conversion. No signicant dierence in baseline characteristics

and pathological characteristics between two groups was observed. When compared with laparotomy group, the

laparoscopy group had longer operative time, shorter hospital stays, and lower blood loss. Two-year overall survival

(OS) was 97.9% and 95.1% in the laparotomy and laparoscopy groups, respectively (p=0.263). In addition, 2-year

disease-free survival (DFS) between both groups was equal (93.7% versus 88.6%, respectively; p=0.309).

Conclusion: Laparoscopic surgery is an ecacious, achievable and safe technique for patients with endometrial

cancer. Good surgical skills and proper surgical techniques are required to eectuate optimal outcomes.

Keywords: Endometrial cancer; oncologic outcomes; laparoscopic surgery (Siriraj Med J 2020; 72: 195-201)

Corresponding author: Pisutt Srichaikul

E-mail: pisutt.srichaikul@gmail.com

Received 30 January 2020 Revised 10 March 2020 Accepted 18 March 2020

ORCID ID: http://orcid.org/0000-0002-6541-7304

http://dx.doi.org/10.33192/Smj.2020.26

INTRODUCTION

Currently, endometrial cancer is the cancer that

commonly found ailand. e surgical procedures that

can be employed to determine the stage of disease in

endometrial cancer includes total hysterectomy, bilateral

salpingo-oophorectomy (BSO), pelvic lymphadenectomy

(PL) and para-aortic lymphadenectomy (PAL). Traditionally,

these procedures are performed by exploratory laparotomy

approach. However, during the last decade, laparoscopic

surgery has played an important role in comprehensive

surgical staging in gynecologic cancer. Laparoscopic

surgery not only reduces postoperative pain, wound

complication, length of hospital stay, and postoperative

adhesion, but it also improves patient quality of life. e

result of all these benets is that patients can receive

their adjuvant treatment earlier.

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196

In early stage endometrial cancer, several studies

found the same postoperative complications, and

survival outcome between exploratory laparotomy

and laparoscopic surgery.

1-9

We performed the first

total laparoscopic hysterectomy (TLH) at our center in

2004, and we subsequently introduced the Siriraj TLH

technique (SiTLH) in 2006.

is meticulous technique,

has allowed us to safely perform PL and PAL since 2007.

us, comparison of the outcomes between laparoscopic

surgery and exploratory laparotomy in endometrial

cancer at Siriraj Hospital was the objective of our present

study.

MATERIALS AND METHODS

e study design was a retrospective cohort study.

Medical records were retrieved from the database of the

Department of Obstetrics and Gynaecology, Faculty of

Medicine Siriraj Hospital, Mahidol University, Bangkok,

ailand during 5

January 2007 to 27

December 2016

study period. All patients were histologically conrmed as

endometrial cancer and primary surgery was scheduled.

The histological subtypes included endometrioid

adenocarcinoma, papillary serous carcinoma, clear

cell carcinoma, and mixed carcinoma. Patients with

incomplete medical records were excluded. Informed

consent was not required due to the retrospective nature

of the study. is study was reviewed and approved by

the Ethics Committee of the Faculty of Medicine Siriraj

Hospital, Mahidol University before the study initiated

(Si 005/2018).

e sample size was calculated using non-inferiority,

based on data of previous study

that reported 90% survival

rate. Calculated sample size using a power of 80% (type

II error = 0.20), ratio between two groups was 3.0. Our

sample size calculation revealed that a minimum sample

size of 300 patients, 225 in exploratory laparotomy group

and 75 in laparoscopic surgery group, would be required

to achieve a 90% condence level.

A total of 324 patients who met our criteria were

enrolled. Two hundred and forty-three patients underwent

exploratory laparotomy, while the others performed surgical

staging by laparoscopic surgery. Surgical procedures

included total hysterectomy, BSO, PL, and PAL. PL and

PAL is indicated in patients with high risk for lymph

node metastasis (non-endometrioid histologic subtype,

extra-uterine involvement, grade 3 with myometrial

invasion of greater than 50%) and can be considered in

patients with intermediate risk (invasion of more than

half of the myometrium or grade 3 with less than 50%

myometrial invasion). However, some patients did not

undergo this kind of surgery due to inadequate exposure,

morbid obesity, and/or patient comorbidity.

Data collection included preoperative patient

characteristics. e duration from skin incision to wound

closure labeled as operative time. Major complications

were dened as mortality, visceral organ injury, vascular

injury, massive blood loss, conversion from laparoscopic

surgery to exploratory laparotomy, venous thromboembolic

events and wound morbidity. Patients who died within

30 days of surgery classied as mortality. Organ injuries

were dened as those requiring surgical correction.

Massive blood loss was dened as total blood loss >1,000

ml. Deep vein thrombosis or pulmonary embolism

categorized as venous thromboembolic events. Wound

morbidity meant wound dehiscence or a deep wound

surgical site infection of fascial or muscle layers that

required readmission or surgical intervention. Patients

with a temperature of greater than 38°C, aer the rst day

of the postoperative period, measured on two separate

occasions at least 12 hours apart, labeled as postoperative

fever. Minor complications included supercial surgical

site infections (skin and subcutaneous infection), urinary

tract infections and fever. Loss of blood was calculated

from the estimation of blood volume on swabs and the

dierence between the volume of uid used during

surgery and blood volume in suction containers. Aer

the treatment, all patients received disease surveillance

for at least 2 years. e period from the start of treatment

to the date of death or the date of the last follow up

dened as overall survival (OS). Whereas, the length of

time from the start of treatment to the date of recurrence

referred as disease-free survival (DFS). Response rate

(RR) was dened as the percentage of patients whose

cancer shrank or disappeared aer treatment.

Comparison of the oncologic outcomes (OS, DFS,

RR) between the laparoscopic surgery and exploratory

laparotomy was the primary outcome. Surgical outcomes

between groups, such as operative time, blood loss,

major complications, and length of hospital stay, were

also compared.

Laparoscopic surgery technique for surgical staging in

endometrial cancer

We developed and introduced the SiTLH technique

in 2006.

e principles of this technique include early

identication of both ureters at the beginning of surgery,

dissection at the retroperitoneal space and then restoration

of the pelvic anatomy from adhesion-free area to the

adhesion area. is technique, allow us to dissect the

vital organs safely, and to perform transperitoneal

lymphadenectomy.

Srichaikul et al.

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Original Article

SMJ

All patients were placed on the table in the lithotomy

position aer general anesthesia was performed. A uterine

manipulator was placed depending on surgeon discretion.

A 10-mm laparoscopic trocar was inserted at the umbilical

or supraumbilical area for the optic, and three or four

5-mm trocars were inserted at the iliac, suprapubic, and

le paraumbilical regions for ancillary instruments.

e 10-step SiTLH BSO was routinely performed. e

anatomic boundaries for PL included common iliac

bifurcation superiorly, deep circumex vein inferiorly,

iliopsoas muscle laterally, obliterated umbilical artery

medially and obturator nerve inferiorly.

Transperitoneal PAL was performed by cutting

the peritoneum along the right common iliac artery and

aorta. e retroperitoneal space was exposed by hanging

the cut peritoneum from the upper abdominal wall. e

surgery was performed to at least the level of the inferior

mesenteric artery (IMA).

Statistical analysis

SPSS for Windows version 18.0 (SPSS Inc., Chicago,

IL, USA) was used for statistical analysis. Descriptive

statistics were analyzed using chi-square test and Fisher’s

exact test. Data are shown as number and percentage,

mean ± standard deviation, or median and range. All

calculated P-values were two-sided, and a P-value <

0.05 was considered statistically signicant. DFS and OS

were calculated using Kaplan-Meier method. Dierences

between survival curves were analyzed using log-rank

test.

RESULTS

During the study period, a total of 324 patients

underwent surgical staging for endometrial cancer. Of

those, 243 patients underwent exploratory laparotomy, and

81 patients underwent laparoscopic surgery. Conversion

rate was zero percent. Baseline characteristics and

pathological characteristics are shown in Table 1 and

Table 2. ose characteristics between groups were the

same. Endometrioid adenocarcinoma was the most

common histological subtype (91.7%), followed by clear

cell carcinoma (4.0%). e most common FIGO stage

was stage IA in both groups (57.2% and 60.5% in the

laparotomy and laparoscopy group, respectively).

Patients who undertook laparotomy had more

estimated blood loss and longer hospital stay, whereas

patients who undertook laparoscopy had a longer

operative time (Table 3). PAL which is a lengthy operative

procedure, was more oen performed in the laparoscopy

group (77.8% versus 53.9%). However, the numbers of

para-aortic lymph node retrieved between both groups

were the same (Table 3). e major complication rate

seemed to be lower in laparoscopy group (8.2% versus

2.5%, p=0.074). e most common complication was

supercial wound infection, (a minor complication),

as shown in Table 4.

With the clinical complete response rate of 98.8%

in the laparoscopy group (Table 5), the 2-year OS was

95.1% which was not signicantly dierent from that of

the laparotomy group (Fig 1). DFS in the laparotomy and

laparoscopy groups was 93.7% and 88.6%, respectively

(Fig 2).

DISCUSSION

e 2-year OS in the laparoscopy group in the present

study was 95.1%, which was not dierent from the 2-year

OS in the laparotomy group. Terao, et al.

reported a

2-year survival rate of 94.6%, which is comparable to the

rate observed in our study. e Gynecologic Oncology

Group (GOG) do a study about laparoscopic surgery in

endometrial cancer, LAP2 study

, conrmed laparoscopic

surgical staging for uterine cancer to be feasible and safe,

with fewer complications. ese benets of laparoscopy

also found in our study.

Palomba et al. showed that laparoscopic surgery in

early stage endometrial cancer is safe and eective.

e

long-term data showed no signicant dierence in OS,

DFS or recurrence when compared between exploratory

laparotomy and laparoscopic surgery.

Furthermore, a

prospective analysis in 2012 reported a 5-year survival

rate of 89.8%.

No signicant dierence in DFS between laparoscopic

surgery and laparotomy was reported by several studies.

In 2012, GOG LAP2 study

reported recurrence and

survival, the 3-year estimated cumulative incidence of

recurrence in the laparoscopy group was 11.39%. Tozzi,

et al.

reported a 2-year DFS of 87.4% in the laparoscopy

group versus 91.6% in the laparotomy group - both of

which are comparable to our study. However, surgical

techniques to prevent tumor spillage during surgery

were not used in all cases in our study. ose techniques

included no uterine manipulator insertion through

the uterine cavity, vaginal vault closure before surgery

began, ligation of both fallopian tubes before surgery

started, and the use of a specimen retrieval bag during

tissue extraction. We expect that DFS will increase even

further if these protective techniques can be used in all

cases.

Due to the principle of the SiTLH technique, the

laparoscopy group had lower blood loss. Early reduction

of uterine blood supply at the beginning of the procedure

not only reduce blood loss, but also reduces the rate of

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198

TABLE 1. Baseline demographic and clinical characteristics (N=324).

TABLE 2. Pathological characteristics (N=324).

Values

Characteristics Laparotomy group Laparoscopy group P value

(n=243) (n=81)

Age, y 57.51+10.55 56.98+10.10 0.692

Body mass index

26.82+5.49 26.74+5.84 0.908

Parity 0.702

0 89 (36.6) 30 (37)

>1 154 (63.4) 51 (63)

Menopause status 0.438

Pre-menopause 74 (30.5) 21 (25.9)

Post-menopause 169 (69.5) 60 (74.1)

History of hormone replacement therapy 3 (1.2) 1 (1.2) 1.000

ECOG performance status 0.530

0 219 (90.1) 71 (87.7)

1 24 (9.9) 10 (12.3)

Values are given as mean + standard deviation or number (percentage).

Calculated as weight in kilograms divided by the square of height in meters.

Values

Characteristics Laparotomy group Laparoscopy group P-value

(n=243) (n=81)

Histologic subtype 0.650

Endometrioid adenocarcinoma 224(92.2) 73(90.1)

Serous carcinoma 1(0.4) 0(0)

Clear cell carcinoma 10(4.1) 3(3.7)

Mixed 8(3.3) 4(6.2)

Histologic grading 0.752

1 127(52.3) 39(48.1)

2 73(30.0) 25(30.9)

3 43(17.7) 17(21.0)

Presence of LVSI

46(18.9) 16(19.8) 0.870

Positive for peritoneal uid cytology 8(3.3) 4(4.9) 0.503

Isolated pelvic lymph node metastasis 16(6.6) 5(6.2) 0.869

Isolated para-aortic lymph node metastasis 1(0.4) 1(1.2) 0.438

Pelvic and para-aortic lymph node metastasis 10(4.1) 3(3.7) 1.000

FIGO

stage 0.969

IA 139(57.2) 49(60.5)

IB 49(20.2) 14(17.3)

II 18(7.4) 6(7.4)

IIIA 9(3.7) 2(2.5)

IIIB 1(0.4) 1(1.2)

IIIC1 16(6.6) 5(6.2)

IIIC2 11(4.5) 4(4.9)

Values are given as number (percentage).,

LVSI, lymphovascular space invasion.,

FIGO, International Federation of Gynecology and

Obstetrics.

Srichaikul et al.

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TABLE 3. Surgical outcomes (N=324).

Values

Outcomes Laparotomy group Laparoscopy group P-value

(n=243) (n=81)

Estimated blood loss, ml 306.7 128.6 <0.001

Duration of operation, min 177.8+52.9 259.2+73.8 <0.001

Length of hospital stay, d 6(5,8) 5(4,6) <0.001

Pelvic lymphadenectomy 239(98.4) 80(98.8) 1.000

Para-aortic lymphadenectomy 131(53.9) 63(77.8) <0.001

Number of lymph node

Pelvic lymph node

14(10,20) 14(9,20) 0.593

Para-aortic lymph node

3(2,5) 3(2,6) 0.390

Residual tumour 0.483

no 237(97.5) 80(98.8)

<1 cm 2(0.8) 1(1.2)

>1 cm 4(1.6) 0(0)

Major complication 20(8.2) 2(2.5) 0.074

Adjuvant treatment 141(58.3) 40(49.4) 0.163

Values are given as mean + standard deviation, number (percentage), or median (interquartile range).,

calculated only in patients who performed pelvic and para-aortic lymphadenectomy.

Values

Complication rate Laparotomy group Laparoscopy group P-value

(n=243) (n=81)

Major complications

Bowel injury

2(0.8) 0(0) 1.000

Bladder injury

1(0.4) 0(0) 1.000

Bowel obstruction

1(0.4) 0(0) 1.000

Wound dehiscence

8(3.3) 1(1.2) 0.458

Blood transfusuion

10(4.1) 1(1.2) 0.303

Minor complications

Fever

1(0.4) 2(2.5) 0.160

Urinary tract infection

2(0.8) 0(0) 1.000

Bowel ileus

1(0.4) 0(0) 1.000

Supercial wound infection

18(7.4) 8(9.9) 0.498

TABLE 4. Intraoperative complications and postoperative adverse events.

Values are given as number (percentage).,

Calculated as number of events divided by total number of patients.

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200

Fig 1. Overall survival in 324 endometrial cancer patients stratied by surgical approach (laparoscopy vs. laparotomy)

Fig 2. Disease-free survival in 324 endometrial cancer patients stratied by surgical approach (laparoscopy vs. laparotomy)

TABLE 5. Response of treatment.

Response rate Values

Laparotomy group (n=243) Laparoscopy group (n=81)

Complete response 234(97.9) 80(98.8)

Partial response 1(0.4) 1(1.2)

Stable disease 1(0.4) 0(0)

progression 3(1.3) 0(0)

Values are given as number (percentage).

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visceral organ injury.

is protective feature can be

explained by the fact that unnecessary blood loss can

obscure surgical eld visibility, which leads to increased

risk of visceral organ injury and massive blood loss

during PL.

The result of our study revealed that PAL was

performed more oen in the laparoscopy group. is

may be due to the fact that laparoscopy provides better

visualization and an ability to access the retroperitoneal

space, especially in obese patients. Surgeon experience

and surgical skill are also the important factors that aect

para-aortic lymph node retrieval.

In the present study, there was no statistically

signicant dierence in the number of para-aortic lymph

node retrieval between two groups. However, the median

number of para-aortic lymph node retrieval was lower than

the other studies.

5,9,12-13

We did not perform systematic

PAL in all cases. Only para-aortic lymph node sampling

was performed in some patients, and limited at the level

below IMA. So, this may be causing the lower number of

para-aortic lymph node in our study. During the last 2

years, systematic PAL was initiated in our center because

surgeons had more experience in this kind of surgery and

advanced bipolar electrosurgery was commonly used.

e further study which included those patients may

provide more information about benet of systematic

PAL in endometrial cancer.

Strengths and limitations

A large sample size and the fact that we include all

histologic subtypes were the strengths of this study. e

limitation of our study included it retrospective design,

and the fact that we included data from a single center.

Another limitation is the type of surgical method used

was determined at the discretion of each surgeon. Last,

the surgical procedure in each surgical technique varies

by surgeon, and these variations could have adversely

inuenced our nding. Importantly, the ndings of this

study suggest laparoscopic surgery as feasible and safe

treatment alternative to laparotomy.

CONCLUSION

Laparoscopic surgery is an ecacious, achievable

and safe technique to treat patients with endometrial

cancer. Good surgical skills and proper surgical technique

are required to eectuate optimal outcomes.

Conict of Interest: e authors declare no personal or

professional conicts 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: is was unfunded study.

REFERENCES

1. Spirtos NM, Schlaerth JB, Gross GM, Spirtos TW, Schlaerth

AC, Ballon SC. Cost and quality of life analyses of surgery

for early endometrial cancer: laparotomy versus laparoscopy.

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2. Magrina JF, Mutone NF, Weaver AL, Magtibay PM, Fowler

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3. Gemignani ML, Curtin JP, Zelmanovich J, Patel DA, Venkatrama

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4. Tozzi R, Malur S, Koehler C, Schneider A. Laparoscopy versus

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5. Walker JL, Piedmonte MR, Spirtos NM, Eisenkop SM, Schlaerth

JB, Mannel RS, et al. Laparoscopy compared with laparotomy

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Oncology Group Study LAP2. J Clin Oncol 2009;27:5331-6.

6. Palomba S, Falbo A, Mocciaro R, Russo T, Zullo F. Laparoscopic

treatment forendometrial cancer: A meta-analysis of randomized

controlled trials (RCTs). Gynecol Oncol 2009;112:415-21.

7. Zullo F, Palomba S, Falbo A, Russo T, Mocciaro R, Tartaglia E,

et al. Laparoscopic surgery vs laparotomy for early stage

endometrial cancer: long-term data of a randomized controlled

trial. Am J Obstet Gynecol 2009;200:296.e1-9.

8. Terao Y, Kitade M, Kusunoki S, Fujino K, Ujihira T, Kimura

M, et al. Surgical and oncological outcome of laparoscopic surgery,

compared to laparotomy, for Japanese patients with endometrial

cancer. Gynecol Minim Invasive er 2016;5:64-8.

9. Kong TW, Lee KM, Cheong JY, Kim WY, Chang SJ, Yoo

SC, et al. Comparison of laparoscopic versus conventional

open surgical staging procedure for endometrial cancer. J

Gynecol Oncol 2010;2:106-11.

10. Srichaikul P, Chalermchockcharoenkit A, Yahata H, Sirimai

K, Sutchritpongsa P. Low complication rate associated with total

laparoscopic hysterectomies using the retroperitoneal approach:

A Series of 1,092 Cases in Siriraj Hospital. Siriraj Med J

2018;70:191-7.

11. Walker JL, Piedmonte MR, Spirtos NM, Eisenkop SM, Schlaerth

JB, Mannel RS, et al. Recurrence and survival aer random

assignment to laparoscopy versus laparotomy for comprehensive

surgical staging of uterine cancer: Gynecologic Oncology

Group LAP2 Study. J Clin Oncol 2012;30:695-700.

12. Todo Y, Kato H, Kaneuchi M, Watari H, Takeda M, Sakuragi N.

Survival eect of para-aortic lymphadenectomy in endometrial

cancer (SEPAL study): a retrospective cohort analysis. Lancet

2010;375:1165-72.

13. Malzoni M, Tinelli R, Cosentino F, Perone C, Rasile M, Luzzolino

D, et al. Total laparoscopic hysterectomy versus abdominal

hysterectomy with lymphadenectomy for early-stage endometrial

cancer: a prospective randomized study. Gynecol Oncol

2009;112:126-33.

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202

Sarin Rungmanee, M.D.*, Wish Banhiran, M.D.**, Phawin Keskool, M.D.**, Paraya Assanasen, M.D.**,

Wattanachai Chotinaiwattarakul, M.D.***, Nongyoaw Nujchanart, R.N.**

*Siriraj Sleep Center, **Department of Otorhinolaryngology, ***Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University,

Bangkok 10700, ailand.

Characteristics and Clinical Presentations of

Patients at the Siriraj Snoring Clinic

ABSTRACT

Objective: To describe characteristics and clinical presentations of patients in Siriraj snoring clinic and to analyze

their relationships with obstructive sleep apnea (OSA) severity.

Methods: ree hundred and seventy-three patients’self-administered questionnaires regarding sleep problems

recorded between January 2012 and December 2013 and 275 polysomnographic reports were reviewed.

Results: Among 373 respondents, there were 247 males (66.2%) and 126 females (33.8%), with an average age

of 48 years and body mass index of 28.2 kg/m

. eir most common complaints and comorbidities were snoring

≥3 nights/week (87.9%), worrying about complications from apnea (72.4%), dyslipidemia (36.7%), hypertension

(34.3%), and diabetes mellitus (12.1%), respectively. Using apnea-hypopnea index (AHI) of ≥5 and ≥30 events/hour,

there were 76.7% and 38.5% of patients diagnosed as OSA and severe OSA, respectively. While using respiratory

disturbance index (RDI) with similar cut-o, almost everyone (98.8%) and 60.2% of patents will be diagnosed as

OSA and severe OSA, respectively. Characteristics signicantly associated with AHI ≥15 events/hour were snoring

≥3 nights/week, witnessed apneas, and nocturia (p < 0.05). e comorbidities which signicantly associated with

OSA group were hypertension, diabetes, and dyslipidemia. ere were only weak signicant relationships between

AHI (and RDI) with ESS and quality of life.

Conclusion: e most common complaints in our clinic were loud snoring and worrying about OSA consequences,

not excessive daytime sleepiness. Based on RDI criteria, almost everyone were diagnosed as OSA; however, it had

poor relationship with patients’symptoms, comorbidities and quality of life. us, for better OSA evaluation, we

should use data from several aspects, not only AHI nor RDI for proper patient management.

Keywords: Obstructive sleep apnea; clinical presentation; characteristic; prevalence (Siriraj Med J 2020; 72: 202-208)

Corresponding author: Wish Banhiran

E-mail: wish.ban@mahidol.ac.th

Received 4 March 2019 Revised 19 June 2019 Accepted 2 July 2019

ORCID ID: http://orcid.org/0000-0002-4029-6657

http://dx.doi.org/10.33192/Smj.2020.27

INTRODUCTION

Obstructive sleep apnea (OSA) is a common disorder

that is characterized by narrowing of the upper airway,

which leads to abnormal ventilation during sleep.

Despite

inconsistences in OSA-related epidemiologic data due

to dierences among the populations being studied and

dierences in how the disease was identied, substantial

evidence has been reported that strongly suggests that

untreated OSA may lead to several adverse eects, including

cardiovascular diseases, impaired neurocognitive function,

decreased quality of life, and increased risk of accidents.

2-8

Young, et al. studied middle-aged adults in the

United States and found a prevalence of OSA [dened as

apnea-hypopnea index (AHI) ≥5 events/hour (hypopnea

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dened as ≥4% oxygen desaturation)] as high as 9%

in women and 24% in men.

In the same study, the

prevalence of OSA syndrome (OSAS) was only 2% in

women and 4% in men when OSAS was dened as AHI

≥5 events/hour plus self-reported hypersomnolence.

However, a subsequent study by that group found that the

prevalence of OSAS plus symptoms of daytime sleepiness

had signicantly increased over time to 14% in men and

5% of women.

In ailand, the prevalence of OSA and

OSAS was reported to be 11.4% (males 15.4%, females

6.3%) and 4.4% (males 4.8%, females 1.9%), respectively.

In spite of these reported high rates of prevalence, it is

estimated that 93% of women and 82% of men with

moderate to severe OSA remain undiagnosed.

e current gold standard method for diagnosing

OSA is attended polysomnography (PSG) or type I sleep

study that is performed in a sleep lab. However, routine

use of PSG in every snoring patient and in every patient

with suspected OSA is impractical due to its high cost,

long waiting lists, and intensive labor requirements.

Furthermore, its reliability and usefulness are increasingly

questionable because the results from the sleep study

may not associate with the clinical presentations of the

patients, i.e. symptoms, signs and quality of life. Waiting

for the diagnosis and treatment based on only AHI

from the PSG is, thus, possibly inappropriate. To date,

the concept of personalized diagnosis and treatment

has become more popular. Putting several aspects of

information, not only PSG data, may be a better way of

patient approach. Understanding comprehensively on

the characteristics and clinical presentation of patients

may guide us to improve service for the better care.

Although the Snoring Clinic at our center has been

established for a decade, data relating to the characteristics

and clinical presentations of the patients that attend our

clinic are scarce. Accordingly, the aim of this study was

to determine the characteristics and clinical presentations

of the patients that attend the Siriraj Snoring Clinic,

and to investigate association between the identied

characteristics and presentations, and severity of obstructive

sleep apnea.

MATERIALS AND METHODS

is retrospective chart review included patients aged

≥18 years who sought treatment for sleep problems at a

snoring clinic of the Department of Otorhinolaryngology,

Faculty of Medicine Siriraj Hospital, Mahidol University

during January 2012 to December 2013. Siriraj Hospital

is a 2,300-bed national tertiary referral hospital that is

located in Bangkok, ailand. is study period was

selected, because it fell just before PSG scoring denition

was changed.

e data obtained from patients in the

snoring clinic included demographic and clinical data, sleep

history, Epworth Sleepiness Scale (ESS) and functional

outcomes of sleep questionnaire (FOSQ) data. e PSG

data including AHI and respiratory disturbance index

(RDI) were obtained from the electronic medical record

(hospital intranet). Among patients that had PSG results

(AHI and RDI) available for review, those results were

investigated for association with ESS and FOSQ scores.

Patients with missing or incomplete sleep history and/

or physical ndings were excluded. e protocol for

this study was approved by Siriraj Institutional Review

Board (Si 728/2016).

Epworth sleepiness scales

e Epworth Sleepiness Scale (ESS)

is an eight-

item questionnaire assesses a person’s likelihood of

falling asleep during eight common situations. Scoring

ranges from 0 to 3 for each item for a total possible score

of 24 points. A higher score indicates a higher level of

sleepiness. In this study, we used the validated ai

version of the ESS.

Functional Outcomes of Sleep Questionnaire (FOSQ)

e Functional Outcomes of Sleep Questionnaire

(FOSQ) is a disease-specic health-related quality of

life questionnaire. It consists of 30 items that focus on

ve domains of normal daily life, including general

productivity (8 items), vigilance (7 items), social outcome

(2 items), activity level (9 items), and sexual relationship

(4 items). e mean of each subscale and a global score

was reported in a set of scores ranging from 1 to 4 and 5

to 20, respectively. A lower score reects a greater level

of dysfunction or worse quality of life. In this study, we

use the validated ai version of the FOSQ.

Polysomnography (PSG)

Standard technician-attended PSG in this study

included the recording of electroencephalography

(EEG), electrooculography (EOG), submentalis (chin)

electromyography (EMG), electrocardiogram (ECG),

thermistors for nasal and oral airow, thoracic and

abdominal impedance belts for respiratory eorts, pulse

oximetry, microphone for snoring, and sensors for leg and

sleep position. Sleep stages and respiratory parameters

were scored according to the recommendations of the

American Academy of Sleep Medicine (AASM) manual

(2007).

Apnea was dened as a 90% drop in oronasal

thermal ow lasting at least 10 seconds. Hypopnea was

dened as 30% or greater drop in airow for 10 seconds

or longer associated with ≥ 4% oxygen desaturation.

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Respiratory event-related arousal (RERA) was dened

as is an event during which patients take a series of

breaths with increasing respiratory eort that leads to

an arousal from sleep that does not satisfy the criteria

for apnea or hypopnea. Severity of OSA was classied

as mild degree (mild OSA) when the AHI [dened as

average of apnea events plus hypopnea events per hour

(h) of sleep] was within the range of 5 to 14 events/h.

Moderate OSA and severe OSA was dened if the AHI

was from 15 to 30 events/h and more than 30 events/h,

respectively. Respiratory Disturbance Index (RDI) was

dened as the average number of respiratory disturbances

(i.e., obstructive apneas, hypopneas, and RERAs) per

hour.

Statistical analysis

SPSS Statistics for Windows version 18 (SPSS Inc.,

Chicago, IL, USA) was used to perform all statistical

analyses. Continuous data are presented as mean ± standard

deviation, and categorical data are shown as frequency

and percentage. One-way ANOVA with Bonferroni

post hoc test and Chi-square test was used to compare

continuous data and categorical data between groups,

respectively. Spearman’s correlation coecient analysis

was used to compare between PSG ndings (AHI or

RDI) and both FOSQ scores and ESS scores. Statistical

signicance was determined at a p-value less than 0.05.

RESULTS

During January 2012 to December 2013, there were

373 patients (247 males and 126 females) with mean age

of 48 ± 13.6 years (range: 18-88) who visited our snoring

clinic and completed sleep history questionnaire. e mean

body mass index (BMI) and ESS score of all participants

was 28.2 ± 6.2 kg/m

and 10.0 ± 4.9, respectively. ere

were 306 patients who completed the FOSQ, and 350

patients who completed the ESS questionnaire. e most

common reasons that patients reported for seeking care

at our clinic were snoring at least 3 nights per week (328

patients, 87.9%), worrying about complications from

apnea (270 patients, 72.4%), and lacking of energy /

tiring during wake time (253 patients, 67.8%),. e three

most common comorbidities among this cohort were

dyslipidemia (137 patients, 36.7%), hypertension (128

patients, 34.3%), and diabetes (45 patients, 12.1%).

Using one-way ANOVA, there were statistically

signicant dierences of BMI, ESS, AHI, and RDI among

various groups of OSA severity. Subsequent analyses

with Bonferroni post hoc test demonstrated that ESS

scores were signicantly dierent between severe OSA

and non-OSA groups and between severe OSA and

mild OSA groups. In addition, BMI were signicantly

dierent among all groups, except for mild OSA and

moderate OSA groups. e clinical characteristics that

associated with moderate-to-severe OSA classied by AHI

(≥15 events/h) were snoring at least 3 nights per week,

snoring bothering other people, witnessed apneas, and

nocturia (p<0.05). e sole characteristic that associated

with moderate-to-severe OSA classied by RDI (≥15

events/h) was worrying about complications from apnea

(p<0.05).

e comorbidities that had statistical signicance

in the OSA group according to AHI (AHI ≥5 events/h)

were hypertension, diabetes, and dyslipidemia. e sole

comorbidity that had statistically signicant correlation

in the OSA group according to RDI (RDI ≥5 events/h)

was hypertension.

e clinical presentations and polysomnographic

ndings of participants are demonstrated in Tables 1

and 2.

Polysomnographic ndings

ere were a total 275 patients (177 males and 98

females) who underwent PSG. Of those, 229 underwent

full-night PSG, and 46 underwent split-night PSG. PSG

ndings revealed a diagnosis of OSA according to AHI

criteria in 211 (76.7%) patients, a diagnosis of mild OSA

in 49 patients (17.8%), moderate OSA in 56 patients

(20.4%), and severe OSA in 106 patients (38.5%). Using

RDI with a similar cut-o point as AHI to diagnose OSA,

238 patients (98.8%) were diagnosed as OSA, 39 patients

(16.2%) as mild OSA, 54 patients (22.4%) as moderate

OSA, and 145 patients (60.2%) as severe OSA.

Correlation between FOSQ scores, ESS, and

polysomnographic ndings

ere was no statistically signicant dierence

between FOSQ scores and severity of OSA as shown

in Table 3. Spearman’s correlation coecient analysis

was used to compare between FOSQ scores, ESS, and

polysomnographic ndings (both AHI and RDI). Spearman’s

correlation coecients between ESS, FOSQ domain

scores, and FOSQ global score, and AHI and RDI are

demonstrated in Table 4. Scatter diagrams showing

correlation between ESS and AHI, and between ESS

and RDI are given in Fig 1.

DISCUSSION

OSA is a highly prevalent disorder among general

population. Its common nighttime manifestations include

snoring, choking at night, witnessed apneic episodes,

nocturia, and frequent arousals; and, its common daytime

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TABLE 1. Characteristics of 275 patients who underwent polysomnography stratied by OSA severity.

Characteristics Non-OSA Mild OSA Moderate OSA Severe OSA p-value

(N=64) (N=49) (N=56) (N=106)

Male gender 34 (12.4%) 25 (9.1%) 36 (13.1%) 82 (29.8%) 0.10

Female gender 30 (10.9%) 24 (8.7%) 20 (7.3%) 24 (8.7%) 0.10

BMI (kg/m

) 24.8 ± 3.9 28.0 ± 4.4 27.8 ± 3.8 30.1 ± 7.0 <0.001*

Age (years) 47.0 ± 14.5 50.9 ± 13.9 50.5 ± 11.0 48.8 ± 12.8 0.30

ESS score 9.1 ± 5.2 9.1 ± 4.9 10.8 ± 4.7 10.9 ± 4.9 0.04*

AHI 2.4 ± 1.4 9.4 ± 2.9 21.7 ± 4.3 58.2 ± 27.7 <0.001*

RDI 15.8 ± 10.7 26.1 ± 13.5 39.7 ± 10.4 66.2 ± 20.9 <0.001*

Data presented as number and percentage or mean ± standard deviation

*e p-values of <0.05 indicate statistical signicance.

Abbreviations: OSA, obstructive sleep apnea; AHI, apnea-hypopnea index; BMI, body mass index; ESS, Epworth Sleepiness Scale; RDI,

respiratory disturbance index

TABLE 2. Clinical presentation among all study participants (N=373), and among patients who underwent

polysomnography (n=275).

Symptoms Allpatients AHI<15 AHI≥15

p-value

N (%) N (%) N (%)

Worrying about complications from apnea 270 (72.4) 76 (27.6) 121 (44.0) 0.18

Social consequences due to snoring 235 (63.0) 67 (24.4) 114 (41.5) 0.06

Excessive daytime sleepiness 185 (49.6) 49 (17.8) 86 (31.3) 0.11

Snoring ≥3 nights per week 328 (87.9) 94 (34.2) 151 (54.9) 0.009*

Snoring bothering other people 132 (35.4) 34 (12.4) 69 (25.1) 0.035*

Nocturnal choking/gasping 204 (54.7) 57 (20.7) 98 (35.6) 0.10

Witnessed apneas 158 (42.4) 34 (12.4) 86 (31.3) <0.001*

Morning headache / Feeling dry 249 (66.8) 68 (24.7) 109 (39.6) 1.47

Lacking energy / Tiring during wake time 253 (67.8) 74 (26.9) 110 (40.0) 0.68

Falling asleep while driving 140 (37.5) 36 (13.1) 74 (26.9) 0.02*

Decits in cognition and vigilance 196 (52.5) 58 (21.1) 88 (32.0) 0.63

Nocturia 126 (33.8) 32 (11.6) 66 (24.0) 0.034*

*e p-values of <0.05 indicate statistical signicance between AHI <15 and AHI ≥15 events/h

Abbreviation: AHI, apnea-hypopnea index

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TABLE 3. FOSQ domain and global scores stratied by OSA severity (N=275).

Non-OSA Mild OSA Moderate OSA Severe OSA p-value

General productivity 2.9 ± 1.1 3.0 ± 0.8 3.3 ± 0.7 3.0 ± 0.9 0.44

Social outcome 3.5 ± 0.9 3.5 ± 0.9 3.6 ± 0.9 3.3 ± 1.2 0.46

Activity level 3.1 ± 0.7 3.1 ± 0.7 3.3 ± 1.1 2.9 ± 0.7 0.13

Vigilance 2.7 ± 1.2 2.9 ± 1.3 2.9 ± 1.1 2.8 ± 1.3 0.78

Sexual relationship 1.8 ± 1.5 2.2 ± 1.67 2.4 ± 1.6 2.3 ± 1.4 0.16

FOSQ global 14.0 ± 4.1 14.8 ± 3.8 15.4 ± 3.5 14.3 ± 4.1 0.32

e data were presented in mean ± standard deviation (SD) with p-values (p < 0.05, it will indicate statistical signicance).

Abbreviations: FOSQ, functional outcomes of sleep questionnaire; OSA, obstructive sleep apnea; AHI, apnea-hypopnea index

TABLE 4. Spearman’s correlation coecients between ESS, FOSQ domain scores, and FOSQ global score, and AHI

and RDI.

Spearman’s Spearman’s

correlation

p-value

correlation

p-value

  coefcient

(AHI)

 coefcient

(RDI)

Epworth Sleepiness Scale (ESS) 0.2 <0.002* 0.12 <0.003

General productivity -0.04 0.56 -0.02 0.76

Social outcome -0.08 0.25 -0.02 0.76

Activity level -0.14 0.03* -0.15 0.03

Vigilance -0.05 0.50 0.02 0.74

Sexual relationship 0.13 0.06 0.12 0.11

FOSQ global -0.002 0.97 0.01 0.85

*e p-values of <0.05 indicate statistical signicance.

Abbreviations: ESS, Epworth Sleepiness Scale; FOSQ, functional outcomes of sleep questionnaire; AHI, apnea-hypopnea index; RDI,

respiratory disturbance index

Fig 1. (A) Scatter diagrams showing correlation between Epworth Sleepiness Scale (ESS) and apnea-hypopnea index (AHI), and (B) between

ESS and Respiratory Disturbance Index (RDI).

A B

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manifestations include excessive daytime somnolence,

poor concentration, poor memory, mood changes, and

irritability.

Not surprisingly, the results of this study

showed the most common reason that patients visit our

clinic is because of snoring problems. e second most

common clinical manifestation was worrying about adverse

consequences of untreated OSA, which is dierent from

the second most common cause of seeking treatment

reported in previous studies.

18,19

Increasing public awareness

about this disease may be one of the reasons why there is

such a long waiting list for PSG at our center. Contrary

to what we had earlier hypothesized, excessive daytime

sleepiness (EDS), although reported as a complaint by

49.6% of patients, was not one of the most commonly

reported complaints. Although our results showed ESS

scores to be signicantly correlated with OSA severity to

a modest degree, the level of excessive daytime sleepiness

among our cohort was probably not severe enough to

motivate them to seek medical attention. Furthermore, it

was probably that some patients frequently complained

of fatigue, tiredness, and lack of energy rather than

sleepiness.

e prevalence of OSA (AHI ≥5 events/h) in our

snoring clinic was 76.7%, which is higher than in general

population.

9-11,21

is was not unexpected because most

patients in our study were symptomatic and/or were at

high-risk for being diagnosed as OSA which are dierent

from general population. However, if we used RDI criteria

(RDI ≥5 events/h), almost every patient (98.8%) would

be diagnosed as OSA, and more patients would be

diagnosed as severe OSA. Moreover, our study revealed

the characteristics associated with moderate to severe

OSA by AHI (AHI ≥15 events/h) to be snoring at least

3 nights per week, snoring that bothers other people,

witnessed apneas, and nocturia (p<0.05); whereas, the

only characteristic associated with moderate to severe

OSA by RDI (RDI of ≥15 events/h) was worrying about

complication from apnea. is may imply that AHI

scored by the recommended hypopnea criteria (30%

drop of airow associated with ≥4% desaturation) from

the AASM manual 2007 seems to be more clinically

relevant and more specic to OSA symptoms than RDI

or possibly AHI from currently recommended hypopnea

criteria of AASM manual 2012.

The comorbidities that were different between

OSA and non-OSA patients when using AHI were

hypertension, diabetes, and dyslipidemia; while no

dierence in comorbidities was observed between OSA

and non-OSA patients when using RDI. Furthermore, no

relationship was observed between OSA and cardiovascular

diseases, which is dierent from the ndings of other

studies.

22-24

Regarding quality of life, we found only a

weak relationship between activity level and AHI/RDI,

which was slightly dierent from some studies.

25,26

All of

these ndings suggest that RDI or AHI alone should not

be used to diagnose OSA. Alternatively, whether AHI

or RDI are used, they should be used in conjunction

with data relating to other aspects of the disease such

as patient symptoms, comorbidities, and quality of life.

Limitations

e mentionable limitations of this study include

its retrospective design and the fact that we included

subjective patient-reported questionnaire data. Further

prospective study is needed to confirm and further

elucidate the associations between severity of OSA, and

patient characteristics and clinical presentations in order

to improve diagnosis, treatment, and outcomes. e

strength of this study is its relatively large sample size,

with a signicant proportion of those patients having

PSG results available for analysis.

CONCLUSION

is study showed that most common chief complaints

of patients in our clinic were loud snoring and worrying

about adverse consequences of untreated OSA, but

not EDS. Furthermore, the clinical characteristics that

associated with AHI ≥ 15 events/h were snoring at least 3

nights per week, snoring bother other people, witnessed

apneas, and nocturia. Using criteria of AHI of ≥ 5

events/h, seventy-six percent of patients were diagnosed

as OSA. However, if using criteria of RDI ≥ 5 events/h,

almost every patients will be diagnosed as OSA. Given

the only weak relationship between AHI (and RDI)

with ESS and quality of life. AHI combined with other

patient factors was found to be superior to RDI alone

for diagnosis of OSA.

ACKNOWLEDGMENTS

e authors gratefully appreciate the kind contributor

of Mr.Suthipol Udompanturak for his assistance with

statistical analysis, Ms.Jeerapa Kerdnoppakhun for her

data and documentary assistance. e authors also thank

all of the patients who were involved in this projects.

Conict of interest declaration: All authors declare no

personal or professional conicts of interest relating to

any aspect of this study.

Funding disclosure: is was an unfunded study.

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Rungmanee et al.

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209

Original Article

SMJ

Atiporn uangtong, M.D., Sirawadee Wiriyaudomchart, M.D., Ketsara Rungsiri, B.P.H.

Department of Ophthalmology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, ailand.

Incidence of Ocular Toxicity from Iron Chelating

Agents at Siriraj Hospital

ABSTRACT

Objective: To determine the incidences of ocular toxicity and ocular ndings, including structural and functional

abnormalities, caused by iron chelating agents and detected by an electrophysiologic test at Siriraj Hospital.

Methods: A retrospective chart review was conducted of patients receiving multiple blood transfusions and iron

chelation therapy who had an eye examination at Siriraj Hospital between January 1995 and December 2017.

Results: Ninety-seven charts were reviewed. e 88 patients included comprised 41 males and 47 females. eir ages

ranged from 1 year 11 months to 47 years, with children predominant (mean: 8.13 years). Beta thalassemia HbE

was the main diagnosis (87.5%). Aer receiving iron chelating agents, 3 patients had abnormal eye ndings with

suspected ocular toxicity. Two had retinal pigmentary changes, but only one of those two displayed a mildly decreased

response in a scotopic electroretinogram. Although the third patient also showed a decreased electroretinogram

response, there were no obvious retinal changes. All three received the iron chelating agents desferrioxamine,

deferiprone, and/or deferasirox at dierent doses and for various durations.

Conclusion: Although some pigmentary retinopathy and decreased electroretinogram responses were found, leading

to ocular toxicity being suspected, there was a very low incidence of ocular toxicity from the chelating agents. In

addition, the dosages of the agents causing ocular toxicity, and the duration of that toxicity, were inconclusive.

Moreover, a gold standard for identifying ocular toxicity caused by chelating agents was not able to be established.

Consequently, the risks and benets of employing eye screening coupled with an invasive procedure like an

electrophysiologic test will need to be weighed, especially with pediatric patients.

Keywords: Ocular toxicity; iron chelating agent; thalassemia; electroretinogram (Siriraj Med J 2020; 72: 209-213)

Corresponding author: Atiporn uangtong

E-mail: atipornpam@yahoo.com

Received 8 November 2018 Revised 29 May 2019 Accepted 7 June 2019

ORCID ID: http://orcid.org/0000-0002-3613-4049

http://dx.doi.org/10.33192/Smj.2020.28

INTRODUCTION

alassemia, an inherited blood disorder, has a high

incidence rate in ailand. Its treatment depends on

the type and severity of the disease involved. Although

blood transfusions are a treatment option for patients

with anemia, an iron overload can occur following

multiple blood transfusions, which can be potentially

fatal. Chelation therapy utilizing iron chelating agents

helps to remove the excessive iron from the body.

e iron chelating agents used at Siriraj Hospital are

desferrioxamine, deferiprone, and deferasirox. Unfortunately,

their use may lead to ocular toxicity, presenting in the

form of a deterioration in visual acuity and color vision,

night blindness, a scotoma or constricted visual eld,

retinopathy, optic neuropathy, and an abnormal retinal

function detectable by electroretinogram (ERG).

1-5

Little

information has been reported on the incidences of these

ocular toxicities, and there are no standard eye-screening

guidelines for patients.

Our study aimed to determine the incidences of ocular

toxicity and ocular ndings, including both structural

and functional abnormalities, detected by ERG and

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210

arising from the use of iron chelating agents at Siriraj

Hospital.

MATERIALS AND METHODS

A retrospective chart review was conducted of

patients who received multiple blood transfusions with

iron chelation therapy and had an eye examination at

Siriraj Hospital between January 1995 and December 2017.

Excluded from the study were patients who had abnormal

eye conditions before receiving iron chelating agents,

such as a previous optic neuropathy or retinopathy due

to toxic agents or other causes. is study was conducted

aer approval by the Siriraj Institutional Review Board,

Faculty of Medicine Siriraj Hospital, Mahidol University

(Si 233/2017).

e baseline visit was dened in two ways. If a

patient had not yet been administered any chelating

agents, it was deemed to be that visit when the patient

had a normal eye examination. However, in cases where

a patient had already commenced the use of the agents,

the baseline visit was the rst visit aer the treatment had

begun when a normal eye examination was performed.

Demographic data (age, sex, body weight, and height)

were recorded. e diagnosis, type and dosage of each

iron chelating agent received, and serum ferritin level

were also recorded. The eye examinations included

LogMAR visual acuity measurements, anterior segment

and fundus examinations, color vision tests, visual eld

tests, and electrophysiologic tests. e follow up eye

examination is routinely done yearly.

Ocular toxicity from the agents was dened as

either a decrease in the best corrected visual acuity

(expressed in a LogMAR scale) of more than two steps

from a patient’s baseline, or any abnormal nding in

any part of an eye examination.

Statistical analysis

A descriptive statistical analysis of the quantitative

data was performed by determining the mean, minimum,

and maximum values. All analyses were carried out

using SPSS Statistics for Windows, version 18 (SPSS

Inc., Chicago, IL, USA).

RESULTS

A 97-chart review was conducted. e 88 included

patients comprised 41 males and 47 females. eir ages

ranged from 1 year 11 months to 47 years. However, with

a mean of 8.13 years, most patients were children. Beta

thalassemia HbE was by far the most common diagnosis

(87.5%).

Aer receiving iron chelating agents, 3 patients

were found to have abnormal eye ndings suggestive

of ocular toxicity (Table 1).

Patient one:

is was a 9-year-old girl with beta thalassemia

HbE. She received deferasirox (21 mg/kg/day) for about

12 months before switching to deferiprone (31.9 mg/kg/

day initially, but adjusted to 60 mg/kg/day) for around 17

months. Desferrioxamine (16 mg/kg/day) was subsequently

added.

At the toxic visit, she was 17 years old. By that

stage, she had received the agents for 7 years. Her serum

ferritin level was 4,148 ng/ml. Changes in the pigment

of the retina were found in both eyes, but her visual

acuity, color vision, and visual eld were unremarkable.

An ERG was not performed during that visit.

Patient two:

is was a 6-year-old boy with beta thalassemia

HbE. He received desferrioxamine (20 mg/kg/day) for

about 3 months before the dose was increased to 40 mg/

kg/day and deferasirox (35 mg/kg/day) was added. He

received both agents for approximately 48 months, and

then they were stopped. Following a 3-month cessation,

the chelation therapy was recommenced using deferasirox

(31 mg/kg/day). Aer 8 months, the agent was switched

to deferiprone (71 mg/kg/day) and desferrioxamine (no

dosage was recorded).

At the toxic visit, he was 15 years old. His serum

ferritin level was 1,912 ng/ml. A pigmentary change was

found in the retina of both eyes, and he had a mildly

decreased scotopic ERG for both eyes. Other ocular

ndings were unremarkable.

Patient three:

is was a 6-year-old girl with beta thalassemia

HbE. She initially received desferrioxamine (no dosage

was recorded). Four years later, deferiprone (80 mg/kg/

day) was added. Because she developed liver toxicity, the

chelating agents were given o and on.

At the toxic visit, she was 20 years old. She received

deferiprone (89.5 mg/kg/day). Her serum ferritin level was

894.3 ng/ml. Only an abnormal photopic and scotopic

ERG were found. Otherwise, her ocular ndings were

normal.

DISCUSSION

Iron chelating agents are used for the treatment of

iron overload in patients with hematologic conditions

that require frequent blood transfusions to prevent

hemosiderosis. If le untreated, hemosiderosis may lead

Thuangtong et al.

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TABLE 1. ree cases were suspected to have ocular toxicity from the iron chelating agents.

Patient Age at Age at Iron chelating Dose of each Serum ferritin Abnormal

(no.) 1

visit toxicvisit agentsattoxic agent attoxicvisit eyendings

(year) (year) visit (mg/kg/day) (ng/ml)

1 9 17 Deferiprone 60 4,148 Pigmentary changes at

Desferrioxamine 16 retina in both eyes

2 6 15 Deferiprone 71–85 1,912 Pigmentary changes at

Desferrioxamine Not recorded retina in both eyes

Mildly decreased

scotopic ERG in both eyes

3 6 20 Desferrioxamine Not recorded 894.3 Decreased ERG

Deferiprone 89.5 response in both eyes

Fig 1. Fundus photography of the patient No.1 showed pigmentary retinopathy of the right eye (A) and le eye (B). Normal ERG ndings

in both eyes (C: upper=right eye, lower=le eye).

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212

to diabetes, cardiac disease, and hepatic dysfunction.

ere are many administration routes (for example,

oral, subcutaneous and intravenous).

Desferrioxamine is widely used as an iron chelating

agent for both intravenous and subcutaneous administration.

It has a systemic toxicity eect on the cardiovascular,

respiratory, gastrointestinal, cutaneous, and nervous

systems. Bone dysplasia and high-frequency sensory

neuronal hearing loss have been reported



. As to ocular

toxicity, desferrioxamine can cause nyctalopia, abnormal

color perception, visual eld defects, cataract formation,

optic neuropathy, and pigmentary retinopathy.

Various

mechanisms of desferrioxamine toxicity have been

hypothesized, such as the induction of oxidation that

damages the blood-retinal barrier and reduces the

concentration of other metal ions, like Cu

and Zn

It is still unclear whether ocular toxicity is dose-dependent

or not. However, Simon S et al.,

showed that the risk of

developing systemic toxicity increased with lower iron

loads and with desferrioxamine dosages higher than 50

mg/kg/day.

Deferiprone, an alternative or adjunctive regimen

to desferrioxamine, is orally administered. It is able to

cross the blood-retinal barrier, and it has been reported to

cause damage to the retinal pigment epithelium (RPE).

Deferasirox is a newer, oral-ecient, iron chelator.

ere has been a case report of deferasirox inducing

maculopathy, which was demonstrated by optical coherence

tomography.

A study by Baath JS et al.,

reported that desferrioxamine-

related ocular toxicity was a rare and mild nding. Out

of 84 patients who received regular desferrioxamine

treatment, only one (1.2%) had desferrioxamine-related

ocular toxicity. e researchers found central blurriness

and retinal pigmentary changes, shown by examination

and decreased central responses in electroretinography.

Nevertheless, those changes proved to be completely

reversible aer a change from intravenous to subcutaneous

therapy at a reduced dose. Maura Di Nicola et al.,

reported

desferrioxamine-related, sight-threatening, ocular toxicity

involving the RPE. Damage to the RPE can lead to visual eld

defects, color vision defects, abnormal electrophysiological

Fig 2. ERG ndings in patient No.2 showed mildly decreased scotopic ERG in both eyes (upper=right eye, lower=le eye).

Fig 3. ERG ndings in patient No.3 showed decreased photopic and scotopic ERG in both eyes (upper=right eye, lower=le eye).

Thuangtong et al.

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Original Article

SMJ

tests, and permanent visual deterioration. Haimovici et

al.,

described early and unusual features in 16 patients

with desferrioxamine-induced retinal toxicity. ey

found macular and/or peripheral pigmentary changes,

reduced electroretinographic amplitudes, and reduced

electrooculographic light-peak to dark-tough ratios.

Peripapillary, papillomacular, and paramacular patterns

of retinal pigment epithelial degeneration were also

observed in one patient. Cohen et al.,

studied 52 regularly

transfused patients who received desferrioxamine by

subcutaneous or intravenous infusion. A symptomatic

loss of vision and hearing developed in one patient. Both

problems improved when chelation therapy was ceased.

In our study, we found 3 patients who were suspected

to have ocular toxicity resulting from iron chelating

agents. Two had pigment alterations in their retinas, but

only one of those two had a mildly decreased response

in a scotopic ERG. Although the third patient had a

decreased ERG response, there were no obvious retinal

changes. All 3 patients had no ocular symptoms or any

disturbance in their visual acuity, color vision, or visual

eld. ey all received desferrioxamine, deferiprone, and

deferasirox as iron chelating agents at dierent doses

and for a variety of durations.

In conclusion, there is a very low incidence of ocular

toxicity arising from the use of these iron chelating agents.

Our 22-year chart review revealed only 3 patients who

were suspected to have ocular toxicity from objective

testing, but without any apparent ocular symptoms. e

dosages of these agents that caused the ocular toxicity,

and the duration of that toxicity, were still inconclusive,

as indicated by our ndings and the previous studies

mentioned above. No gold standard for identifying the

ocular toxicity arising from these agents was able to be

established. Consequently, eye screening with an invasive

procedure, such as an electrophysiologic test, should be

considered aer assessing the related risks and benets,

especially with pediatric patients.

We could not calculate the incidence of this toxicity

due to a small number of sample size. Our study was

a retrospective study and had some limitations. First,

there was a lack of detail in the patients’ charts about the

dosages of the iron chelating agents given. In addition,

several agents were frequently given at the same time,

which means that the ocular toxicity could have resulted

from either any one of them or the particular combination

of agents. Second, each patient could not complete all

investigations such as lacking of visual eld test in young

patient. Finally, although the incidence of thalassemia

in ailand is high, eye examinations are not routinely

provided; this means that cases of ocular toxicity may

go undiagnosed.

ACKNOWLEDGMENTS

e authors wish to acknowledge the help of Miss

Mathuwan Srikong, from the Medical Education Technology

Center of the Faculty of Medicine, Mahidol University,

for providing us the gures.

Conict of interests: All authors declare no conict

of interests.

REFERENCES

1. Di Nicola M, Barteselli G, Dell’Arti L, Ratiglia R, Viola F.

Functional and structural abnormalities in deferoxamine

retinopathy: A review of the literature. Biomed Res Int 2015;

2015:249617.

2. Szwarcberg J,Mack G,Flament J. b of deferoxamine: description

and analysis of three observations. J Fr Ophtalmol 2002;25:

609-14.

3. Marciani MG1, Cianciulli P, Stefani N, Stefanini F, Peroni L,

Sabbadini M, et al. Toxic eects of high–dose deferoxamine

treatment in patients with iron overload: An electrophysiological

study of cerebral and visual function. Haematologica 1991;76:

131-4.

4. Olivieri NF, Buncic JR, Chew E, Gallant T, Harrison RV,

Keenan N, et al. Visual and Auditory Neurotoxicity in Patients

Receiving Subcutaneous Deferoxamine Infusions. N Engl J

Med 1986;314:869-73.

5. Haimovici R, D’Amico DJ, Gragoudas ES, Sokol S; Deferoxamine

Retinopathy Study Group. e expanded clinical spectrum of

deferoxamine retinopathy. Ophthalmology 2002; 109:164-71.

6. Sen P, Bhende M, Ravi P, Roy R. Multifocal electroretinogram

in desferrioxamine-related macular toxicity. Retin Cases Brief

Rep 2010;4:224-8.

7. Simon S, Athanasiov PA, Jain R, Raymond G, Gilhotra JS.

Desferrioxamine-related ocular toxicity: A case report.Indian

J Ophthalmol 2012;60:315-7.

8. Taneja R, Malik P, Sharma M, Agarwal MC. Multiple transfused

thalassemia major: ocular manifestations in a hospital-based

population. Indian J Ophthalmol 2010;58:125-30.

9. Pan Y, Keane PA, Sadun AA, Fawzi AA. Optical coherence

tomography ndings in deferasirox-related maculopathy.

Retin Cases Brief Rep 2010;4:229-32.

10. Baath JS,Lam WC,Kirby M,Chun A. Deferoxamine-related

ocular toxicity: incidence and outcome in a pediatric population.

Retina 2008;28:894-9.

11. Cohen A, Martin M, Mizanin J, Konkle DF, Schwartz E. Vision

and hearing during deferoxamine therapy. J Pediatr 1990;117

(2 Pt 1):326-30.

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214

Sunee Limsrivanichakorn, M.Sc., Popchai Ngamskulrungroj, M.D., Ph.D., Amornrut Leelaporn, Ph.D.

Department of Microbiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, ailand.

Activity of Antimicrobial Combinations Against

Extensively Drug-Resistant Acinetobacter baumannii

as Determined by Checkerboard Method and E-test

ABSTRACT

Objective: Combination therapy is needed to treat extensively drug-resistant (XDR) Acinetobacter baumannii

infection. Colistin (Col) in combination with another drug is usually used for that purpose. e aim of this study

was to determine the activity of antimicrobial combinations against XDR A. baumannii using both standard

checkerboard (CB) method and E-test. E-test was also evaluated for application in a diagnostic bacteriology laboratory

by comparing its ecacy with that of CB method.

Methods: Eighty clinical isolates of XDR A. baumannii were used to determine the activity of the following

antimicrobial combinations by CB method and E-test: Col+cefoperazone/sulbactam (Cps), Cps+moxioxacin

(Mox), and Col+Mox. Comparison of CB and E-test was also evaluated.

Results: By CB method, Col+Cps yielded a synergistic eect rate (12.5%) higher than those of the other 2 combinations

(CpS+Mox 5% and Col+Mox 0%). e majority of test results revealed additivity. Col+Cps, Cps+Mox, and Col+Mox

exhibited additive eect against 78.75%, 85.0%, and 87.5% of isolates, respectively. Overall, E-test and CB yielded

only 37.5% concordant rates. However, high concordant rates were specically observed in additive eect of Col+Cps

(73.8%) and Cps+Mox (80.4%).

Conclusion: Col+Cps exhibited better activity than the other two combinations against XDR A. baumannii. E-test

is the method that should be used, but its use is limited to the additive results of Col+Cps and Cps+Mox.

Keywords: Synergy test; XDR Acinetobacter baumannii; colistin; cefoperazone/sulbactam; moxioxacin (Siriraj

Med J 2020; 72: 214-218)

Corresponding author: Amornrut Leelaporn

E-mail: amornrut.lee@mahidol.ac.th

Received 1 August 2019 Revised 24 September 2019 Accepted 15 October 2019

ORCID ID: http://orcid.org/0000-0003-3989-151X

http://dx.doi.org/10.33192/Smj.2020.29

INTRODUCTION

Acinetobacter baumannii, which is one of the most

troublesome pathogens in clinical settings worldwide,

has a very high rate of resistance to a wide variety

of antimicrobial agents, including aminoglycosides,

uoroquinolones, broad-spectrum beta-lactams, and

carbapenems. Extensively drug-resistant (XDR) isolates

are common, and pandrug-resistant (PDR) strains have

been reported.

erefore, the use of monotherapy is now

limited, antimicrobial combinations for the treatment of

A. baumannii infection are needed. However, appropriate

regimens and suitable methods for the determination

of in vitro synergy in a routine diagnostic laboratory

setting are not yet available.

Among the agents that are eective for treating

A. baumannii infection, colistin (Col) in combination

with another drug is usually used for XDR A. baumannii

therapy. Moxioxacin (Mox), a uoroquinolone, has been

reported to have better activity than ciprooxacin against

Acinetobacter species.

For beta-lactam combined with

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beta-lactamase inhibitor, combination with sulbactam

(i.e., cefoperazone/sulbactam, Cps) seems to have better

activity against A. baumannii than other combinations

since sulbactam has direct antimicrobial activity against

the organism.

3,4

To detect the in vitro synergy of antimicrobial

combinations, time-kill and checkerboard (CB) tests are

standard methods that are commonly used.

However,

these techniques are time-consuming, labor-intensive, and

inappropriate for use in a diagnostic bacteriology laboratory.

E-test, which is an easy-to-perform method, has been

modied to evaluate antimicrobial combination activity.

erefore, the aims of the present study were to determine

the activity of the antimicrobial combinations Col+Cps,

Cps+Mox, and Col+Mox against XDR A. baumannii

by using CB method and E-test, and to evaluate E-test

for application in routine clinical service by comparing

its ecacy with that of CB method. Since CB method

and E-test are based on the same testing principle for

determining bacteriostatic activity, CB method was

selected as the standard test instead of time-kill method

(bactericidal activity determination).

MATERIALS AND METHODS

Eighty non-repetitive isolates of XDR A. baumannii

were collected from a culture collection maintained at the

Department of Microbiology, Faculty of Medicine Siriraj

Hospital, Mahidol University, Bangkok, ailand. ey

were cultured from various clinical samples (sputum,

56%; blood, 25%; urine, 7.5% and others, 11.5%) from 19

wards during a 6-year period (2006-2011). e isolates

were presumptively identied as genus Acinetobacter by

presence of the following characteristics: gram-negative

coccobacilli, catalase-positive, oxidase-negative, glucose-

nonfermenter, and ability to grow on MacConkey agar.

e ability of isolates to grow at 44°C was further evidence

that the isolates were A. baumannii. e A. baumannii

isolates used in this study were resistant to amikacin,

gentamicin, cotrimoxazole, ceazidime, cefotaxime,

ceriazone, cefepime, piperacillin/tazobactam, imipenem,

and meropenem, but were susceptible to Col.

Standard powder of antimicrobial agents and E-test

strips of Col, Mox, and Cps were kindly provided by

Atlantic Pharmaceutical Co., Ltd., ailand; Bayer ai

Co., Ltd.; and, Pzer (ailand) Ltd., respectively. Ethical

approval for this study was not required since no human

subjects were involved and no patient information was

included or reported.

CB method and E-test were performed according

to published methods.

5,6

Pseudomonas aeruginosa ATCC

27853 was used as the control organism. e interpretive

criteria for susceptibility were ≤2 g/ml, susceptible for

Col

; 16 g/ml, susceptible for Cps (16/8, cefoperazone/

sulbactam)

; and, 2 g/ml, susceptible for Mox. For CB,

two-fold dilutions of Col (2 to 0.031 µg/ml), Mox (32 to

0.125 µg/ml), and Cps (256 to 0.25 µg/ml) were used.

ese dilutions were prepared fresh immediately prior

to use. ree pairs of antimicrobial combinations (i.e.,

Col+Cps, Col+Mox, and Cps+Mox) were tested by both

methods. Minimal inhibitory concentrations (MICs) of

each drug alone and in combination with other drugs

were read aer 20-hours of incubation at 35

C. For the

isolates with a MIC exceeding the E-test strip detection

limit, the next two-fold dilution was used for fractional

inhibitory concentration (FIC) calculation. e FIC index

(FICI) was dened as the FIC of drug A plus the FIC of

drug B. e FIC of each drug was calculated using the

MIC of the drug in combination divided by the MIC of

that drug alone. e FICIs were interpreted, as follows:

synergy = FICI of ≤0.5; additivity = FICI of >0.5 to ≤1;

indierence (no interaction) = FICI of >1 to ≤4; and,

antagonism = FICI of >4.

RESULTS

Susceptibility to Col, Cps, and Mox of all XDR

A. baumannii isolates tested is demonstrated in Table 1.

All XDR isolates in this study were still susceptible to

Col, and the majority (56.25%) of them exhibited MIC

at 1 g/ml. All XDR isolates were found to be resistant

to Cps and Mox with MIC ranges of 32 to >256 mg/ml

and 4 to 32 g/ml, respectively. e MIC

and MIC

of Cps were 128 g/ml and 256 g/ml, respectively;

whereas, those MICs of Mox were 16 g/ml and 32

g/ml, respectively.

e in vitro activities of antimicrobial combinations

among Col+Cps, Cps+Mox, and Col+Mox tested by

CB and E-test methods against 80 isolates of XDR

A. baumannii are shown in Table 2. When tested by CB

method, synergistic eect was mostly observed from the

combinations of Col+Cps (12.5%) and Cps+Mox (5.0%).

ere was no signicant dierence (p>0.05) between the

synergy rates of those two combinations. Synergy was not

found in any isolate tested with Col+Mox combination.

ese results indicate that Cps-based combinations

were superior to the others. e most common result

interpretation was additivity for all three antimicrobial

combinations, including Col+Cps (78.8%), Cps+Mox

(85%), and Col+Mox (87.5%).

Based on the MIC values of Cps, all 80 isolates

studied could be divided into 3 following groups: ≤64,

128, and ≥256 g/ml (Tables 3 and 4). For Col+Cps

combination, the result showed that better synergistic

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216

TABLE 1. Susceptibility results of 80 Acinetobacter baumannii isolates to each antimicrobial agent

Antimicrobial agent MIC range MIC

MIC

% Susceptibility

Col 0.25 - 2 1 1 100

Cps 32 - >256 128 256 0

Mox 4 - 32 16 32 0

Abbreviations: MIC

= minimum inhibitory concentration for 50% of isolates tested; MIC

= minimum inhibitory concentration for 90%

of isolates tested; Col = colistin; Cps = cefoperazone-sulbactam; Mox = moxioxacin

TABLE 2. Results of in vitro antimicrobial combination activity determined by checkerboard and E test methods

against 80 isolates of Acinetobacter baumannii

Interpretation* Number of isolates (%)

Col+Cps Cps+Mox Col+Mox

CB E-test Con** CB E-test Con** CB E-test Con**

S 10 3 0 4 2 0 0 0 0

(12.5) (3.7) (0) (5) (2.5) (0) (0) (0) (0)

A 63 42 31 68 46 37 70 14 7

(78.8) (52.5) (73.8) (85) (57.5) (80.4) (87.5) (17.5) (50)

I 7 35 2 8 32 2 10 66 11

(8.7) (43.8) (28) (10) (40) (6.3) (12.5) (82.5) (16.7)

Total 80 80 33 80 80 39 80 80 18

(100) (100) (41.3) (100) (100) (48.8) (100) (100) (22.5)

Abbreviations: CB = checkerboard method; Con = concordance; Col = colistin; Cps = cefoperazone-sulbactam; Mox = moxioxacin; S =

synergy; A = additivity; I = indierence; *No antagonism detected in this study; **Concordant rate was calculated using the E-test result as

the total member.

TABLE 3. Results of colistin plus cefoperazone-sulbactam activity against each group of Acinetobacter baumannii

based on cefoperazone-sulbactam minimum inhibitory concentration

Cps MIC (μg/ml) Number of isolates % S % A % S+A

≤64 22 9.09 72.73 81.82

128 48 10.42 83.33 93.75

≥256 10 30 70 100

Abbreviations: Cps = cefoperazone-sulbactam; MIC = minimum inhibitory concentration; % S = percent synergy; % A = percent additivity;

%S+A = percent synergy plus additivity

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TABLE 4. Results of cefoperazone-sulbactam plus moxioxacin activity against each group of Acinetobacter baumannii

based on cefoperazone-sulbactam minimum inhibitory concentration

Cps MIC (μg/ml) Number of isolates % S % A % S+A

≤64 22 9.09 59.09 68.18

128 48 2.08 95.83 97.91

≥256 10 10 90 100

Abbreviations: Cps = cefoperazone-sulbactam; MIC = minimum inhibitory concentration; % S = percent synergy; % A = percent additivity;

% S+A = percent synergy plus additivity

eect was obtained from the higher Cps MIC values

(Table 3). However, this event was not observed for the

Cps+Mox combination (Table 4).

Results obtained from E-test exhibited lower

activity than from CB method for all antimicrobial

combinations (Table 2). Synergy rates observed from

Col+Cps and Cps+Mox by E-test were only 3.7% and

2.5%, respectively. Antagonism was not detected in any

antimicrobial combination tested.

Correlation of the results generated by CB method

and E-test is also shown in Table 2. Concordant results

were commonly observed for the additive eect across all

3 combinations. High additivity concordance was only

observed in Col+Cps (73.8%) and Cps+Mox (80.4%).

Unfortunately, low concordance of results was observed

overall (41.3%, 48.8%, and 22.5% from Col+Cps, Cps+Mox,

and Col+Mox, respectively).

DISCUSSION

Col, which is a drug that was first released for

clinical use in 1959 is eective for many kinds of bacteria,

including A. baumannii. However, clinical use of this

agent is limited by its toxicity (nephrotoxicity and

neurotoxicity), and this led to the introduction of newer

and less toxic agents, such as carbapenems. However,

A. baumannii continues to develop increasing resistance

to these newer eective drugs. Importantly, the majority

of XDR strains are still susceptible to Col, but these

organisms exhibit rather high MICs that are close to the

MIC breakpoint (≤2 g/ml, susceptible). In the present

study, approximately 56% and 6% of isolates had Col

MICs of 1 and 2 g/ml, respectively. High Col MIC

values of A. baumannii isolates were also reported by

another groups of investigators.

8,9

Since Col is considered

a last-resort option for treatment of resistant bacterial

infection, and Col resistance genes have been reported

to spread both vertically and horizontally

, this drug

should be used with both care and caution. It has been

recommended that Col should be used in combination with

another antimicrobial agent to obtain pharmacological

or synergistic eect, lower dose-related toxicity, and

lower resistance development rate.

Sulbactam is a member of the serine β-lactamase inhibitor

family, and it is unable to inhibit any carbapenemases.

e activity of sulbactam against A. baumannii clinical

isolates was found to be mediated via inhibition of the

penicillin-binding proteins (PBPs) PBP1 and PBP3,

with very low frequency of resistance.

Additionally,

the outer membrane of A. baumannii appeared to allow

good sulbactam uptake, thereby promoting antibacterial

activity. However, the pbp3 mutant could result in a high

level of resistance to sulbactam. Sulbactam in combination

with other antimicrobial agent was shown to exhibit less

signicant eect than Cps (cefoperazone-sulbactam)-based

combination against A. baumannii. Cps was included

in this study; however, all isolates tested were found to

be resistant to the drug with high MIC

(256 g/ml)

(Table 1).

For CB method, Col+Cps was found to exhibit slightly

higher in vitro activity than the activity observed from

the other two combinations against XDR A. baumannii.

E-test, which is an easy-to-perform method, was found

to generate results that largely did not agree with those

from CB method. However, E-test usually yielded lower

activity of antimicrobial combination than CB, which

suggests a low possibility of a very major error result from

E-test. Similar results were also reported previously.

11,12

Specically – due to the generally low concordance rate,

E-test may be limited to the additive result of Col+Cps

and Cps+Mox.

Many studies

3,13-17

in the in vitro activity of Col

combined with another agent against A. baumannii have

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218

been published. Examples of agents used in combination

with Col include carbapenems, sulbactam, fosfomycin,

tigecycline, rifampicin, minocycline, lipopeptides, and

glycopeptides. Among those combinations, Col+meropenem

or Col+imipenem was shown to demonstrate superior

activity. To date, up to 90% of A. baumannii isolates

were found to be resistant to carbapenems. Moreover,

the synergistic activity was found to depend on the

level of resistance to carbapenems. If the strains were

resistant to a high level of those drugs, synergism was

not demonstrated.

is nding is dierent from the

result observed in the present study. We found the

synergy rate from Col+Cps to be increased at a high

level of Cps resistance (Table 3). A similar result was

obtained from the combination between tigecycline and

Cps studied by Li, et al.

ey found the synergistic and

additive eects of tigecycline+Cps to be increased with

higher tigecycline MIC values. However, the Cps+Mox

combination in this study did not demonstrate either

of those characteristics. ese results indicate dierent

eects of resistance levels on synergy rates depending on

each antimicrobial combination. Moreover, it seems that

antimicrobial synergy testing may need to be assessed

on an isolate-by-isolate basis, and a clinical trial is also

needed. In addition and importantly, an eective control

measure must be implemented whenever XDR or PDR

A. baumannii is detected.

ACKNOWLEDGMENTS

This study was supported by a grant from the

Routine to Research Project, Faculty of Medicine Siriraj

Hospital, Mahidol University, Bangkok, ailand (grant

no. 08MI04001/001/08). We thank Atlantic Pharmaceutical

Co., Ltd., ailand; Bayer ai Co., Ltd.; and, Pzer

(ailand) Ltd. for providing E-test strips and standard

powder of antimicrobial agents. We also thank sta

members of the Bacteriology Laboratory, Department

of Microbiology, Faculty of Medicine Siriraj Hospital

for assistance with the collection of XDR A. baumannii.

REFERENCES

1. Peleg AY, Seifert H, Paterson DL. Acinetobacter baumannii:

Emergence of a Successful Pathogen. Clin Microbiol Rev

2008;21:538-82.

2. Spence RP, Towner KJ. Frequencies and mechanisms of resistance

to moxifloxacin in nosocomial isolates of Acinetobacter

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3. Li T, Sheng M, Gu T, Zhang Y, Yirepanjiang A, Li Y. In vitro

assessment of cefoperazone-sulbactam based combination

therapy for multidrug-resistant Acinetobacter baumannii

isolates in China. J orac Dis 2018;10:1370-6.

4. Penwell WF, Shapiro AB, Giacobbe RA, Gu RF, Gao N, resher

J, et al. Molecular mechanisms of sulbactam antibacterial

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Antimicrob Agents Chemother 2015;59:1680-9.

5. Sopirala MM, Mangino JE, Gebreyes WA, Biller B, Bannerman

T, Balada-Llasat JM, et al. Synergy testing by Etest, microdilution

checkerboard, and time-kill methods for pan-drug-resistant

Acinetobacter baumannii. Antimicrob Agents Chemother

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6. Bonapace CR, White RL, Friedrich LV, Bosso JA. Evaluation

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comparison with Etest, time-kill, and checkerboard methods.

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7. Clinical and Laboratory Standards Institute. Performance

standards for antimicrobial susceptibility testing. 29

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Wayne, PA: CLSI; 2019.

8. Dafopoulou K, Zarkotou O, Dimitroulia E, Hadjichristodoulou

C, Gennimata V, Pournaras S, et al. Comparative evaluation of

colistin susceptibility testing methods among carbapenem-

nonsusceptible Klebsiella pneumoniae and Acinetobacter baumannii

clinical isolates. Antimicrob Agents Chemother 2015;59:4625-

30.

9. Hindler JA, Humphries RM. Colistin MIC variability by method

for contemporary clinical isolates of multidrug-resistant Gram-

negative bacilli. J Clin Microbiol 2013;51:1678-84.

10. Ma F, Shen C, Zheng X, Liu Y, Chen H, Zhong L, et al. Identication

of a novel plasmid carrying mcr-4.3 in an Acinetobacter

baumannii strain in China. Antimicrob Agents Chemother

2019;63.

11. Marie M, Krishnappa L, Alzahrani A, Mubaraki M, Alyousef

A. A prospective evaluation of synergistic eect of sulbactam

and tazobactam combination with meropenem or colistin

against multidrug-resistant Acinetobacter baumannii. Bosn J

Basic Med Sci 2015;15:24-9.

12. Tan TY, Lim TP, Lee WH, Sasikala S, Hsu LY, Kwa AL. In

vitro antibiotic synergy in extensively drug-resistant Acinetobacter

baumannii: the eect of testing by time-kill, checkerboard,

and Etest methods. Antimicrob Agents Chemother 2011;55:

436-8.

13. Claeys KC, Fiorvento AD, Rybak MJ. A review of novel

combinations of colistin and lipopeptide or glycopeptide

antibiotics for the treatment of multidrug-resistant Acinetobacter

baumannii. Infect Dis er 2014;3:69-81.

14. Jiang Z, He X, Li J. Synergy effect of meropenem-based

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16. Bae S, Kim MC, Park SJ, Kim HS, Sung H, Kim MN, et al.

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Limsrivanichakorn et al.

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SMJ

Jarunee Leetheeragul, M.N.S., Ratree Sirisomboon, B.Sc., Kanjana Pimol B.N.S., Tripop Lertbunnaphong, M.D.,

Pattarawan Limsiri, M.D.

Department of Obstetrics and Gynaecology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, ailand.

Incidence and Pregnancy Outcomes of Primary

Postpartum Hemorrhage Following Implementation

of Postpartum Drape with a Calibrated Bag after

Normal Vaginal Delivery

ABSTRACT

Objective: To evaluate the incidence, risk factors, and pregnancy outcomes of primary postpartum hemorrhage

(PPH) aer the implementation of postpartum drape with a calibrated bag (PDCB) aer normal vaginal delivery.

Methods: is retrospective chart review compared patients who had normal vaginal delivery in June 2012 prior

to PDCB implementation with patients who had normal vaginal delivery in June 2014 aer PDCB implementation

at Siriraj Hospital.

Results: In total, 856 patients were included in this study, with 458 and 398 patients delivered in June 2012 and June

2014, respectively. Baseline characteristics were comparable between the two groups. e incidence of primary PPH

increased signicantly aer the implementation of PDCB (2.8% in 2012 vs. 8.5% in 2014; p < 0.01). e incidence

of severe PPH was also signicantly increased (0.4% in 2012 vs. 2.3% in 2014; p = 0.02). Uterine atony was the most

common cause and the diagnosis increased aer PCDB implementation. e use of additional uterotonic drugs

was also signicantly increased aer PDCB implementation (30.8% in 2012 vs. 85.3% in 2014; p < 0.01). e blood

transfusion rate was comparable between the two groups. No peripartum hysterectomy or ICU admission was

observed in this study. Aer PDCB implementation, pregnancy-induced hypertension was found to be a signicant

risk factor for primary PPH (p < 0.01).

Conclusion: e incidence of primary and severe PPH, and the rate of the use of additional uterotonic drugs were

all signicantly increased aer the implementation of PDCB. Pregnancy-induced hypertension was found to be a

signicant risk factor for primary PPH.

Keywords: ailand; incidence; pregnancy outcomes; primary postpartum hemorrhage; postpartum drape; calibrated

bag; normal vaginal delivery (Siriraj Med J 2020; 72: 219-225)

Corresponding author: Pattarawan Limsiri

E-mail: patrsiri@hotmail.com

Received 13 July 2018 Revised 3 September 2019 Accepted 24 October 2019

ORCID ID: http://orcid.org/0000-0002-1156-4130

http://dx.doi.org/10.33192/Smj.2020.30

INTRODUCTION

Primary postpartum hemorrhage (PPH) is dened

as a blood loss of greater than or equal to 500 mL

within 24 hours postpartum.

PPH is a leading cause of

maternal death worldwide, accounting for 27.1% of all

maternal mortality.

Aer childbirth, physiologic ligation

caused by uterine myometrial contraction is the vital

mechanism for the prevention of massive bleeding from

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220

the placental bed, and failure of this mechanism causes

uterine atony—the most common cause of primary

PPH.

To reduce maternal morbidity and mortality,

active management of the third stage of labor involving

the use of uterotonic agents, controlled cord traction,

and uterine massage is widely recommended for the

prevention of atonic PPH.

However, the main pitfall

of the PPH prevention strategy in routine obstetrics

practice is an underestimation of postpartum blood loss.

Objective measurement of postpartum blood loss is the

essential factor that alerts the obstetrician to initiate PPH

management. ere are many tools for the measurement

of postpartum blood loss, including photospectometry,

gravimetric method (weighed soaked swabs), collector

drape, and visual estimation.

Photospectometry is the

most accurate method, but its use was found and reported

to be impractical in a routine clinical setting.

5,6

Visual

estimation was reported to be the least accurate and

reliable method of blood loss measurement, as it was

found to consistently underestimate blood loss when

compared with objective methods.

6-8

Two studies found

the visual estimation method to be associated with an

error rate of 30% when compared with the gravimetric

method or collector drape.

6,8

A study conducted by our

team in 2013, which evaluated postpartum blood loss

measured in 100 mL discreet categories, conrmed the

inaccuracy and underestimation of the visual estimation

method when compared with objective measurement

using a sterile under-buttock drape (low correspondence

and poor agreement, with a Cohen’s kappa coecient

of 0.07; p < 0.05).

In 2014, our center implemented a new protocol

to evaluate postpartum hemorrhage by an objective

measurement of postpartum blood loss using a postpartum

drape with a calibrated bag (PDCB). In this protocol,

postpartum blood loss ≥ 350 mL is considered to be an

early warning sign for PPH. e purpose of this study was

to evaluate the incidence and risk factors of primary PPH

as well as pregnancy outcomes aer the implementation

of PDCB in 2014 compared with the same following the

traditional subjective measurement of blood loss that

was performed in 2012 before the implementation of

PDCB.

MATERIALS AND METHODS

Study design and population

is retrospective chart review compared patients

who had term normal vaginal delivery in June 2012

prior to PDCB implementation with patients who had

term normal vaginal delivery in June 2014 aer PDCB

implementation at Siriraj Hospital-ailand’s largest

national tertiary referral center. Cases with fetal anomalies,

stillbirth, multifetal pregnancy, and maternal hematologic

diseases that involve clotting mechanisms were excluded.

Demographic data, clinical characteristics, pregnancy

outcomes, and treatment information were recorded and

analyzed. e protocol for this study was approved by

the Siriraj Institutional Review Board (SIRB), Faculty of

Medicine Siriraj Hospital, Mahidol University, Bangkok,

ailand (Si 599/2015).

Sample size calculation and statistical analysis

e sample size for this study was calculated using

the incidence of PPH from our previous study, which

found an increase in postpartum hemorrhage from 3.5%

to 9.1% when comparing the subjective visual estimation

method with the objective sterile under-buttock drape

method, respectively.

We used a type 1 error of 0.05

and a type 2 error of 0.2, and the ratio between the

groups was 1:1. e calculation plus a 10% increase to

compensate for errors of any type yielded a minimum

sample size of at least 396 patients per group.

PASW statistics version 18.0 for Windows (SPSS, Inc.,

Chicago, IL, USA) was used for data analysis. Descriptive

data are presented as a number and percentage or the

mean ± standard deviation. Comparisons between the

groups were performed using the independentt-test for

continuous data, and the chi-square test or Fisher’s exact

test for categorical data. e second and third stages of

labor were analyzed using a nonparametric test. Linear

regression analysis was used for evaluation of the PPH

risk factors. A p-value of less than 0.05 was considered

statistically signicant.

RESULTS

In total, 856 patients were enrolled in this study,

with 458 patients delivered in the 2012 group and 398

patients delivered in the 2014 group. Demographic data,

clinical characteristics, and pregnancy outcomes were

comparable between the two groups (Table 1). Table 2

shows the incidence, cause, and treatment relative to

primary PPH. It can be seen that postpartum hemorrhage

increased signicantly aer the implementation of PDCB

(2.8% in 2012 vs. 8.5% in 2014; p < 0.01). e incidence

of severe PPH, which is dened as a blood loss greater

than 1,000 mL, was also signicantly increased aer

PDCB implementation (0.4% in 2012 vs. 2.3% in 2014;

p = 0.02). In 2014, the most common cause of PPH was

uterine atony, followed with birth passage injury, and

retained placenta, respectively (47.1%, 32.4%, and 14.7%).

In addition, both atonic and non-atonic PPH had more

diagnoses aer PDCB implementation and the percentage

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TABLE 1. Demographic data, clinical characteristics, and pregnancy outcomes in 856 vaginal delivery patients.

2012 deliveries 2014 deliveries

(n=458) (n=398) p-value

Mean±SD Mean±SD

Age (years) 27.0±6.3 27.7±6.4 0.11

Gestational age (weeks gestation) 38.1±1.8 38.2±1.7 0.22

Baseline hematocrit (%) 34.9±3.3 35.2±3.1 0.24

Fetal birth weight (grams) 2,964.5±434.9 2,982.5±396.0 0.53

n (%) n (%) p-value

Nulliparous 212 (46.3%) 176 (44.2%) 0.54

Maternal anemia (Hct <30%) 34 (7.4%) 20 (5.0%) 0.15

Gestational diabetes 22 (4.8%) 20 (5.0%) 0.88

Pregnancy-induced hypertension (PIH) 15 (3.3%) 24 (6.0%) 0.05

Infant birth weight 0.24

AGA (10

- 90

percentile) 359 (78.4%) 329 (82.7%)

SGA (<10

percentile) 41 (9.0%) 32 (8.0%)

LGA (>90

percentile) 58 (12.7%) 37 (9.3%)

Perinatal asphyxia (Apgar score at 1 min ≤7) 17 (3.7%) 13 (3.3%) 0.72

Median (IQR) Median (IQR) p-value

Second stage of labor (minutes) 18 (11, 28) 17 (11, 29) 0.66

Third stage of labor (minutes) 6 (4, 9) 6 (5, 9) 0.09

A p-value <0.05 indicates statistical signicance

Abbreviations: SD, standard deviation; Hct, hematocrit; AGA, appropriate for gestational age; SGA, small for gestational age; LGA, large

for gestational age; IQR, interquartile range

of unidentied causes was reduced (46.1% in 2012 vs.

5.8% in 2014). e use of additional uterotonic drugs was

also signicantly increased aer PDCB implementation

(30.8% in 2012 vs. 85.3% in 2014; p < 0.01). e blood

transfusion rate was comparable between groups (7.7 %

in 2012 vs. 11.8% in 2014; p > 0.05). ere were no cases

of massive blood transfusion, peripartum hysterectomy,

ICU admission, or maternal death in this study. Tables 3

and 4 show the risk factors associated with primary PPH

in the PDCB group, pregnancy-induced hypertension

was found to be the only signicant risk factor for the

development of primary PPH (p < 0.01).

DISCUSSION

In this study, the incidence of primary PPH and

severe PPH both increased aer the implementation

of PDCB. It is known and accepted that the correct

measurement of postpartum blood loss can lead to an early

diagnosis and management of postpartum hemorrhage.

e gravimetric method involving weighing a blood-

soaked material has been proved to be more accurate than

a visual estimation of postpartum blood loss.

However,

Ambardekar S, et al. performed a randomized trial

to compare the ecacy of two dierent methods for

postpartum blood loss measurement (direct method or

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TABLE 2. Incidence of, cause of, and treatment for PPH between groups (N=856).

2012 deliveries 2014 deliveries

(n=458) (n=398) p-value

n (%) n (%)

Incidence

Primary PPH (EBL ≥500 mL) 13 (2.8%) 34 (8.5%) <0.01

Severe PPH (EBL ≥1,000 mL) 2 (0.4%) 9 (2.3%) 0.02

2012 (n=13) 2014 (n=34)

n (%) n (%)

p-value

Cause 0.19

Uterine atony 3 (23.1%) 16 (47.1%)

Non-uterine atony 4 (30.8%) 16 (47.1%)

Birth passage injury 1 (7.7%) 11 (32.4%)

Retained placenta 3 (23.1%) 5 (14.7%)

Unspecied causes 6 (46.1%) 2 (5.8%)

Treatment

Use of additional uterotonic agents 4 (30.8%) 29 (85.3%) <0.01

Blood transfusion 1 (7.7%) 4 (11.8%) 1.00

A p-value<0.05 indicates statistical signicance

Abbreviations: PPH, postpartum hemorrhage; EBL, estimated blood loss

TABLE 3. Risk factors associated with primary PPH aer implementation of PDCB (N=398).

Postpartum hemorrhage

Risk factors n (%) p-value

Yes No

(n=34) (n=364)

Parity ≥3 1 (2.9%) 14(3.9%) 1.00

Poor ANC (<4 visits) 1 (2.9%) 36 (9.9%) 0.35

Maternal anemia (Hct <30%) 0 (0.0%) 16 (4.4%) 0.38

Gestational diabetes 3 (8.8 %) 16 (4.4%) 0.22

Pregnancy-induced hypertension 5 (14.7%) 15 (4.1%) 0.02

BMI on admission ≥25 kg/m

26 (76.5%) 235 (64.6%) 0.19

Prolonged 3

stage of labor (>30 min) 4 (11.8%) 59(16.21%) 0.63

Operator (medical/nursing students) 1 (2.9%) 36 (9.9%) 0.35

Infant birth weight 0.26

AGA (10

- 90

percentile) 25 (73.5%) 304 (83.5%)

SGA (<10

percentile) 5 (14.7%) 27 (7.4%)

LGA (>90

percentile) 4 (11.8%) 33 (9.1%)

A p-value <0.05 indicates statistical signicance

Abbreviations: PPH, postpartum hemorrhage; PDCB, postpartum drape with calibrated bag; ANC, antenatal care; Hct, hematocrit; AGA,

appropriate for gestational age; SGA, small for gestational age; LGA, large for gestational age

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TABLE 4. Linear regression analysis of factors associated with primary PPH aer implementation of PDCB.

Beta SE p-value 95% CI

Pregnancy-induced hypertension 1.306 0.555 0.02 1.24-10.97

Prolonged 3

stage of labor (>30 min) -0.359 0.556 0.518 0.24-2.08

BMI on admission ≥25 kg/m

0.530 0.423 0.210 0.74-3.89

A p-value <0.05 indicates statistical signicance

Abbreviations: PPH, postpartum hemorrhage; PDCB, postpartum drape with calibrated bag; SE, standard error; CI, condence interval

blood collecting drape vs. indirect method or weighed

blood-soaked material) among 1,195 patients. ey

found that the direct method had a higher ecacy for

postpartum blood loss measurement, given that the

direct method had a greater mean blood loss and double

the incidence of PPH.

Previous studies conrmed that

objective measurements using a collection bag or drape

are appropriate for the measurement of postpartum blood

loss.

6,11

In 2016, Bamberg et al. conducted a prospective

cohort study on the use of a collection bag aer vaginal

delivery in 809 patients. ey found similar results, with

an increasing incidence of both PPH and severe PPH.

ey also recommended this method as a tool for the

diagnosis of PPH.

In December 2016, the Royal College

of Obstetricians and Gynaecologists (RCOG) released a

new guideline relative to the prevention and management

of PPH. ey also conrmed the underestimation of

postpartum hemorrhage by the visual estimation method

and suggested the use of more reliable methods, including

blood collecting drapes or the weighing of soaked swabs

aer vaginal delivery.

Abbaspoor Z, et al. rearmed

the eectiveness of a collection bag in the diagnosis of

>500 mL postpartum blood loss (sensitivity of 80%,

Specicity = 95. 7%, PPV = 88.9%, and NPV= 91.8%).

Accordingly, it is clear that the objective measurement of

postpartum blood is superior to the subjective measurement

of postpartum blood, especially via the use of PDCB, and

consequently, it is presently recommended in routine

obstetrics practice, where it is approved as a precise tool

for the early diagnosis of primary postpartum hemorrhage.

In this study, the use of 350 mL of postpartum blood

loss as an early warning sign for PPH had the eect of

increasing the rate of the use of uterotonic agents aer

the implementation of PDCB. Although uterotonic

agents are the main medication for the prevention of

postpartum hemorrhage, they all have adverse eects. For

example, oxytocin may cause hemodynamic instability

or water intoxication, while methylergonovine can cause

vasoconstriction leading to hypertension.

e risk of

these potential adverse eects should be considered and

weighed up on a case-by-case basis when using uterotonic

agents based on blood loss ndings from using the PDCB

method. Evaluation of the clinical signs and symptoms,

especially the pulse and blood pressure, rather than the

blood loss volume alone should be considered as standard

practice for the prevention of PPH before prescribing

additional uterotonic agents.

Pregnancy-induced hypertension was found to be

the only independent risk factor for the development of

primary PPH in this study. Many risk factors associated

with primary PPH have been reported in the literature,

including previous PPH, grand multiparity, macrosomia,

prolonged used of oxytocin, and prolonged third stage

of labor.

16,17

Shortening the duration of the third stage

of labor showed benet for PPH prevention, which was

consistent with the recommended process of active

management of the third stage of labor (AMTS).

1,4

Pregnancy-induced hypertension was also included in

a review by Sebghati and Wetta et al. in 2013, and in a

guideline from the Royal College of Obstetricians and

Gynaecologists (RCOG), as it causes PPH by disturbing

maternal coagulation.

13,17,18

All pregnant women with

pregnancy-induced hypertension in our setting, both with

or without severe features, were treated with magnesium

sulfate for the prevention of seizures that might raise

concerns of a tocolytic eect.

17,19

Our previous 2010

study explored the risk factors for PPH by comparing

the characteristics of 222 patients between those with and

without PPH. We found the duration of the third stage

of labor and pregnancy-induced hypertension to be the

risk factors for primary PPH, and uterine atony to be the

most common cause of PPH-all of which are similar to

the ndings of this study.

However, this study found

only pregnancy-induced hypertension to be a signicant

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risk factor for PPH aer the implementation of PDCB.

A possible explanation for this may be that PDCB had

not yet been introduced in 2010, and consequently, our

postpartum blood loss data at that time may have been

inaccurate. e incidence of PPH that we reported in

2010 was only 2.4%, which may have been inaccurately

low. It is, therefore, possible that the risk factor analysis

that we performed in that study may have been based

on a rate that was lower than it should have been.

e strength of this study is that our analysis was

based on data derived from a real-life clinical setting,

using adequate statistical power, and from two dierent

groups: one delivering before and the other aer the

implementation of PDCB. erefore, our ndings in

the present study reect and support the value and

application of PDCB. It is possible that dierences in the

study population, the healthcare providers, and patient

management practices between 2012 and 2014 could

have aected the outcomes of this study. However, the

demographic and clinical characteristics between the groups

were similar, and our study population also covered the

period representing the beginning of residency training

(June 2012 and June 2014). As such, doctors would have

given the same level of care, and patients would have

received the same level of care. is, therefore, lowers the

opportunity for study bias. Although the size of our study

satised the sample size calculation-required minimum,

our sample size may not have been large enough to identify

statistically signicant dierences between methods for

major complications of primary PPH, including massive

transfusion, peripartum hysterectomy, ICU admission,

and maternal death. A larger sample size or multi-center

trial, especially in primary or community settings, should

be considered to further elucidate the benet of PDCB.

However, a 2010 cluster randomized controlled trial

performed by Zhang et al. compared eectiveness between

a collection bag and visual estimation for reducing severe

PPH in 25,381 patients from 13 European countries aer

vaginal delivery. ey found no signicant dierence

regarding the incidence of severe PPH between groups.

ey hypothesized that their results suggested a common

improper use of the collection bag. eir hypothesis

resulted in an increased awareness of the proper use of

the collection bag and more vigilant PPH management,

with a resulting associated increase in the rate of medical

intervention.

A systemic review of 36 studies (both

quantitative and qualitative) by Hancock et al. in 2015

reported similar ndings. ey found that the use of a

collection bag or drape improved the accuracy of blood

loss measurement over other methods, but that they did

not reduce the rate of severe PPH. ey recommended

that there are many factors in addition to blood volume

that inuence outcomes, including and especially the

speed of blood ow, nature of blood loss, and patient

condition.

Taken together, these ndings suggest that

an early diagnosis of PPH by an objective measurement

of postpartum blood loss using PDCB is not the only

factor that aects the outcomes of PPH. In fact, multiple

factors inuence the outcomes of PPH, and all of these

factors need to be considered in the decision-making

by healthcare providers, including when establishing

organizational policy and when designing a local protocol

for eective PPH management.

In conclusion, in the present study, it was found

that the incidence of primary and severe PPH and the

rate of use of additional uterotonic drugs all signicantly

increased aer the implementation of PDCB. Pregnancy-

induced hypertension was found to be a signicant risk

factor for the development of primary PPH. Further study

in a larger, multi-center study population is needed to

evaluate major complications, especially massive blood

transfusion, peripartum hysterectomy, ICU admission,

and maternal mortality.

ACKNOWLEDGMENTS

e authors gratefully acknowledge Dr. Dittakarn

Boriboonhiransarn of the Department of Obstetrics and

Gynaecology, Faculty of Medicine Siriraj Hospital, for

his assistance with suggestion and statistical analysis.

Conict of Interest Declaration: All authors declare they

had no personal or professional conicts 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: is study was funded by a grant

from the Siriraj Routine to Research (R2R) unit (Grant

no. R2R.316/16).

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et al. Global causes of maternal death: a WHO systematic

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Obstetrics. Prevention and treatment of postpartum hemorrhage

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5. Schorn MN. Measurement of blood loss: review of the literature.

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6. Patel A, Goudar SS, Geller SE, Kodkany BS, Edlavitch SA,

Wagh K, et al. Drape estimation vs. visual assessment for

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7. Razvi K, Chua S, Arulkumaran S, Ratnam SS. A comparison

between visual estimation and laboratory determination of

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9. Lertbunnaphong T, Lapthanapat N, Leetheeragul J, Hakularb P,

Ownon A. Postpartum blood loss: visual estimation versus

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10. Ambardekar S, Shochet T, Bracken H, Coyaji K, Winiko B.

Calibrated delivery drape versus indirect gravimetric technique

for the measurement of blood loss aer delivery: a randomized

trial. BMC Pregnancy Childbirth 2014;14:276.

11. Prasertcharoensuk W, Swadpanich U, Lumbiganon P. Accuracy

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Gynaecol Obstet 2000;71:69-70.

12. Bamberg C, Niepraschk-von Dollen K, Mickley L, Henkelmann

A, Hinkson L, Kaufner L, et al. Evaluation of measured postpartum

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to postpartum hemorrhage management strategies: a prospective

observational study. J Perinat Med 2016;44:433-9.

13. Prevention and Management of Postpartum Haemorrhage:

Green-top Guideline No. 52. BJOG 2017;124:e106-e149.

14. Abbaspoor Z, Vaziri L. e Eectiveness of a Collector Bag

for Measurement of Post-partum Hemorrhage. Afr J Reprod

Health 2017;21:99-103.

15. Vallera C, Choi LO, Cha CM, Hong RW. Uterotonic Medications:

Oxytocin, Methylergonovine, Carboprost, Misoprostol.

Anesthesiol Clin 2017;35:207-19.

16. Postpartum hemorrhage. Practice Bulletin No. 183. American

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17. Sebghati M, Chandraharan E. An update on the risk factors

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Health (Lond) 2017;13:34-40.

18. Wetta LA,Szychowski JM,Seals S,Mancuso MS,Biggio JR,Tita

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requiring treatment aer vaginal delivery. Am J Obstet Gynecol

2013;209:51.e1-6.

19. Witlin AG, Friedman SA, Sibai BM. e eect of magnesium

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20. Lertbunnaphong T, Leetheeragul J, itadilok W. Risk Factors

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21. Zhang WH, Deneux-araux C, Brocklehurst P, Juszczak E,

Joslin M, Alexander S, et al. Eect of a collector bag for measurement

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trial in 13 European countries. BMJ 2010;340:c293.

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Mongkol Laohapensang, M.D.*, Patcharaphan Srikuancharoen, M.D.**, Niramol Tantemsapya, M.D.*

*Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, **Department of Surgery, Chaophraya Yommaraj

Hospital, Suphanburi 72000, ailand.

Factors Related to the Clinical Outcomes of the

Kasai Procedure in Infants with Biliary Atresia

ABSTRACT

Objective: e Kasai portoenterostomy has been accepted as the primary therapeutic treatment for biliary atresia.

However, successful bile drainage does not always promise a long-term native liver survival. Several clinical factors

were evaluated to discover associations with the outcomes.

Methods: A retrospective chart review was conducted of infants with biliary atresia who underwent the conventional

Kasai portoenterostomy at Siriraj Hospital, January 2006-August 2018. e patient demographics, perioperative

clinical and laboratory data, adjuvant therapies, complications, and interventions were analyzed in correlation to

the short- and long-term outcomes. e short-term outcome evaluated was the resolution of jaundice, while the

long-term outcome was remaining jaundice-free with the native liver.

Results: e complete medical records of 80 patients were retrospectively reviewed. eir mean age at the time of

the Kasai portoenterostomies was 97 days. Overall, 66.3% achieved jaundice clearance. e mean follow-up duration

was 50.5 months, with 51.3% of the patients remaining jaundice-free with their native liver. A prolonged duration

of a prophylactic antibiotic was signicantly related to the jaundice clearance, with a p-value of 0.002. Moreover,

a lower number of episodes of cholangitis was signicantly related to a good long-term outcome (p-value, 0.024).

Conclusion: e prolonged provision of a prophylactic antibiotic as adjuvant therapy aer the Kasai portoenterostomy

was associated with jaundice clearance. An increased incidence of cholangitis episodes was associated with poor

long-term outcomes. Postoperative adjuvant therapy should be standardized and maintained for the care of biliary

atresia patients to improve their outcomes.

Keywords: Adjuvant therapy; biliary atresia; cholangitis; Kasai portoenterostomy outcome; prophylactic antibiotic

(Siriraj Med J 2020; 72: 226-237)

Corresponding author: Niramol Tantemsapya

E-mail: niramol.tan@mahidol.ac.th

19 December 2019 Revised 3 February 2020 Accepted 19 February 2020

ORCID ID: http://orcid.org/0000-0003-3886-6793

http://dx.doi.org/10.33192/Smj.2020.31

INTRODUCTION

Biliary atresia is an idiopathic inflammatory

cholangiopathy of infancy. It is characterized by

progressive brosing obliteration at varying levels of the

intrahepatic and extrahepatic bile ducts, and inevitable

cirrhosis.

1,2

It is the most common cause of neonatal direct

hyperbilirubinemia and cirrhosis in children, and the most

common indication for pediatric liver transplantation

worldwide.

2,3

e Kasai portoenterostomy

has been

accepted as the primary therapeutic treatment for the

restoration of bile ow and the preservation of the liver.

However, the procedure produces variable outcomes.

Successful drainage does not always predict a long-term,

jaundice-free native liver survival as progressive irreversible

liver injury and complications of cirrhosis (mainly portal

hypertension) can occur despite adequate bile drainage

Laohapensang et al.

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being achieved.

3,5-8

Previous studies from large-scale

institutions have demonstrated various pathological,

clinical, and surgical factors associated with successful

bile drainage and long-term, transplant-free survival.

1,3,7-10

Unfortunately, the majority of infants in developing

countries reach tertiary-care centers when they are older

than the maximum recommended age of 2 months

for the performance of a Kasai portoenterostomy. As

well, liver transplantation is not always suitable for

every family. Faced with limitations in nancial support,

transportation, and the provision of continuing care for

the immunosuppressed children, a number of biliary

atresia children die of end-stage liver disease. We therefore

conducted this study to identify any clinical factors

that are associated with improved outcomes for Kasai

portoenterostomy.

MATERIALS AND METHODS

A retrospective chart review was conducted of infants

with biliary atresia who underwent the conventional Kasai

portoenterostomy procedure at Siriraj Hospital, January

2006 - August 2018. Patients who were operated on at

another hospital or who developed complications unrelated

to biliary atresia or the Kasai operation were excluded.

An analysis was made of the patient demographics and

laboratory data with respect to the short- and long-term

outcomes. e laboratory tests comprised the gamma-

glutamyl transpeptidase (GGT) levels prior to, and at

specic times aer, the operation, as well as the full range

of liver function tests (total bilirubin, direct bilirubin,

aspartate transaminase, alanine transaminase, and alkaline

phosphatase). Also analyzed were the perioperative

clinical data (postoperative steroid administration; the

duration of the steroid; and intravenous and prophylactic

antibiotic administration) to ascertain their impact on

the short- and long-term outcomes. e short-term

outcome evaluated was the achievement of jaundice

clearance, which was dened as a serum total bilirubin

level of ≤ 1.2 mg/dL at any time point aer the procedure.

Patients who did not achieve normalized bilirubin levels

were considered to have the poor short-term outcome

of no jaundice clearance. e long-term outcomes were

categorized as “good” and “poor”. A good long-term

outcome was dened as a patient being jaundice-free

with the native liver for more than 6 months aer the

Kasai portoenterostomy, with regular monitoring up

to the last follow-up appointment. On the other hand,

the poor long-term outcomes comprised patients who

remained clinically jaundiced or developed cirrhosis

with the native liver, patients who underwent a liver

transplantation, and disease-related deaths. In cases of

patients who achieved jaundice clearance, the durations

until the total bilirubin reached normal levels were

evaluated. Details of the overall levels of complications

that were suspected to aect the long-term outcomes (such

as the development of cholangitis, the duration until the

rst episode of cholangitis, and the number of episodes

of cholangitis) were correlated to both the short- and

long-term outcomes. e diagnosis of cholangitis aer

the portoenterostomy procedure was based on clinical

symptoms of either progressive jaundice, with or without

fever and acholic stool. ese were proven by increase

bilirubin and GGT levels from baseline in association

with leukocytosis and increase C-reactive protein level.

e number of salvage interventions (namely, redo-

portoenterostomies and percutaneous biliary drainage)

were reviewed to establish any associations with the

long-term outcomes.

Statistical analyses

Data were prepared and analyzed using PASW

(Predictive Analytics Soware) Statistics 18.0 (IBM

SPSS Inc., Chicago, IL, USA). Descriptive statistics were

presented as mean and standard deviation for normally

distributed data, or as median with range in the case of the

non-normally distributed data. For both the short- and

long-term comparison groups, the independent sample

t-test was used to compare the normally distributed

data related to the good and poor outcomes, while the

Mann–Whitney U test was employed for the non-normally

distributed data. Categorical data were analyzed using

Pearson’s chi-squared test, Yates’s continuity correction,

or Fisher’s exact test to compare the proportional data

of the two groups. A receiver operating characteristic

curve was employed to identify the optimal cut-o points

of age at operation to classify the patients with good

outcomes. e sensitivity, specicity, positive predictive

value, negative predictive value, and accuracy (all with the

corresponding 95% condence interval [95% CI]) were

calculated for each cut-o point. Statistical signicance

was determined to be a p-value of < 0.05. e statistically

signicant factors identied in a univariate analysis

were subsequently tested in a multivariate analysis. e

latter model used multiple binary logistic regression

and adjusted odds ratio (OR) in order to adjust for

confounding factors and demonstrate the magnitude of

any associations between the independent factors and

the outcomes.

Ethics approval

e protocol for this study was approved by the

Institutional Review Board of Siriraj Hospital (Si 641/2018).

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228

RESULTS

A total of 85 cases with biliary atresia were identied

as having been treated at Siriraj Hospital from January

2006 to August 2018. Complete medical records of 80

of those patients were available and formed the basis of

the study. ere was a slight female predominance (a

3:2 female-to-male ratio), as demonstrated in Table 1.

e mean age at Kasai portoenterostomy was 97 days,

ranging from 21-204 days. Approximately 94% of

the cases received an adjuvant steroid for an average

duration of 4 weeks. All cases received intravenous

empirical antibiotics, mostly for durations of 2-3 weeks.

A prophylactic antibiotic was provided to 97.5% of cases

and maintained for durations of 12-24 months aer the

operation. Altogether, 66.3% of the patients achieved

jaundice clearance while the remainder (33.7%) never

attained normal bilirubin levels. e mean duration until

jaundice clearance was 4 months, ranging from 4-72

weeks aer the operation. e incidence of postoperative

cholangitis was 87.5%, occurring in 70 out of the total

of 80 cases. e average duration to the development

of cholangitis was approximately 2 months aer the

operation, with cases arising as early as within the rst

week and as late as 12 months. e overall mean number of

cholangitis events was 3 episodes throughout the follow-up

period. e incidences of the salvage procedures-redo-

Kasai operation and percutaneous transhepatic biliary

drainage-were 7.5% and 15%, respectively. e mean

follow-up duration was 50.5 months, with 51.3% of the

patients remaining jaundice-free with their native liver

for more than 6 months aer the Kasai portoenterostomy.

By using a receiver operating characteristic curve

to classify patients with reference to the short-term

outcome, the optimal cut-o point for the age at operation

was determined to be 90 days. In fact, the accuracy in

predicting the long-term outcome was higher for the

cut-o point of 80 days. However, as the majority of

patients in this study were older, we elected to use the

cut-o point of 90 days in the multivariate analysis

(Tables 2 and 3). e sensitivity, specicity, positive

predictive value, negative predictive value, and accuracy

(all with the corresponding 95% CI) of each age group

in predicting the outcomes are detailed in Tables 2 and 3.

e univariate analysis of the potential factors related

to the good short-term outcome (the achievement of

jaundice clearance) is presented in Table 4. e clinical

factors signicantly associated with jaundice clearance

were an age at operation of less than 90 days, a prolonged

duration of use of a prophylactic antibiotic, and the

absence of postoperative cholangitis. e laboratory

factors which were signicantly lower among patients

with jaundice clearance were the total and direct bilirubin

levels, and the hepatic enzymes (aspartate transaminase

and alanine transaminase). e only laboratory factor

signicantly higher among patients with jaundice clearance

was the serum GGT level on postoperative day 1. e

subsequent multivariate analysis of all of the signicant

factors associated with jaundice clearance revealed that

the only independent factor was the duration of the

prophylactic antibiotic, with an adjusted OR of 1.128

(95% CI, 1.045–1.217) and a p-value of 0.002 (Table 5).

e univariate analysis of the potential factors related

to the good long-term outcome (remaining jaundice-free

with the native liver for more than 6 months aer the

operation) is demonstrated in Table 6. Approximately

half of the study population (41 out of the 80 patients)

remained jaundice-free with their native livers, all of

which (100%) originally achieved jaundice clearance

aer the Kasai portoenterostomy. Twelve out of the 53

patients who initially achieved jaundice clearance later

became jaundiced or progressed to cirrhosis, accounting

for 30.8% of the poor long-term outcome group. e

clinical factors found to be signicantly associated with

the good long-term outcome were the initial achievement

of jaundice clearance, an age at operation of less than

80 days, a prolonged duration of use of a prophylactic

antibiotic, a shorter duration until the attainment of

jaundice clearance, the absence of postoperative cholangitis,

and a lower number of episodes of cholangitis.

As previously mentioned, the cut-o point for the

age at operation of 80 days more accurately predicted the

long-term outcome than the cut-o point for the age of

90 days. Consequently, the age at operation of less than

90 days did not demonstrate any signicant correlation

to the good long-term outcome in the univariate analysis.

As detailed in Table 6, the median age at operation of

77 days for the patients with a good long-term outcome

was considerably lower than the median of 99 days for

those with a poor long-term outcome (p-value, 0.021).

e multivariate analysis of all of the signicant factors

associated with the good long-term outcome established

that the only independent factor was the lower number

of episodes of cholangitis, with an adjusted OR of 0.678

(95% CI, 0.484-0.949) and a p-value of 0.024 (Table 7).

As indicated in Tables 5 and 7, the multivariate

analyses were not applied to certain factors. is was

because those factors were involved in all, or none, of

the measuring outcomes. Specically, jaundice clearance

was achieved in 100% of the cases with a good long-

term outcome, while postoperative cholangitis occurred

in 100% of the cases with poor short- and long-term

outcomes. erefore, the ORs, 95% CIs, and p-values

of those factors could not be calculated in the logistic

regression analyses.

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TABLE 1. Patient demographics and clinical data (n = 80).

Factors Incidence/mean ± SD Percentage/range

Gender

Female 49 61.3%

Male 31 38.7%

Age at Kasai operation (days) 96.7 ± 39.8 21–204

Body weight at operation (kilograms) 5.2 ± 0.9 2.8–6.9

Postop steroid administration

No 5 6.2%

Within 7 days 55 68.8%

After 7 days 20 25%

Duration of steroid administration (days) 26 ± 9.5 0–60

Duration of intravenous antibiotics (days) 19.8 ± 10.1 6–63

Prophylactic antibiotic

Yes 78 97.5%

No 2 2.5%

Duration of prophylactic antibiotic (months) 21.8 ± 22.8 0–144

Jaundice clearance

Yes 53 66.25%

No 27 33.75%

Duration till jaundice clearance (weeks; n = 53) 16.4 ± 13.8 4–72

Postoperative cholangitis

Yes 70 87.5%

No 10 12.5%

Duration till cholangitis (weeks; n = 70) 9.2 ± 18.5 1–144

Cholangitis episodes (n = 70) 3 ± 2.6 0–12

Redo-Kasai operation 6 7.5%

PTBD 12 15%

Liver transplantation (LT) 6 7.5%

Follow up duration (months) 50.5 ± 45.8 1–153

Status (follow-up > 6 months)

Jaundice-free (NL) 41 51.3%

Deceased/cirrhosis/LT 39 48.7%

Abbreviations: PTBD, percutaneous transhepatic biliary drainage; LT, liver transplantation; NL, native liver; SD, standard deviation

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230

TABLE 2. Accuracy of ages at dierent cut-o points in predicting short-term outcome.

TABLE 3. Accuracy of ages at dierent cut-o points in predicting long-term outcome.

SensitivitySpecicityPPVNPVAccuracy

(95% CI) (95% CI) (95% CI) (95% CI) (95% CI)

Age < 80 days 0.547 0.704 0.784 0.442 0.600

n = 37 (0.415–0.673) (0.515–0.841) (0.628–0.886) (0.304–0.589) (0.490–0.700)

Age < 90 days 0.642 0.667 0.791 0.486 0.650

n = 43 (0.507–0.757) (0.478–0.814) (0.648–0.886) (0.334–0.641) (0.541–0.745)

Abbreviations: PPV, positive predictive value; NPV, negative predictive value

(95% CI) (95% CI) (95% CI) (95% CI) (95% CI)

Age < 80 days 0.585 0.667 0.649 0.605 0.625

n = 37 (0.434–0.722) (0.510–0.794) (0.488–0.782) (0.456–0.736) (0.515–0.723)

Age < 90 days 0.634 0.564 0.605 0.595 0.600

n = 43 (0.481–0.764) (0.410–0.707) (0.456–0.736) (0.435–0.737) (0.490–0.700)

Abbreviations: PPV, positive predictive value; NPV, negative predictive value

DISCUSSION

e current research is a continuation of an earlier

study at the same single center

, but it included more

participants and monitored them for a longer period.

Previous studies have reported the impact of patient

age at the time of surgery on the outcomes of the Kasai

portoenterostomy.

7,12,13

Our review obtained a nding

consistent with that of many other studies, which is

that a younger age at surgery improves the rates of

jaundice clearance and transplant-free survival with

the native liver.

3,7,9,10,12,13

In more detail, this study found

that a patient age of less than 90 days was signicantly

associated with the good short-term outcome of the

achievement of jaundice clearance. Moreover, those

aged less than 80 days were significantly associated

with the good long-term outcome (maintaining the

jaundice-free status with the native liver for more than 6

months aer the operation). In ailand, the majority of

patients receive a Kasai portoenterostomy later than the

maximum recommended age of 2 months. Concerned

about the burdensome need to provide constant care

to those patients, the authors were motivated to nd

any signicant controllable factors impacting on the

improvement of their care and the achievement of better

outcomes. Despite the present study’s ndings, it is not

our hospital’s policy to withdraw salvage surgery when

infants with biliary atresia present at an age over 90

days. On the contrary, the hospital encourages the Kasai

portoenterostomy in children presenting as late as 4 or

5 months of age with less than a hard liver consistency.

e aim is to provide the opportunity-no matter how

limited-for the children to grow, and for their families to

appreciate the children’s requirements and understand

the long-term care needed prior to the imminent liver

transplantation. e Kasai portoenterostomy procedure

may provide more time for those patients and their

families for whom a liver transplantation may not be

feasible in the future for a range of reasons.

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TABLE 4. Univariate analysis of laboratory and clinical factors related to good short-term outcome (jaundice

clearance).

Factor Jaundice clearance P-value

Yes (n = 53) No (n = 27)

Gender, n (%) 0.985

Female 33 (62.3%) 16 (59.3%)

Male 20 (37.7%) 11 (40.7%)

Age at Kasai operation (days)

Mean ± SD 87.2 ± 35.8 115.3 ± 41.3

Age < 90, n (%) 34 (64.2%) 9 (33.3%) 0.002

Age ≥ 90, n (%) 19 (35.8%) 18 (66.7%) 0.017

Body weight at operation (kg) 0.503

Mean ± SD 5.3 ± 0.94 5.2 ± 0.98

Liver function test, median (min-max)

Total bilirubin (TB) 9.1 (4.3–17.5) 10.6 (6.85–31.3) 0.003

Direct bilirubin (DB) 8.0 (3.2–14.4) 9.1 (5–26.1) 0.015

Aspartate transaminase (AST) 205 (3–1101) 286 (114–843) 0.001

Alanine transaminase (ALT) 129 (10–505) 193 (42–554) 0.023

Alkaline phosphatase (ALP) 492 (270–871) 487 (383–846) 0.171

Gamma-glutamyl transpeptidase (GGT) 705 (121–2491) 450 (84–2184) 0.132

GGT on postoperative day 1 n = 49 n = 23 0.014

Median (min-max) 913 (114–3031) 478 (79–3062)

GGT at 3 months after operation n = 34 n = 18 0.397

Median (min-max) 650.5 (15–1796) 524 (34–1990)

GGT at 4 months after operation n = 32 n = 13 0.764

Median (min-max) 435.5 (20–2752) 316 (27–2302)

GGT at 5 months after operation n = 27 n = 9 0.144

Median (min-max) 315 (20–2480) 784 (136–1311)

GGT at 6 months after operation n = 26 n = 8 0.239

Median (min-max) 212 (18–1990) 369 (70–1280)

Postoperative steroid administration 0.671

None, n (%) 4 (7.5%) 1 (3.7%)

Within 7 days, n (%) 37 (69.8%) 18 (66.7%)

After 7 days, n (%) 12 (22.7%) 8 (29.6%)

Duration of steroid (days), median (min-max) 28 (0–60) 28 (0–38) 0.724

Duration of intravenous antibiotic (days)

Median (min-max) 18 (7–42) 14 (6–63) 0.477

Prophylactic ATB (n = 78), n (%) 52 (98.1%) 26 (96.3%) 1.000

Duration of prophylactic antibiotic (months) < 0.001

Median (min-max) 24 (0–144) 5 (0–60)

Postoperative cholangitis, n (%) 43 (81.1%) 27 (100%) 0.014

Duration till cholangitis (weeks) n = 43 n = 27

Median (min, max) 5 (1–144) 4 (1–28) 0.666

Episodes of cholangitis, median (min, max) 2 (0–12) 2 (1–8) 0.124

Abbreviations: ATB, antibiotic; SD, standard deviation

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Factor Unadjusted OR Adjusted OR

(95% CI)

P-value

(95% CI)

P-value

Age < 90 days 3.579 (1.347–9.512) 0.011 2.817 (0.630–12.592) 0.175

TB 0.803 (0.680–0.949) 0.010 0.581 (0.245–1.380) 0.219

DB 0.795 (0.653–0.968) 0.022 1.893 (0.680–5.264) 0.222

AST 0.997 (0.994–0.999) 0.013 1.001 (0.995–1.007) 0.822

ALT 0.994 (0.989–1.000) 0.034 0.991 (0.976–1.005) 0.217

Postop GGT 1.001 (1.000–1.002) 0.048 1.000 (0.999–1.002) 0.528

Duration of prophylactic ATB 1.118 (1.051–1.189) < 0.001 1.128 (1.045–1.217) 0.002

Postoperative cholangitis Not applicable Not applicable

TABLE 5. Univariate and multivariate analyses adjusted for signicant factors associated with jaundice clearance,

plus postoperative cholangitis.

Abbreviations: TB, total bilirubin; DB, direct bilirubin; AST, aspartate transaminase; ALT, alanine transaminase; Postop GGT, postoperative

gamma-glutamyl transpeptidase; ATB, antibiotic

e study identied several probable factors associated

with jaundice resolution aer a Kasai portoenterostomy.

Signicant laboratory results were found with the good-

short-term-outcome group, with lower levels of bilirubin

and liver enzymes being found with earlier, rather than

later, ages at diagnosis and at operation. For that reason,

the multivariate analysis did not nd those factors to

be signicant independent correlates of the short-term

outcome. e only independent factor associated with

the achievement of jaundice clearance was the prolonged

provision of a prophylactic antibiotic. Nevertheless, a

conclusion could not be made that the administration

of a prophylactic antibiotic secured a better short-term

outcome. is is because a number of individuals with poor

outcomes expired prior to the scheduled discontinuation

of the prophylactic antibiotic at 18-24 months aer

the operation, resulting in an overall shorter duration

of prophylactic antibiotic usage for the poor-outcome

group.

Postoperative cholangitis, a common and serious

complication following the Kasai portoenterostomy, has

been varyingly reported to occur in between 40% and 93%

of cases.

5,10,14-17

Moreover, its occurrence has been found

to signicantly reduce the survival rate of patients with

either good or inadequate bile ow

7,16,17

, and repeated

episodes-especially within the rst 2 years of surgery-have

been associated with a decrease in native liver survival

and, ultimately, with the need for liver transplantation.

18-21

In the current study, the overall incidence of cholangitis

was 87.5%, and perioperative intravenous antibiotics

were universally provided (usually for 1-2 weeks, but

even longer if the cholangitis worsened). e majority

of the antibiotics were combinations of third generation

cephalosporins and metronidazole. A postoperative,

adjuvant, prophylactic antibiotic was subsequently provided

to prevent recurrence of the cholangitis, most episodes

of which typically occur within 12 months of the Kasai

procedure.

16,21,22

Nevertheless, recent trials and systematic

reviews have yielded inconclusive results for determining the

eectiveness of prophylactic antibiotics for the prevention

of cholangitis aer the Kasai portoenterostomy.

19,22–24

addition, there is no strong evidence that the prolonged

use of oral prophylactic antibiotics beyond the early

postoperative period oers any greater protection against

cholangitis.

5,19,23

Still, most experienced institutions provide

oral prophylactic antibiotics for periods of 6 months

or longer, similar to the requirements of our hospital’s

protocol. A randomized control trial by Bu et al.

found

that there was a signicantly lower rate of recurrent

cholangitis among patients provided with prophylactic

antibiotics than that for a historical control group who

did not receive antibiotics. Although a Dutch national

cohort by deVries et al.

did not identify any reduction

in the cholangitis rate of the prophylactic antibiotic

group, it did demonstrate that the prophylactic usage

was associated with a higher, 4-year, transplant-free

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TABLE 6. Univariate analyses of laboratory and clinical factors related to good long-term outcome (remaining

jaundice-free with native liver).

Factor Jaundice-free with native liver P-value

Yes (n = 41) No (n = 39)

Jaundice clearance (n = 53), n (%) 41 (100%) 12 (30.8%) < 0.001

Age at operation (days), median (min-max) 77 (31–162) 99 (21–204) 0.021

< 90 days, n (%) 26 (63.4%) 17 (43.6%) 0.116

≥ 90 days, n (%) 15 (36.6%) 22 (56.4%)

< 80 days, n (%) 24 (58.5%) 13 (33.3%) 0.027

≥ 80 days, n (%) 17 (41.5%) 26 (66.7%)

Preoperative GGT n = 35 n = 36 0.765

Median (min-max) 705 (121–2335) 596 (84–2491)

Postoperative GGT n = 38 n = 34 0.250

Median (min-max) 874.5 (114–2345) 732 (79–3062)

GGT at 3 months after operation n = 26 n = 26 0.985

Median (min-max) 581 (15–1796) 578 (34–1990)

GGT at 4 months after operation n = 27 n = 18 0.926

Median (min-max) 439 (20–2752) 305.5 (27–2302)

GGT at 5 months after operation n = 21 n = 15 0.067

Median (min-max) 282 (20–2480) 624 (100–1311)

GGT at 6 months after operation n = 20 n = 14 0.069

Median (min-max) 198.5 (18–1990) 383.5 (70–1280)

Postoperative steroid administration 0.495

No, n (%) 3 (7.3%) 2 (5.1%)

Within 7 days, n (%) 30 (73.2%) 25 (64.1%)

After 7 days, n (%) 8 (19.5%) 12 (30.8%)

Duration of steroid (days), median (min-max) 28 (0–60) 28 (0–38) 0.074

Duration of intravenous antibiotics (days) 0.674

Median (min-max) 17 (7–42) 18 (6–63)

Prophylactic antibiotic (n = 78), n (%) 40 (97.6%) 38 (97.4%) 1.000

Duration of prophylactic antibiotic (months) 0.006

Median (min-max) 21 (0–88) 11 (0–144)

Duration till jaundice clearance (weeks) n = 41 n = 12 0.006

Median (min-max) 9 (4–72) 20.5 (9–60)

Postoperative cholangitis, n (%) 31 (75.6%) 39 (100%) 0.001

Duration till cholangitis (weeks) 0.368

Median (min-max) 3 (1–29) 4 (1–144)

Episodes of cholangitis, median (min-max) 1 (0–12) 3 (1–11) < 0.001

Redo-Kasai operation, n (%) 2 (4.9%) 4 (10.3%) 0.426

PTBD, n (%) 4 (9.8%) 8 (20.5%) 0.301

Abbreviations: GGT, gamma-glutamyl transpeptidase; PTBD, percutaneous transhepatic biliary drainage

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TABLE 7. Univariate and multivariate analyses of all signicant factors associated with good long-term outcome,

plus jaundice clearance and postoperative cholangitis.

Factor

Unadjusted OR Adjusted OR

(95% CI)

P-value

(95% CI)

P-value

Jaundice clearance Not applicable Not applicable

Age < 90 days 2.243 (0.915–5.500) 0.077 0.700 (0.139–3.536) 0.666

Duration of prophylaxis antibiotic 1.009 (0.988–1.030) 0.391 0.982 (0.950–1.016) 0.304

Duration till jaundice clearance 0.962 (0.920–1.005) 0.085 1.000 (0.941–0.062) 0.998

Postoperative cholangitis Not applicable Not applicable

Episodes of cholangitis 0.703 (0.562–0.880) 0.002 0.678 (0.484–0.949) 0.024

survival rate of 54% compared to 34% for the control

group. Our protocol of providing a prophylactic antibiotic

for 18-24 months aer the Kasai operation is based on

several lines of evidence. Firstly, recurrent cholangitis

frequently occurs during the rst 2 years of the Kasai

procedure. In addition, the auto-anastomosis of the

internal stula between the bile ductules in the portal

plate and the intestinal mucosa matures within 6 weeks of

the operation.

Finally, wound maturation takes 18-24

months in general. Another reasonable approach would

be to provide protection during the immunosuppression

phase of concomitant steroids and discontinue their use

aer 1 year, i.e., once the cholangitis risk is signicantly

decreased.

In the present study, the multivariate analysis

of the factors associated with jaundice clearance was not

able to be applied to postoperative cholangitis due to the

100% involvement of the postoperative cholangitis in the

group of patients without jaundice clearance (Table 4).

In the analysis of the factors associated with a good

long-term outcome (remaining jaundice-free with the

native liver for more than 6 months aer the operation),

the only independent factor that was found was the

lower number of episodes of cholangitis. Interestingly,

the episodes were not a signicant factor related to the

short-term outcome of jaundice clearance. is is because

the incidences of cholangitis occurred for a median of 2

episodes in the group with jaundice resolution as well as

in the group without jaundice resolution. On the other

hand, the patients who remained jaundice-free with

their native liver developed cholangitis for a median of 1

episode, while those who had a poor long-term outcome

had a median of 3 episodes of cholangitis throughout

their follow-up period (adjusted OR, 0.678; 95% CI,

0.484–0.949; p-value, 0.024). ese ndings are consistent

with previous studies which reported that, rstly, an

increased number of cholangitis episodes negatively

aected the native liver survival, and secondly, having

episodes more than 2 years aer the Kasai portoenterostomy

appeared to be a prognostic marker for a future liver

transplantation.

18,20,21

In addition to cholangitis, the univariate analysis

demonstrated other significant factors affecting the

long-term outcome, namely, an age at operation of less

than 80 days, the achievement of jaundice clearance, a

prolonged provision of a prophylactic antibiotic, and a

shorter duration to attain jaundice clearance. In a long-

term study of native liver patients who had survived

for more than 20 years aer the Kasai operation, Nio

et al.

concluded that the age at operation, the early

development of cholangitis, and the time to jaundice

resolution were prognostic factors inuencing long-

term native liver survival. In contrast, the multivariate

analysis performed for the current study found that the

number of cholangitis episodes was the only independent,

signicant factor aecting the long-term outcomes.

Jaundice clearance was present in 100% of the patients

who achieved a good long-term outcome, while the

development of cholangitis was present in 100% of the

patients who had poor long-term outcomes. erefore,

a logistic regression analysis could not be performed for

the 2 variables, jaundice clearance and the development

of cholangitis.

Consistent with other studies

26,27

, it is evident from

the present study that jaundice clearance following the

Kasai portoenterostomy was essential for long-term

native liver survival. If the age at the operation is the

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rst controllable factor in the management of biliary

atresia, surgical technical standardization would be the

second factor impacting on the resolution of jaundice.

To maintain a jaundice-free, native liver survival,

postoperative adjuvant therapy would be the third key

factor. Our surgical technique was based on the original

Kasai operation.

It was modied in accordance with

the Tohoku University standardization protocol, which

entails a moderate dissection when transecting the brous

remnants of the porta hepatis in the same plane as the

liver capsule.

Another important adjuvant therapy is the provision

of corticosteroids during the postoperative care period

following a Kasai portoenterostomy. The results of

randomized controlled trials

3,28,29

and meta-analyses

30,31

have indicated that the administration of moderate- to

high-dose steroids is benecial by increasing the rate

of jaundice clearance during the rst 6 months aer

the operation. e majority of those trials found that

the elevated rate of jaundice clearance occurred only in

patients operated on at a younger age. Even so, those

patients did not demonstrate any improvement in their

long-term, native liver survival rates. e meta-analysis

by Chen et al.

also revealed that a longer duration of

steroid therapy following the Kasai portoenterostomy

failed to elicit any further benecial outcomes. Our

postoperative steroid regimen typically consisted of a

low dose of oral prednisolone (2 mg/kg/day), which was

tapered by half each week for 4 consecutive weeks; that

dosage was provided to 94% of the patients in the current

study. No dierences were evident in either the short-

or long-term outcomes of the steroid and non-steroid

groups; however, this was most likely the result of the

very low number of participants in the non-steroid group.

Furthermore, variations in the timing of the initiation of

the steroids did not produce any signicant dierences

in the outcomes of the no-steroid, early-steroid, and late-

steroid groups. Nevertheless, at our institution, the use of

steroids is deemed to be an important adjuvant therapy

during the postoperative care period. ey are also used

for the treatment of cholangitis aer a portoenterostomy,

given the evident inammatory process presented and

the very rare incidence of side eects associated with

the steroids.

e incidences of the salvage procedures (redo-

portoenterostomy and percutaneous biliary drainage) were

quite low. e redo-portoenterostomy would be provided

for patients with a history of biliary drainage or jaundice

clearance aer the rst portoenterostomy, which later

developed recurrent jaundice. e percutaneous biliary

drainage was the intervention for those with recurrent

jaundice or cholangitis, which imaging proved biliary

collection or biloma. e analysis of their correlation

to the long-term outcomes did not demonstrate any

statistical signicance.

Finally, the analysis of GGT activity was included in

the present study to discover any correlation the activity

might have with bile drainage or any prognostic value

that would facilitate the prediction of portoenterostomy

outcomes. Serum GGT has been utilized to indicate

cholestasis, and an elevated level has been reported to

be highly accurate in dierentiating biliary atresia from

other causes of neonatal cholestasis.

32,33

Interestingly,

the present study found that the median serum GGT

level on postoperative day 1 was signicantly higher

for the patients with jaundice resolution than for those

without (913 and 478 IU/L, respectively; p-value, 0.014).

Furthermore, in our comparison of the good and poor

long-term outcomes, the median serum GGT levels on

postoperative day 1 were 874.5 vs. 732 IU/L, respectively,

although with no statistical signicance. Despite several

drop-out variables at each time point, the serum GGT

activity of the patients with jaundice clearance tended

to peak on day 1 before gradually decreasing below the

serum GGT levels for the patients who had persistent

jaundice during months 5 and 6 post-surgery, albeit

without statistical signicance. By contrast, the GGT

activity of the patients with persistent jaundice tended

to start in the high 300-500s IU/L and either persist at

that level or climb to a peak in month 5 aer surgery.

Having examined the correlation between GGT activity

and the outcomes aer the Kasai portoenterostomy, Ihn

et al.

reported that a concentration exceeding 550 IU/L

at month 5 was one of the independent risk factors for

decreased native liver survival. Our review of the serum

GGT level did not elicit any statistical signicance in both

the short- and long-term outcome analysis. Nevertheless,

given appropriate long-term care, a decreasing serum GGT

level is expected in month 5 for the patients, especially

in the case of those who achieved a normalized bilirubin

level within 4 months of the operation. us, it is highly

desirable to collect a larger and more complete set of data

to analyze the GGT activity in patients with long-term

native liver survival, even though the results would be

mainly of prognostic value.

With the inherent limitations of a retrospective

review, this is another descriptive study on the outcomes

of the treatment of biliary atresia. It is dicult for a

single center with a limited number of patients to reach

statistical signicance in the analysis of the listed factors.

Still, the study demonstrated comparable outcomes to

research by other large-scale centers, with its 66.3%

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236

jaundice clearance rate; a 51.3% jaundice-free, native

liver survival within a mean follow-up duration of 50

months; and an essentially acceptable treatment regimen.

Further clarication and collaboration with other centers

may help standardize the treatment protocol for this rare

disease.

CONCLUSION

e prolonged provision of a prophylactic antibiotic

as adjuvant therapy during the postoperative care of

biliary atresia patients aer the Kasai portoenterostomy

was associated with a good short-term outcome (the

achievement of jaundice clearance). e increased number

of cholangitis episodes was associated with poor long-

term outcomes, including poor native liver survival.

Postoperative adjuvant therapy should be standardized

and maintained for the care of biliary atresia patients to

improve their outcomes.

ACKNOWLEDGMENTS

e authors thank Dr. Sasima Tongsai from the

Clinical Epidemiology Unit Research Center, Faculty

of Medicine Siriraj Hospital, for her contribution in

the form of an extraordinary statistical analysis for the

study.

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238

Naruttha Norphun, M.D., Jarurin Pitanupong, M.D., Aimorn Jiraphan, M.D.

Department of Psychiatry, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla 90110, ailand.

Stress and Coping Strategies among Thai Medical

Students in a Southern Medical School

ABSTRACT

Objective: To assess stress, and coping strategies and related factors among medical students.

Methods: is cross-sectional study surveyed all 1

to 6

year medical students at the Faculty of Medicine, Prince

of Songkla University, from March to May, 2019. ree questionnaires were employed: 1) Demographic data 2)

e Suanprung stress test 3) e Brief COPE inventory ai version. Data were analyzed using descriptive statistics,

and the results were presented as percentage, frequency, average and standard deviation. Factors associated with

coping strategies were analyzed by means of chi-square or kruskal-wallis test.

Results: ere were 827 respondents from 1,109 medical students, and 74.6% response rate. e majority of medical

students were female (60.7%) with moderate and high stress level scores (44.9% and 38.6%, respectively). e

medical students commonly used adaptive coping strategies (self-distraction, acceptance, active coping, and positive

reframing) rather than maladaptive coping strategies (denial and substance use). According to the association between

general demographic characteristics and coping strategies, we found that; gender, GPA, religion and medical illness

had signicant correlation with adaptive coping strategies. Whereas, high stress levels were signicantly associated

with maladaptive coping strategies.

Conclusion: Most medical students use adaptive coping strategies. Gender, GPA, religion and medical illness had

signicant correlation with adaptive coping strategies.

Keywords: Medical students; stress; coping strategies (Siriraj Med J 2020; 72: 238-244)

Corresponding author: Jarurin Pitanupong

E-mail: pjarurin@medicine.psu.ac.th

Received 21 November 2019 Revised 27 January 2020 Accepted 4 February 2020

ORCID ID: http://orcid.org/0000-0001-9312-9775

http://dx.doi.org/10.33192/Smj.2020.32

INTRODUCTION

Stress is the result of an individual’s perception that

they lack resources to cope with a perceived situation

occurring in the past, present or foreseeable future.

Stress occurs when the individual is confronted with a

situation that is perceived as overwhelming and with

which they cannot cope.

A previous study found medical students had

higher levels of stress than other groups of the general

population.

e prevalence of stress suering among

medical students was 54.0% for 3rdacademic year and

55.0% for 4thacademic year students.

In ailand, the

prevalence of those suering from stress among medical

students in Ramathibodi Hospital was 61.4%

, and in

Khon Kaen University, 55.8%.

Response to stress can be categorized into: 1)

Emotional aspects: fear, anxiety, worry, guilt, depression

and irritability; 2) Cognitive reactions: their appraisal of

stressful situations and strategies; 3) Behavioral responses:

crying, abuse of self or others, smoking and drinking; 4)

Physiological reactions: sweating, trembling, stuttering,

headaches, weight loss or gain, and body aches.

Coping

Norphun et al.

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strategies that involve engagement can reduce both

anxiety and depression as well as their eects on mental

and physical health.

However, coping strategies which

center on disengagement; such as: problem avoidance,

wishful thinking, social withdrawal and self-criticism have

negative consequences, and correlate with depression,

anxiety, poor mental health

and physical problems.

In 2007, a cross-sectional survey, which explored

4,287 students at 7 medical schools in the United States,

found burnout was reported by 49.0% of medical students,

and 11.2% reported suicidal ideation within the past year.

A study conducted in ailand in 2007, found coping

strategies among clinical medical students at Khon Kaen

University included: tension reduction, seeking social

support, positive thinking and planful problem solving.

Whilst in 2010, among 2

academic year medical students

at ammasat University, common coping strategies

were: investing in close friends, relaxing, being humorous,

and developing self-reliance and optimism.

In 2008, a cross-sectional study at the Faculty of

Medicine, Prince of Songkla University, discovered 29.1%

of medical students had mental health problems. Factors

related to mental health problems were: female, 2

academic year and rural home province.

Another study

in 2015, among clinical medical students, found that no

history of drinking and having a history of exercise had

a higher happiness status than that of other groups.

medical students, 53.3% were drinkers, with the gender

proportion of alcohol usages at 60.0% in males, and

48.1% in females. Gender as well as substance usage were

signicant correlated factors with high-risk drinking.

According to this information, the questions are: “What

are the stress coping strategies among medical students?”;

and: “Are substance use or alcohol consumption other

stress coping strategies of medical students?”. In the

past, there were no in-depth studies that explored these

questions among medical students at Prince of Songkla

University. erefore, the purpose of the study was to

determine stress, coping strategies and related factors

among medical students, and enhance the focusing of

these problems.

MATERIALS AND METHODS

e Ethics Committee of the Faculty of Medicine,

Prince of Songkla University approved this cross-sectional

study (REC: 60-472-03-4). e study explored all 1

academic year medical students that studying at the

Faculty of Medicine, Prince of Songkla University, Hat

Yai Hospital Medical Education Center, and Yala Hospital

Medical Education Center, from March to May, 2019.

ere were 1,109 medical students, categorized by 1

academic year as follows: 189, 182, 185, 184, 189 and

180, respectively. e inclusion criterion was being a

medical student who could complete all questionnaire.

e exclusion criterion was medical students who being

foreign students or on a leave of absence.

Methodology

e medical students were communicated by a

research assistant in their classes beforehand. Aer the

end of class, the medical students had free time of 1 hour,

so a research assistant invited them to participate, by

introducing the rationale and overview information of this

research. In cases where cooperation was successful, the

research assistant distributed self-reporting questionnaires

consisting of 3 parts, and thoroughly explained them in

detail to participants. e medical students took 5 minutes

to consider whether or not to join in the study. Aer this,

the research assistant distributed the documentation,

whilst assuring the volunteers that their identities would

be protected. en, the signatures of participants were

not required, and all participants retained the right to

withdraw from the study at any time.

All participants were allowed to nish and return

the questionnaires immediately or later time. ey were

permitted to submit the questionnaire two options: drop it

in the box at the front of the classroom, or bring it back and

place it in the box located at the Psychiatry Department.

us, participant condentiality was protected.

Instruments

e questionnaire comprised of 3 parts:

1) General information consisting of: gender, age,

academic year, religion, accumulative GPA, income,

parental marriage status, hometown, and underlying

diseases.

2) e Suanprung stress test, which uses questions to

determine stress levels for the last six months contains 20

items, rated on a 5-point Likert scale; with item responses

ranging from: “1” (no stress) to “5” (extremely high

stress). Total scores were classied into four levels: 0 to

23 as mild, 24 to 41 as moderate, 42 to 61 as high and

more than 61 as severe stress. e Suanprung stress test

was shown to have an overall Cronbach’s alpha greater

than 0.7.

3) e Brief COPE inventory ai version, consisted

of 28 questions, and 14 subscales of coping strategies.

e Brief COPE scale was designed to assess a broad

range of coping responses among adults for all diseases.

It contains 28 items, and is rated by a four-point Likert

scale, ranging from: “I haven’t been doing this at all”

(score one) to “I have been doing this a lot” (score four).

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240

Cronbach’s alpha of the Brief COPE inventory ai

version was 0.7.

In the stress-coping model, specic coping behaviors

are understood as predominantly adaptive or maladaptive.

Adaptive coping strategies are: active coping, planning,

positive reframing, acceptance, humor, religion, using

emotional support and using instrumental support.

Whereas, maladaptive coping strategies include: self-

distraction, denial, venting negative emotions, substance

use, behavioral disengagement and self-blame.

15,17

Statistical analysis

All data were analyzed, in order to present the

sample’s behavior using descriptive statistics. e results

are described as: percentage, frequency, average and

standard deviation. e correlated factors with coping

strategies were analyzed using Chi-square or Kruskal-

wallis test.

RESULTS

Demographic data

Medical students who completed the questionnaires

were 827; the response rate was 74.6%. Of the participants,

502 were female (60.7%) (Table 1). Mean age was 21.4±2.0

years, with mean cumulative grade point average (GPA)

being 3.5±0.4. Median income (IQR) was 8,000 (6,000-

10,000) baht, per month.

Stress level and coping strategies

e majority of medical students had moderate and

high stress level scores (44.9% and 38.6%, respectively)

(Fig 1). Coping strategies frequently performed by medical

students were adaptive types; acceptance, active coping,

positive reframing and maladaptive types; self-distraction.

Whereas maladaptive types; denial and substance use

were coping strategies that medical students did not

perform at all (Fig 2).

e association between demographic data, stress level

and coping strategies

The association between general demographic

characteristics and coping strategies are described (Table 2).

Using adaptive coping strategies for controlling stress

levels was signicantly associated with: gender, religion,

GPA, and medical illness. According to gender and GPA

factors, the study found that females and those with a high

GPA (≥3.5) used adaptive coping strategies more than

males and those with a low GPA (<3.5), respectively. ere

was no signicant dierence in the use of both adaptive

and maladaptive coping strategies between pre-clinic and

clinic medical students. In addition, medical students

who had a medical illness (such as allergy, dyspepsia,

migraine) oen used adaptive coping strategies.

Analysis of the association between demographic

characteristics and stress levels, showed that only the

variable concerning academic year of medical study

(pre-clinical and clinical year) was signicantly related

to stress levels (p<0.001). Pre-clinical medical students,

had high to severe stress levels, more so than clinical

medical students (52.9% and 39.5%, respectively)

(Fig 3).

DISCUSSION

is study found the prevalence of moderate and

high stress level scores among medical students were

44.9% and 38.6%, respectively. In ailand, a previous

study at the Faculty of Medicine, Ramathibodi Hospital

reported 61.4% of medical students had experienced some

degree of stress.

At the Faculty of Medicine, Khon Kaen

University, it was found that 55.8% of medical students

had morbid stress.

However, a study at Siriraj Hospital

reported only 17.9% of medical students had stress.

e

cause of these dierent results may be that the subjects

of this study only included 3

year medical students.

In other countries, 56.0% of Malaysian

, and 63.0% of

Saudi Arabian medical students also had a high level

of stress. Academic problems were the most common

stressors of studying in medical training. Reasons for

this could be that academic achievement has always been

the top priority for medical students. Medical students

with stress also reported signicantly more academic

problems than students without stress.

In our study, medical students used adaptive coping

(self-distraction, acceptance, active coping and positive

reframing) rather than maladaptive coping strategies

(denial, behavioral disengagement and substance use).

ese were the same coping strategies commonly used

among medical students at ammasat University,

India

and other countries.

21,22

However, females utilized

adaptive coping strategies more than males, which may

be caused by female appraisal of threatening events as

more stressful; hence, they were also more aected by the

stress of those around them. is in turn led them to be

more emotionally involved than their male counterparts.

As they used more emotional coping strategies to deal

with stress than males, this leads to more adaptive coping

strategies being used in females.

Among medical students who have high grades

(GPA≥3.5), the use of adaptive coping strategies is similar

to a study from Argentina.

e reason may be the adaptive

ability to study, and more coping strategies and problem

solving skills than others. Additionally, this may lead

Norphun et al.

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TABLE 1. Demographic characteristics (n=827).

Demographic characteristics Number (%)

Gender

Female 502 (60.7)

Male 323 (39.1)

Unreported 2 (0.2)

Academic year of medical student

1 168 (20.3)

2 121 (14.6)

3 161 (19.5)

4 98 (11.9)

5 161 (19.5)

6 118 (14.3)

Religion

Buddhism 700 (84.6)

Islam 31 (3.7)

Islam 3 southern border provinces 30 (3.6)

Christianity/other 32 (3.9)

Unreported 34 (4.1)

Home province

Songkhla 336 (40.6)

3 southern border provinces 126 (15.2)

Other 352 (42.6)

Unreported 13 (1.6)

Parental marriage status

Couple 707 (85.5)

Divorce/pass away 112 (13.5)

Unreported 8 (1.0)

Underlying disease

Medical illness

No 694 (83.9)

Yes 130 (15.7)

Unreported 3 (0.4)

Psychiatric illness

No 784 (94.8)

Yes 39 (4.7)

Unreported 4 (0.5)

Fig 1. Percentage of stress level among medical students

(n= 827).

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242

Fig 2. Coping strategies score (n=827).

*Mean score interpretations were as below:

2.00 = have not been doing this at all, 2.01 to

4.00 = have been doing this a little bit, 4.01 to

6.00 = have been doing this a medium amount,

6.01 to 8.00 = have been doing this a lot

TABLE 2. Multiple linear regression of the association between demographic data and coping strategies.

Demographic Adaptive Maladaptive

Median (IQR) Beta P-value Median (IQR) Beta P-value

   (coefcient)   (coefcient)

Gender

Male 2.7 (2.4, 3.0) reference 2.0 (1.8, 2.2)

Female 2.8 (2.5, 3.1) 0.105 0.003 2.1 (1.8, 2.2)

Year of medical student

Pre-clinic 2.8 (2.4, 3.1) 2.1 (1.8, 2.2)

Clinic 2.8 (2.4, 3.0) 2.0 (1.8, 2.2)

Religion

Buddhism/christianity/ 2.8 (2.4, 3.0) reference 2.0 (1.8, 2.2)

others

Islam 3 provinces 3.0 (2.8, 3.3) 0.288 0.002 2.2 (1.9, 2.3)

Islam 2.9 (2.7, 3.0) 0.096 0.265 2.1 (1.8, 2.2)

Grade point average

<3.5 2.7 (2.4, 3.0) reference 2.0 (1.8, 2.3)

>3.5 2.8 (2.5, 3.1) 0.099 0.005 2.1 (1.8, 2.3)

Medical illness

No 2.8 (2.4, 3.0) reference 2.0 (1.8, 2.2) reference

Yes 2.9 (2.5, 3.1) 0.116 0.018 2.1 (1.8, 2.3) 0.027 0.367

Stress level

Mild-moderate 2.8 (2.4, 3.1) reference 1.9 (1.8, 2.1) reference

High-severe 2.8 (2.5, 3.0) 0.021 0.553 2.2 (1.9, 2.4) 0.258 <0.001

*Signicant (p-value <0.05)

Norphun et al.

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them to acquire better academic performance. Besides,

this study found Muslim students in 3 southern border

provinces used religious coping strategies more than

others. is result is similar to studies in Malaysia.

19,22

is may be related to medical students’ strong religious

beliefs, providing guidance on how to live and giving

individuals meaning and identity.

In addition, medical

students who had high-severe levels of stress tended to

use maladaptive coping strategies, rather than those

of the mild-moderate group, since performance and

coping skills could be markedly impaired in persons

who perceived greater stresses in certain situations.

Among the academic year, the clinical medical

students stress score was less than pre-clinical medical

students. ese results were similar to studies in India

and Morocco.

Pre-clinical medical students may be

stressed by the overwhelming amount of information

they have to learn, whilst handling the lifestyle of a

medical college.

However, there was no signicant

dierence in coping strategies between pre-clinical and

clinical medical students. is nding might be because

of an adaptive or mature defense mechanism being an

innate or part of developing changes of both pre-clinical

and clinical medical students. In addition, a mature

defense mechanism is a part of medical professionalism

development in medical education curricula. us, a

longitudinal and prospective study about individual

changes, from pre-clinical to clinical phase, in coping

strategies and other areas would be interesting for further

study.

Furthermore, there is correlation between high level

stress and maladaptive coping strategies. e results of

maladaptive coping strategies may eventually have a

negative impact on physical and mental health. erefore,

faculty policy should be reviewed to focus on stress in

medical students, indicating a need for stress management

programs within their medical education.

Limitations

is study was of a cross-sectional survey, and employed

self-reporting for individual perception assessment. Besides

its high response rate (74.6%), the information might

not have led to nding bias. However, the population

was limited to only medical students in the Faculty of

Medicine, Prince of Songkla University. en, it is too

soon to generalize these data to a nationwide setting.

Implications and future recommendations

Further studies should cover more medical schools

within ailand and employ a more quantitative method.

In other words, a multi-center survey is recommended.

CONCLUSION

Half of the medical students perceived stress, and

they use mainly adaptive coping strategies; rather than

maladaptive coping strategies. Gender, GPA, academic year,

medical illness and religion had signicant correlations

with coping strategies. High level stress was correlated

with maladaptive coping strategies. In the future, focusing

on medical students’ stress coupled with coping strategies

could prevent the harmful eects of stress on health and

academic performance.

ACKNOWLEDGMENTS

is study was fully funded by the Faculty of Medicine,

Prince of Songkla University, ailand. e authors are

very thankful for the data analysis operated by Mrs.Nisan

Werachattawan and Ms.Kruewan Jongborwanwiwat.

Moreover, we would like to show our gratitude to all

medical student who cooperated in this survey.

Fig 3. Stress level and year of medical

student.

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Panita Chavapattanakul, B.A.*, eerapat Wongkumsin, Ed.D.**, Ratcharin Kongkasuwan, M.D.***

*Graduate Student in Department of Psychology, Faculty of Social Sciences, Kasetsart University, Bangkok 10900, ailand.

**Department of Psychology, Faculty of Social Sciences, Kasetsart University, Bangkok 10900, ailand.

***Department of Rehabilitation Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, ailand.

The Relationship between Resilience Quotient,

Social Support and Spiritual Well-Being

of Caregivers of Patients with Hemiplegia

ABSTRACT

Objective: ere are three main objectives of this study. e rst is to study the levels of resilience quotient, social

support and spiritual well-being of caregivers of patients with hemiplegia. e second is to study the relationship

between resilience quotient and spiritual well-being of caregivers of patients with hemiplegia. e third objective is

to study the relationship between social support and spiritual well-being of caregivers of patients with hemiplegia.

Methods: e sample of this study is composed of 170 caregivers of patients with hemiplegia who received treatment

at the Department of Rehabilitation Medicine, Faculty of Medicine Siriraj Hospital. Data for this study were collected

using a psychological questionnaire, and then by adopting analytical statistics, which are percentage, mean, standard

deviation and Pearson’s Product Moment Correlation Coecient.

Results: Aer data collection and analysis, caregivers of patients with hemiplegia were found to have relatively

high levels of resilience quotient and social support. Moreover, they have a high level of spiritual well-being. Taken

together, these results suggest that there is a positive correlation between resilience quotient and the spiritual well-

being of caregivers of patients with hemiplegia, with statistical signicance at the .01 level. ere is also a positive

correlation between social support and the spiritual well-being of caregivers of patients with hemiplegia, with a

statistical signicance at the .01 level.

Conclusion: is research results can be used as a guideline for eorts to enhance the resilient quotient, social

support and spiritual well-being of caregivers by providing knowledge, information and caregiving equipment to

them. Moreover, caregivers should be encouraged to enjoy their free time by engaging in creative activities and

religious activities, which are believed to help increase mental peace.

Keywords: Resilience quotient; social support; spiritual well-being; caregiver of patients with hemiplegia (Siriraj

Med J 2020; 72: 245-252)

Corresponding author: Panita Chavapattanakul

E-mail: pchavapattanakul@gmail.com

Received 20 December 2019 Revised 30 January 2020 Accepted 11 February 2020

ORCID ID: http://orcid.org/0000-0001-5401-0050

http://dx.doi.org/10.33192/Smj.2020.33

INTRODUCTION

e development of the quality of life of people

with disabilities in ailand has changed over time. In

order to enhance the eectiveness of development of

people with disabilities, a strategy was established in the

National Development Plan for Life Quality of the

Disabled to promote and strengthen the eectiveness

of eorts to assist people with disabilities and related

organizations. Specically, guidelines and processes are to

be provided to enhance the eectiveness and oer support

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246

for caregivers of people with disabilities.

According to

the national statistics on people with disabilities, the

number of people with physical disabilities rose from

880,662 people in September 2017

to 1,004,733 people

in September 2018, an increase of 14.09%.

e number

of people with physical disabilities signicantly increased

within a year because hemiplegia is a disorder caused

by stroke, which damages the brain function suddenly.

It is the number one cause of disability and death in

ailand, where it is estimated that 50,000 people die

from hemiplegia and it disables 250,000 people each

year.

e result is an increasing number of relatives

of people with disabilities who need to adjust to new

and unexpected roles as caregivers. e phenomenon

of adjusting to these new roles can cause stress and

anxiety to new caregivers in the long run. Far too oen,

the new caregivers are likely to confront physical and

mental problems which they nd it dicult to handle,

and which may cause them to suer a loss of condence

and self-esteem in their lives.

Resilience quotient is the capability of a person to

adjust or adapt oneself and recover when facing crises.

A crisis can happen when a family member becomes

disabled suddenly and requires a caregiver who has

ability to cope with the situation. is caregiver has to

be resilient to deal with suering and disappointment

that the unexpected situation might have on the health

expectations of person with disabilities. erefore, a

caregiver needs a high resilience quotient in order to

understand both what the disabled person wants, and

how to handle the situation so that the caregiver can

eventually recover from the suering brought on by the

crisis. Additionally, there is a chance that a person with

disabilities will face a health complication, thus, a caregiver

needs to be capable of emotional-self regulation and the

ability to handle things morally and conscientiously. Yet,

a caregiver should also have the ability to bring one’s

own potential and skills, and use them productively in

giving care to a person with disabilities.

Social support is a support given by means of

delivering information, material or mental support from

a person, a group of people, or an institution. is social

support should have a positive result in any actions taken

by the support receiver.

Caregivers, acting alone, oen

have diculties in taking care of people with disabilities,

and social support is considered to be an important

factor in successfully supporting caregivers of people

with disabilities. is social support typically originates

with family members, who provide attention and caring

for caregivers of people with disabilities. Furthermore,

social support can be expanded to include other close

relatives who are able to oer material or nancial support,

or engage in positive relationships with the caregiver.

In addition, social support can come from a group of

caregivers, themselves, who may share information

between them, and contribute to better understandings

and knowledge that helps each individual cope with his

or her situation. Social support can have an eect on the

thoughts, attitudes and behavior

of caregivers towards

the act of giving care to people with disabilities. More

than that, hospitals or other institutions can provide

information or material supports that helps in facilitating

caregiver in giving care to people with disabilities.

Spiritual well-being is a state in which ones has both

physical and psychological integrity, positive perspectives

in living a meaningful life, and satisfaction in personal

beliefs, including religion.

Additionally, people with

spiritual well-being are those who have clear life goals,

hope, creativity, and feel the need to give and receive love.

us, a caregiver of people with disabilities must have

spiritual well-being in order to be a successful caregiver,

able to enhance the lives of people with disabilities. e

caregiver is responsible for creating and organizing

activities for people with disabilities so that they can

appreciate and live a meaningful life. Religion is one of the

spiritual anchors that can hold together one’s mind, and

oers important principles that can guide one through

the diculties that arise in life. Also, religion teaches

people to forgive, give love, sacrice oneself for others,

follow important principles in life, and be delighted and

pleased in what they are doing as caregivers.

For this reason, the researcher is interested in studying

the resilience quotient, social support and spiritual well-

being of caregivers of patients with hemiplegia who are

receiving treatment at the Department of Rehabilitation

Medicine, Faculty of Medicine Siriraj Hospital. Siriraj

Hospital was selected because of its holistic care system

that provides physical, mental and social treatment, all of

which are provided by personnel through a multidisciplinary

approach which involves a number of professionals

working together: rehabilitation physician, rehabilitation

nurse, physical therapist, occupational therapist, speech

therapist, orthotics, psychologist and social worker.

e researcher hopes that this research will be useful

for clinicians, physicians, scholars, hospital sta and

administrators, and the personnel of any related institutions

in enhancing the spiritual well-being of people with

disabilities and those who care for them. In this study,

it is hypothesized that there is a correlation between

resilience quotient and spiritual well-being, as well as

a correlation between social support and the spiritual

well-being of caregivers of patients with hemiplegia.

Chavapattanakul et al.

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MATERIALS AND METHODS

Study design and population

is research study is a descriptive study and is

certied for human research ethics by the Siriraj Institution

Review Board (SIRB) of the Faculty of Medicine Siriraj

Hospital, Mahidol University, Bangkok, ailand (Si

279/2019). e study involved the collection of data from

caregivers aged of 18 years old and older who are the

main caregivers of patients with hemiplegia that receive

treatment at the Department of Rehabilitation Medicine,

Faculty of Medicine, Siriraj Hospital. Each month in 2018,

there was an average of around 229 patients, counted

by the number of unique patients who come to receive

treatment individually, without repeated counting.

Data collection

e sample of this study comprises 168 caregivers of

patients with hemiplegia, which is calculated by Yamane’s

sample size formula (1973)

from the accidental sampling.

e data were collected through the use of a psychological

questionnaire designed by the researcher; and the validity

and reliability assessment of the questionnaire was also

performed by the researcher. ere were 170 returned

questionnaires, which exceeds the number of the sample

because two more caregivers of patients with hemiplegia

were found on the last day of data collection. Since they

met the standards for qualication, their data wasn’t

eliminated.

Spiritual Well-Being

Hungelmann, 1996

 Faith and Belief

 Life and Self-Responsibility

 Life Satisfaction

Social Support

Schaefer, 1981

 Emotion

 Knowledge and Information

 Material and Services

Resilience Quotient

Department of Mental Health, 2009

 Emotional Stability

 Hope and Morale

 Problem Management

Research Framework

Fig 1. From the research framework, the researcher studied the correlation between resilient quotient and spiritual well-being and social

support and spiritual well-being.

Research instrument

e research instrument contains ve sections. e

rst section collects personal information of caregivers

such as sex, age, education, relationship with patients,

duration of caregiving, occupation, monthly family

income, balance of income and expense, health condition,

family members, number of family members who need

support, and caregiver counselling. e second section

addresses characteristics of patients with hemiplegia, and

includes the demographic characteristics of patients with

hemiplegia who are taken care of by the respondents. e

characteristics include the length of time that the patient

has undergone treatment, sex, age, health condition,

medical care and education. e third section is a set of

questions used to develop the resilience quotient, adopted

from the concept of resilience quotient from Department

of Mental Health

which covers three elements: emotional

stability, hope and morale, and problem management.

ere are 18 questions in this section; for each question,

the respondent needs to choose the answer that best

describes him or herself. e validity index of this set

of questions is .93 and the reliability index is .98. In

the fourth section, the questionnaire covers all three

components of Schaefer’s

concept of social support,

which are emotion, knowledge and information, and

material and services. ere are 18 questions in this

section; for each one, the respondent needs to choose

the answer best describes him or herself. e validity

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248

index of this set of questionnaires is .96 and the reliability

index is .94. Lastly, the questionnaire addresses the level

of spiritual well-being developed from the concept of

Hungelmann

that described three elements of spiritual

well-being as faith and belief, life and self-responsibility,

and life satisfaction. ere are 18 questions on this section;

for each question the respondent needs to choose the

answer best describes him or herself. e validity index

of this set of questionnaires is .96 and the reliability index

is .97.

Statistical analysis

e researcher used descriptive analysis to analyze

general information and study the level of resilience

quotient, social support and spiritual well-being of caregivers

of patients with disabilities. In this study, descriptive

analysis is combined with frequency, percentage, mean

and standard deviation. In addition, the researcher adopts

Pearson’s Product Moment Correlation Coecient in

order to analyze the relationships between resilience

quotient, social support, and spiritual well-being.

RESULTS

e researcher found that 69.42% of the caregivers

are women and 30.69% of caregivers are men. e average

age of the caregivers was 52.10, the youngest is 19 years of

age; the oldest is 83. Additionally, the highest proportion

of respondents, 27.64%, were over the age of 60, while

27.06% were aged between 51 and 60, 25.89% aged

between 41-50, and 19.41% aged between 19-40. With

regard to education, 52.94% of caregivers have completed

a bachelor’s degree or higher, 17.06% completed upper

secondary education, 12.94% completed lower secondary

education, and 17.06% completed primary education.

Forty percent of caregivers are children of the patients,

23.53% are spouses of the patients, 15.88% are relatives

of the patients, 11.18% are parents of the patients, and

9.41% are paid caregivers.

e average duration of caregiving is 4 years; the

shortest duration is 1 month, and the longest duration is

30 years. It was found that almost half of the caregivers

had been giving care to patients for more than 24 months,

which accounted for 48.80% of samples, followed by those

with a caregiving duration between 13 and 24 months,

at 24.70%. Approximately 18.80% had been giving care

for less than six months, while only 7.70% had been

caregivers for between 6 and 12 months. With respect

to occupation, 25.88% of caregivers are housewives and

househusbands, 21.18% are merchants, 20.59% are paid

employees in the business sector, 17.06% are unemployed,

and 15.29% are civil servants. e caregivers have an

average monthly family income of 33,308.82 baht. e

lowest average monthly family income is 5,000 baht,

and the highest is 100,000 baht. Furthermore, 44.12% of

caregivers have an average family income between 5,000

and 20,000 bath per month, 29.41% have an average family

income of more than 40,000 baht, and 26.47% have an

average family income between 20,001 and 40,000 baht.

Finally, it was reported that 42.35% of caregivers have a

surplus of income compared to expenses, while 30.59%

reported a decit between income and expenses, and

27.06% said that income and expenses are equal.

Most of the caregivers (61.76%) do not have congenital

diseases, while the remaining 38.42% of caregivers reported

that they do. e average number of members in the

families of caregivers is 4.76, with the lowest number

being 2 and the highest number of family member

being 10. Proportionally, 27.65% of caregivers have 4

family members, 27.65% have a 6-10 family members,

24.70% have 5 family members, and 20% have 2-3 family

members. e average number of family members who

needs nancial support is 1.65, with the lowest being

1 and the highest being 6. Proportionally, 60.59% of

caregivers’ family have 1 family member who needs

nancial support, while 39.41% have 2 family member

who need nancial support. 72.94% of caregivers have

received advice about caregiving and only 27.06% have

not.

e information about patient’s characteristics, shows

that the average length of time that patients have been

receiving treatment at the Department of Rehabilitation

Medicine is 3.34 years; the shortest duration is 1 month,

and the longest is 25 years. Proportionally, 32.35% of

patients have been receiving treatment between 1 and 2

years, 25.88% have been receiving treatment for more than

5 years, and 24.12% have been receiving treatment for

less than a year. Most of the patients are male, accounting

for 66.47%, while only 33.53% of patients are female. e

average patient age is 64.15; the youngest patient is 18

and the oldest is 92. Proportionally, 31.76% of patients

aged between 18-59, 28.24% are aged between 60-69,

22.35% are aged between 70-79, and 17.65% are at least

80 years old. e health condition of patients can be

divided into 2 groups. e rst is the group of patients

who are unable to walk, accounting for 54.12%. e

second group comprises patients who are able to walk,

accounting for 45.88%. When it comes to paying for

treatment, 40% of all patients are using health insurance

for the treatment, 38.24% are using civil servants’ medical

insurance, 11.18% are using a benets card for persons

with disabilities, 5.88% are using a social security card,

and only 4.70% are paying on their own. For the education

Chavapattanakul et al.

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of patients, 39.41% of patients completed secondary

education, 33.53% completed primary education, and

27.06% completed at least a bachelor’s degree.

e research results show that the caregivers of

patients with hemiplegia have a relatively high resilience

quotient, which means that they have exibility in their

lives and have the ability to adapt themselves and handle

problems during crises. In the same way, it is shown

that the social support for caregivers of patients with

hemiplegia is at a relatively high level, which indicates

that the caregivers receive good information, material

and encouragement supports. Moreover, the spiritual

well-being of the caregivers is at a high level, which can

be interpreted to mean that they have great physical and

mental well-being, they are satised with their lives, and

value themselves. ese results can be seen in Table 1

below.

e research shows that resilience quotient has

a positive correlation with the spiritual well-being of

caregivers of patients with hemiplegia, with statistical

signicance at the .01 level (r = .71) as shown in Table 2.

**means having a statistical signicance at the 0.1 level

TABLE 1. Mean, standard deviation and level of resilience quotient, social support and spiritual well-being of

caregivers of patients with hemiplegia.

Variable x S.D. Level

Resilience quotient 4.06 .41 Relatively high

Social support 4.13 .45 Relatively high

Spiritual well-being 4.25 .41 High

TABLE 2. Correlation Coecient (r) and p-value of resilience quotient and spiritual well-being of caregivers of

patients with hemiplegia.

Resilience quotient Spiritual well-being

Faith and belief Life and self- Life satisfaction Overall

responsibility

r p r p r p r p

Emotional stability .46** .00 .52** .00 .57** .00 .58** .00

Hope and morale .58** .00 .56** .00 .57** .00 .64** .00

Problem management .48** .00 .57** .00 .51** .00 .58** .00

Overall .59** .00 .65** .00 .65** .00 .71** .00

e overall dimension of the resilience quotient

and its determinants, which are emotional stability,

hope and moral, and problem management, is shown

to have positive correlation with spiritual well-being

at the overall dimension as well as each determinant,

including faith and belief, life and self-responsibility, and

life satisfaction at the .01 level of statistical signicance.

e results indicate that there is a positive correlation

between social support and spiritual well-being of

caregivers of patients with hemiplegia with a statistical

signicance at the .01 level (r = .71) as can be seen from

the data in Table 3.

e overall dimension and each determinant of

social support, which are emotion, knowledge and

information, and material and services are revealed to

have positive correlation with spiritual well-being at

the overall dimension along with each determinant of

spiritual well-being, which are faith and belief, life and

self-responsibility, and life satisfaction at the .01 level

of statistical signicance.

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TABLE 3. Correlation Coecient (r) and p-value of social support and spiritual well-being of caregivers of patients

with hemiplegia.

**means having a statistical signicance at the 0.1 level

Social support Spiritual well-being

Faith and belief Life and self- Life satisfaction Overall

responsibility

r p r p r p r p

Emotion .58** .00 .62** .00 .65** .00 .69** .00

Knowledge and information .52** .00 .47** .00 .54** .00 .57** .00

Material and services .46** .00 .40** .00 .52** .00 .52** .00

Overall .62** .00 .59** .00 .68** .00 .71** .00

DISCUSSION

In this study, it is found that the resilience quotient

of caregivers of patients with hemiplegia is at a relatively

high level ( x = 4.06). is might be because the average

age of caregivers of patients with hemiplegia is 52.10

years old, meaning that they are typically adults who

have experienced several problems previously, so they

tend to be mature and patient. is corresponds with

data from the Department of Mental Health,

which

indicate that those who have experienced life problems

and crises are people who have higher resilience quotient

than those who have not. Moreover, patience in adults

can help them adjust and adapt themselves promptly

when facing serious situations or crises, and they are

likely to have fewer physical impacts from mental issues

than people with lower patience. e social support of

caregivers of patients with hemiplegia is at a relatively

high level ( x = 4.13). Based on this result, it appears that

the caregivers have received sucient social support,

assistance, and information, leading to good results in

giving care of patients with hemiplegia. ese supports

include material and nancial supports that enhance

the ability of caregivers, and which, in the long run, may

benet the lives of patients with hemiplegia in positive

way, in accordance with National Development Plans

for Life Quality of the Disabled. e spiritual well-being

of caregivers of patients with hemiplegia is also at a high

level ( x = 4.25), which may be because the caregivers

understand the life of people with disabilities and how

these people struggle daily, so the caregivers desire to

give the best care to these people. e caregivers see how

meaningful life is, so they are willing to devote their lives

to be caregivers for people with hemiplegia. Furthermore,

religion can be a spiritual anchor to caregivers.

e correlation analysis shows that there is a positive

correlation between the resilience quotient and spiritual

well-being of caregivers of patients with hemiplegia,

with statistical signicance at the .01 level, which is in

line with the hypothesis. It can be interpreted that the

higher the resilience quotient caregivers of patients with

hemiplegia have, the more spiritual well-being they will

have. is is likely because caregivers have the ability to

manage and cope with problems, crises, and pressure, so

they are able to deal with changes and become productive

caregivers. Moreover, religion is another factor that aects

the way caregivers perform as the religion teaches people

to be good and do good things. For caregivers, helping

others by devoting themselves in giving care is in line

with this religious teaching. ese results are consistent

with data in the previous study, “e eect of the E&R

Program on mental health of caregivers of children with

developmental and intellectual disabilities Rajanukun

Development Center (Muangkae) Rajanukun Institute”

by Anchalee Watthong and Sala Techameena

(E&R

Program is a training program that enhances the resilient

quotient to people for them to overcome life crises as

well as to strengthen people’s spiritual encouragement).

is research revealed that supporting the resilience of

caregivers of children with developmental and intellectual

disabilities leads to better performance of caregivers

in giving care to children, because the caregivers gain

better understanding of problems and know how to

manage those problems with creative solutions. Yet, it

is a characteristic of caregivers who have spiritual well-

Chavapattanakul et al.

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Original Article

SMJ

being to participate in creative activities to make their

lives meaningful, which is also in accordance with the

notion of Pravet Wasee: “If what we are doing is correct

and good, we will achieve spiritual well-being.”

Furthermore, the correlation analysis shows that

there is a positive correlation between social support

and spiritual well-being of caregivers of patients with

hemiplegia, with a statistical signicance at the .01 level.

is indicates that the more social support caregivers

receive, the more spiritual well-being they will enjoy.

In other words, social support given to caregivers will

help them accomplish what they are doing; thus, the

caregiving is likely to be successful and eective. When

people accomplish what they are doing, they tend to be

proud and satised; this is what is called spiritual well-

being. Giving social support to caregivers by providing

information about caregiving for patients is essential and

has a high positive impact on caregivers’ performance.

is nding was also reported by Sukheeluk, Nuanchana

and Rabudda

in their research, “e result of developing

caregiver potential for stroke patients at home in Maharaj

district, Phranakhon Si Ayuthhaya province.” In this

research, it was identied that caregivers of patients of

stroke gained condence and courage in giving care

wholeheartedly and that they were able to manage

problems when they received social support, including

joining activities, training, and exchanging knowledge

and information on caregiving of patients. erefore,

caregivers who receive social support are likely to have

higher motivation, possess greater courage, and be better

caregivers. More than that, a family is one of the main

supports for caregivers, providing material support,

nancial support and courage that can mitigate the

diculties from caregiving that may result from patients’

unstable emotional states or from the expectations from

the patient’s family. is also accords with the previous

study by Panphadung, Nilmanut and Kitrungrote,

“Spiritual Well-Being of Family Caregivers of Hospitalized

Patients with Advanced Gynecological Cancer.” In this

study, it was reported that caregivers need to cope with the

misunderstandings and ignorance that could arise from

the patient’s family or relatives about certain aspects of

caregiving. Hence a lot of eort is required for caregivers

to provide favorable caregiving, which can have an eect

on the spiritual well-being of caregivers.

In this study, there was a time constraint on collecting

data from the caregivers of patients with hemiplegia

who are receiving treatment at the Department of

Rehabilitation Medicine, Faculty of Medicine Siriraj

Hospital. Due to the small number of caregivers at the

hospital each day, it took two months to get all the

designated samples. Notwithstanding this limitation,

the study suggests that resilience quotient and social

support have correlations with spiritual well-being.

Siriraj Hospital has a holistic care system that oers

physical, mental and social treatment which are provided

by personnel involved in a multidisciplinary approach

which includes a rehabilitation physician, rehabilitation

nurse, physical therapist, occupational therapist, speech

therapist, orthotist, psychologist and social worker.

erefore, with the holistic care, the patients receive

comprehensive treatment, which may have positive

eects on the caregivers of patients with hemiplegia. ese

positive eects include a high level of resilience quotient

acquired aer the caregivers have been able to get through

crises and have also been able to bring the patients to

receive eective and timely treatment. In addition, the

caregivers receive social supports that help them greatly

in enhancing their skills and knowledge about giving

care to patients with hemiplegia. When the caregivers

have a suciently high resilience quotient and receive

social supports, they are likely to have higher spiritual

well-being because resilience quotient and social support

both have positive correlations with spiritual well-being.

us, the caregivers are very likely to have good mental

health, be seless, satised in their lives, and feel that

what they are doing is valuable to themselves and others.

However, the ndings in this study are based solely on

information collected from the caregivers of patients with

hemiplegia at Department of Rehabilitation Medicine,

Faculty of Medicine Siriraj Hospital. It is impossible

to know if the results of this study are applicable to

caregivers of patients with other health conditions, or

those from dierent areas or cultural backgrounds, or

whether similar studies of dierent populations will

be relevant or get the same results. erefore, further

studies in dierent conditions need to be conducted in

the future.

The research results can be applied to benefit

caregivers in a number of ways. Resilience should be

promoted for caregivers of patients with hemiplegia

so they can get through problems and diculties that

happen during caregiving which could undermine their

courage. Additionally, creative activities and relaxing

activities such as drawing, reading, doing sports, craing

or religious activities should be promoted for caregivers to

enjoy. Also, social support should be made easily available

to caregivers of patients with hemiplegia by providing

necessary materials such as wheelchairs and walking

sticks, providing guiding information and advice about

caregiving for patients with hemiplegia, and arranging

experience exchanges among caregivers of patients with

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252

hemiplegia. Exchanging and sharing experiences among

caregivers of patients with hemiplegia is considered to

be very important because it has a positive impact on

the spiritual well-being of caregivers through the acts of

giving and receiving support to each other, which helps

caregivers to appreciate themselves and gain motivation

and condence to give the best care to patients

ACKNOWLEDGMENTS

e researcher would like to thank the nurses and

sta at the Department of Rehabilitation Medicine, Faculty

of Medicine Siriraj Hospital for their facilitation in data

collection at the department. Finally, great appreciation

is expressed to the sample group of caregivers of patients

with hemiplegia for the excellent cooperation oered in

answering the questionnaire.

REFERENCES

1. Department of Empowerment of Persons with Disabilities. e

h National Development Plans for Life Quality of the Disabled

2017-2021. Department of Empowerment of Persons with

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2. Department of Empowerment of Persons with Disabilities.

Statistic report on persons with disabilities in ailand. Department

of Empowerment of Persons with Disabilities; 2017.p.4.

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Statistic report on persons with disabilities in ailand. Department

of Empowerment of Persons with Disabilities; 2018.p.3.

4. Charnnarong N. Stroke is the number cause of death of ai

people. In: Hfocus Delve into health system. Available from:

https://www.hfocus.org/content/2019/04/17033

5. Department of Mental Health. From bad to good RQ Resilience

Quotient. Nonthaburi: Social Mental Health Oce, Department

of Mental Health, Ministry of Public Health; 2009.

6. House J. Work Stress and Social Support Reading. Mass:

Addison Wesley; 1981.

7. Schaefer C, Coyne J, Lazarus R. e Health-Related Functions

of Social Support. J Behav Med1981;4 4:381-406.

8. Charoenjittikul C. Spirit: Caregiving. Journal of Huachiew

Chalermprakiet University 2004;7 14:78-87.

9. Highfield F, Cason C. Spiritual need of patient: are they

recognized? Cancer Nurs1983;6 3:187-192.

10. Hungelmann J,Kenkel-Rossi E,Klassen L,Stollenwerk R.

Focus on spiritual well-being: harmonious interconnectedness

of mind-body-spirit-use of the JAREL spiritual well-being

scale. Geriatr Nurs1996;17 6:262-266.

11. Yamane T. Statistics: An Introductory Analysis. 3rd ed. New

York: Harper & Row; 1973.p.725-733.

12. Watthong A, Techameena S. e eect of the E&R Program

on mental health of caregivers of children with developmental and

intellectual disabilities Rajanukun Development Center

(Muangkae) Rajanukun Institute. Rajanukun Institute, Ministry

of Public Health; 2011.p.29.

13. Wattayakorn P, Chongchareon W, Chukumnerd P. Spiritual

Well-Being and Spirituality at Work of Head Nurses in General

Hospitals, Southern ailand. Academic Journal of Prince of

Songkla University; 2016;27 3:115-126.

14. Sukheeluk P, Nuanchana K, Rabudda L. e result of developing

caregiver potential for stroke patients at home in Maharaj

district, Phranakhon Si Ayuthhaya province Available from:

https://www.ayo.moph.go.th/main/index.php?mod=MultiF

orms&id=2aa0221e1b882110ef5554b 77f26c4f

15. Panphadung S, Nilmanut K, Kitrungrote L. Impact of a Buddhism-

Based Spiritual Wellbeing Promotion Programme on the

Spiritual Wellbeing of Family Caretakers Responsible for

Hospitalised Advanced Gynaecological Cancer Patients. ai

J Nurs 2015;30:16-28.

Chavapattanakul et al.

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Saowaluk Silpasakorn, B.Sc.*, Yoon-Won Kim, Ph.D.**, Yupin Suputtamongkol, M.D.*

*Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, ailand, **Department of Microbiology, College of

Medicine, Hallym University, Chuncheon, South Korea.

Evaluation of Combined Rapid Immunoglobulin

M and Immunoglobulin G Lateral Flow Assays for

the Diagnosis of Leptospirosis, Scrub Typhus, and

Hantavirus Infection

ABSTRACT

Objective: Leptospirosis, scrub typhus, and hantavirus infection are commonly identied as causes of acute

undierentiated fever in rural parts of Asia. Although the characteristic presentations of these infections are well

described, many of them present with nonspecic manifestations. Diagnosis is usually made by combined history

of exposure, clinical features and positive antibody detection. e development of rapid antibody detection assay,

using an immunochromatographic test (ICT) for the diagnosis of multi-diseases, has provided tools for more

accurate diagnosis and appropriate antibiotic treatment of the acute undierentiated fever syndrome.

Methods: We evaluated the diagnostic performance of a commercially available combined rapid ICT for the

diagnosis of leptospirosis, scrub typhus, and hantavirus infection, using archived blood samples from 434 patients

with laboratory-conrmed leptospirosis (131) or scrub typhus (128), and from patients with other causes of fever as

the negative control (175). Polysaccharide of nonpathogenic Leptospira patoc, a chimeric recombinant protein cr56

and two other recombinant proteins, r21 and kr56, from dierent serotypes of Orientia tsutsugamushi, and 21kDa

species-specic antigen and recombinant CNP antigen derived from the Soochong virus were used as antigens

for the diagnosis of leptospirosis, scrub typhus, and hantavirus infection in the combined ICT used in this study.

Results: For the diagnosis of leptospirosis; in acute phase, the sensitivity and specicity of the ICT detection of

IgM/IgG were 38.2% (95% CI, 29.9- 46.5%), and 99.0% (95% CI 97.9-100%); while in convalescent phase, the same

were 84.6% (95%CI, 77.1- 92.0%), and 96.2% (95%CI, 92.5- 99.8%), respectively. For scrub typhus, in acute phase,

the sensitivity and specicity of the ICT detection of IgM/IgG were 71.9% (95% CI, 64.1- 79.7%), and 97.4% (95%

CI 95.6 - 99.2%); while in convalescent phase, the same were 84.6% (95%CI, 74.8- 94.4%), and 90.2% (95%CI, 85.3-

95.1%) respectively. For hantavirus infection, nine patients had detectable IgM for hantavirus infection. All these

cases were diagnosed as scrub typhus by indirect immunouorescent assay.

Conclusion: e performance of this combined ICT for leptospirosis and scrub typhus were comparable to those

published data of other ICTs. However, the rapid test for the diagnosis of leptospirosis, using antigen detection, is

needed. Hantavirus infection was not detected in this study population.

Keywords: Immunochromatographic assay; leptospirosis; scrub typhus; hantavirus (Siriraj Med J 2020; 72: 253-258)

Corresponding author: Yupin Suputtamongkol

E-mail: ysuputtamongkol@gmail.com

Received 27 November 2019 Revised 17 February 2020 Accepted 26 February 2020

ORCID ID: http://orcid.org/0000-0001-7324-1698

http://dx.doi.org/10.33192/Smj.2020.34

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INTRODUCTION

Acute undierentiated febrile illness is a leading

cause of hospital visit among adults in rural areas of

South–East Asia. e common causes of such fever

include scrub typhus, murine typhus, leptospirosis,

and hantavirus infection.

1,2

Leptospirosis is a worldwide

zoonotic disease, caused by pathogenic members of the

genus Leptospira.

Human infection occurs through the

direct or indirect exposure to the organism excreted in

the urine of both wild and domestic mammals. Scrub

typhus is the most common rickettsial infection in the

Asia- Pacic region. It is caused by Orientia tsutsugamushi,

an obligate intracellular Gram-negative bacterium.

Human accidentally infected through the bite of the

infected chiggers. Over a billion people are at risk of

scrub typhus and approximately one million cases occur

annually.

4,5

In ailand, scrub and leptospirosis are the

main causes of acute undierentiated fever, aer dengue

infection is excluded.

1,6

Hemorrhagic fever with renal syndrome (HFRS) is

caused by various hantaviruses in the genus Hantavirus of

the family Bunyaviridae. Seoul virus (Seoul orthohantavirus,

SEOV), the only species of the genus Hantavirus that is

found to be globally spread as hantavirus, is a common

cause of HFRS. HFRS is a viral zoonosis transmitted

by rodents.

To date, only 2 patients with hantavirus

infection have been reported in ailand.

8,9

However, the

incidence of HFRS could be underestimated in ailand

due to the unavailability of a diagnostic test.

Although the characteristic clinical presentations of

leptospirosis, scrub typhus, and HFRS are well described,

many patients present with protean and nonspecic

symptoms and signs.

Consequently, the diagnoses of

either of these infections are usually made by combination

of a history of exposure, well recognized symptoms and

signs, and positive antibody detection.

5,6

In addition,

hantavirus infection and leptospirosis can share similar

clinical and exposure risks.

e availability of rapid

antibody tests using an immunochromatographic test

(ICT) has provided tools for point-of-care serologic

testing. ImmuneMed AFI Rapid® is one such commercially

available rapid ICT for the qualitative detection of both

IgM and IgG antibodies to hantavirus, O. tsutsugamushi,

and Leptospira spp. in a patient’s serum, plasma, or whole

blood. In this study, we conducted the study to determine

the diagnostic performance of this assay, using the stored

serum/ plasma samples of patients who presented with

an acute febrile illness caused by leptospirosis, scrub

typhus, or other diagnoses.

MATERIALS AND METHODS

Patients with leptospirosis or scrub typhus

Blood samples (n=259) were collected from patients

(male : female = 2 :1), aged 15- 84 years old (median age

45 years old) who presented with acute febrile illness

at four hospitals in Thailand between January 2000

and December 2018. ree hospitals are located in the

northeastern region of the country (Maharaj Nakhon

Ratchasima Hospital, Loei Provincial Hospital and

Banmai Chaiyapod Hospital, Burirum Province). In

these hospitals, blood samples were collected as part

of the epidemiological and clinical studies of patients

with acute undierentiated fever.

6,11,12

Included in these

studies were adult patients (>18 years) who presented

with acute fever (oral temperature, >38.0°C for less than

15 days) in the absence of an obvious focus of infection.

Blood samples were also collected from patients, using

the same inclusion criteria, at Siriraj Hospital, Bangkok,

ailand. All of these clinical studies were conducted aer

the approval of the Ethical Review Subcommittee, Public

Health Ministry of ailand and the Siriraj Institutional

Review Board, Faculty of Medicine Siriraj Hospital,

Mahidol University (Si 014/2019). All patients provided the

informed written consent before enrollment to the study.

Blood samples were collected on the day of admission,

and/or during convalescence or aer discharge from

the hospital. Plasma was divided into that needed for

immediate use and a leover sample was stored at –70°C.

Non-scrub typhus and non-leptospirosis samples

Blood samples (n= 175) from patients with other

tropical febrile illnesses (laboratory-conrmed) were

collected from the same hospitals as the patients with

leptospirosis and scrub typhus. All of these samples were

tested by indirect immunouorescent assay (IFA) and

were shown to be negative for O. tsutsugamushi and

Leptospira. e diagnoses of patients in this control group

were dengue infection in 59 patients; zika virus infection

in 16 patients; inuenza A or inuenza B in 26 patients;

murine typhus in 60 patients; other bacterial infections,

such as Escherichia coli septicemia, melioidosis, and

salmonellosis in 8 patients; and Plasmodium falciparum

malaria in 6 patients.

e IFA assay for the laboratory conrmation of

leptospirosis, scrub typhus, and murine typhus was

performed as described previously.

6,11,12

e Leptospira

interrogans, serovar autumnalis; pooled O. tsutsugamushi

from Karp, Kato and Gilliam strains; and Rickettsia

typhi (Wilmington strain) were used as the antigens

for the detection of IgM and IgG antibodies for the

Silpasakorn et al.

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diagnosis of leptospirosis, scrub typhus, and murine

typhus respectively. Samples with inconclusive IFA

results such as suspected co-infection or low antibody

titers were not included in this study.

Combined ICT for leptospirosis, scrub typhus, and

hantavirus infection

Polysaccharide of nonpathogenic Leptospira patoc,

a chimeric recombinant antigen cr56 and two other

recombinant antigens, r21 and kr56, from various

serotypes of O. tsutsugamushi, and 21kDa genus-specic

protein and recombinant CNP protein derived from

the Soochong virus of the genus Hantavirus were used

as the antigens for the detection of IgM/ IgG for the

diagnosis of leptospirosis, scrub typhus, and hantavirus

infection respectively.

13-15

e ImmuneMed AFI Rapid®

(ImmuneMed, Inc., South Korea) test was performed

according to the manufacturer’s instructions. In brief,

approximately 3 L of serum was applied to the ICT

sample well, and then approximately 7 drops (300 L)

of the sample diluent was added into the sample well

immediately. Results of the assay were interpreted visually

at 15 minutes, as either negative if only the control band

was stained or as positive when both the test and control

bands were clearly stained (Fig 1).

was either an IgM or IgG IFA assay titer ≥ 1:400 at an

acute phase sample or a four-fold increase between paired

acute and convalescent phase samples. Inconclusive

results were considered negative in the statistical analysis.

A two-by-two table was constructed, in which the IFA

results, as a gold standard test were cross-tabulated with

the ICT assay result to calculate the percentage of true-

positive, false-positive, false-negative, and true-negative

results. e standard diagnostic accuracy indices of the

sensitivity and specicity with 95% condence intervals

(CIs) were calculated, using the SPSS 21.0 soware (SPSS

Inc., Chicago, IL, USA).

RESULTS

Overall there were 434 patients included in this study,

with the median duration of fever was 4 days (ranged

from 3 to 14 days). Of these 193 patients’ convalescent

samples were available. e median duration between

acute and convalescent periods of 10 days (IQR, 6 to 14

days). Among 131 patients with laboratory-conrmed

leptospirosis, convalescent samples were available in 91

patients. In acute- phase samples, the sensitivities of the

ICT tests for the detection of IgM and IgG antibodies

for the diagnosis of leptospirosis were 37.4% (95% CI,

29.1- 45.7%), and 9.2% (95% CI 4.3-14.1%) respectively

(Table 1). e specicities of IgM and IgG were 99.0%

(95%CI, 97.9- 100%), and 100% (95%CI, 88.2-100%)

respectively. False positive IgM/IgG antibody detection

was found in only 3 patients (in 2 patients with scrub

typhus, and 1 patient with murine typhus) among 303

acute patients. e sensitivities of the test were improved

to 84.6% in the convalescent phase, with false positive

IgM/IgG antibody detection in 4 patients (3 patients with

inuenza infection) among 104 convalescent patients.

Among 128 patients with IFA-conrmed scrub

typhus, convalescent samples were available in 52 patients.

e sensitivities of the ICT tests for the detection of

IgM and IgG antibodies against O. tsutsugamushi in the

acute- phase samples were 68.0% (95% CI, 55.9- 76.1%),

and 41.4% (95% CI 32.9- 49.9%) respectively. In acute-

phase, the specicities of IgM and IgG antibodies against

O. tsutsugamushi were 97.4% (95%CI, 95.6-99.2%), and

99.7% (95%CI, 99.1-100%) respectively. False positive

IgM/IgG antibody detection was found in 8 patients (in 7

patients with leptospirosis and in 1 patient with S. aureus

bacteremia) among 306 acute patients. e sensitivities

of this ICT test was improved as 84.6% when the test was

performed using convalescent samples. In the convalescent

samples, false positive IgM/ IgG antibody detection

was found in 14 patients, comprising; 12 patients with

leptospirosis (3 of them also had a positive IFA for scrub

Fig 1. Examples of the visually interpretation of results from three

patients with negative result (no 660, le panel), positive band for

both scrub typhus IgM, IgG and hantavirus IgM (no 651, middle

panel), and positive scrub typhus IgM (no 652, right panel). C, H,

S, L represented control, hantavirus, scrub typhus, and leptospirosis

respectively.

Data analysis

e diagnostic performance was determined by

comparing the IgM and IgG ICT results with the result

from the IFA for each patient. e diagnostic criterion for

the reference IFA assay for scrub typhus and leptospirosis

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256

typhus), and 2 patients with inuenza infection, among

143 convalescent patients. Details of the sensitivities and

specicities of IgM/IgG for the diagnosis of leptospirosis

and scrub typhus, in the acute and convalescent samples

are shown in Table 1.

For hantavirus infection, overall there were 9 patients

with a positive IgM test, comprising 2 patients who

were positive in both acute and convalescent samples,

4 patients who were negative in the acute phase but

positive in the convalescent sample, and 3 patients who

were positive in only acute samples. None of the acute

and convalescent tested positive for IgG. All patients

who had positive IgM for hantavirus infection also had

positive IgM for scrub typhus. All the patients were

empirically treated with oral doxycycline and became

afebrile during follow-up. As an example, one woman

among the positive patients to hantavirus but who was

negative to dengue IgM/IgG had fever for 5 days with a

normal white blood cell count, but increased in atypical

lymphocytes, and thrombocytopenia. is patient fully

recovered aer the treatment with doxycycline. Only an

acute- phase sample was available in this patient. Her IFA

IgM/ IgG antibody titers against O. tsutsugamushi were

1:800 and 1:200, respectively. ese positive hantavirus

IgM samples were retested by another IFA for the detection

of hantavirus infection at the ImmuneMed laboratory,

Korea. None of them was conrmed hantavirus infection

with the second IFA.

DISCUSSION

Among patients with non-malaria fever, leptospirosis

and scrub typhus were diagnosed in approximately 10%

to 30% of them.

1,6,7

e awareness and an early diagnosis

of both leptospirosis and scrub typhus has impact on

choice of antibiotic treatment during the acute phase

of illness. Empirical treatment with oral doxycycline

is considered to be the most cost-eective strategy for

the initial treatment of patients with clinically suspected

leptospirosis or scrub typhus.

However, in the absence

of rapid and reliable laboratory tests for both diseases,

misdiagnosis and delayed appropriate patient management

occur frequently. Consequently, there is an urgent need

for a more accurate and easy to perform point-of-care

leptospirosis and scrub typhus diagnostics.

For the syndromic approach of acute fever, this

rapid ICT for the simultaneous detection of IgM/IgG

for the diagnosis of leptospirosis, scrub typhus, and

hantavirus infection demonstrated comparable sensitivity

and specicity to the previously reported individual ICTs

for either leptospirosis

or scrub typhus.

TABLE 1. Sensitivities and specicities of the ICT for the diagnosis of leptospirosis and scrub typhus in acute and

convalescent samples.

Acute phase samples Convalescent phase samples

IgM IgG IgM/IgG IgM IgG IgM/IgG

Leptospirosis 49/131 12/131 50/131 77/91 43/91 77/91

Others 3/303 0/303 3/303 4/104 0/104 4/104

Sensitivity, % 37.4 9.2 38.2 84.6 47.3 84.6

95%CI 29.1-45.7 4.3-14.1 29.9- 46.5 77.1-92 37-57.5 77.1-92.0

Specicity, % 99.0 100 99.0 96.2 100 96.2

95%CI 97.9-100 88.2-100 97.9-100 92.5- 99.8 NA 92.5- 99.8

Scrub typhus 87/128 53/128 92/128 44/52 32/52 44/52

Others 8/306 1/306 8/306 14/143 1/143 14/143

Sensitivity, % 68.0 41.4 71.9 84.6 61.5 84.6

95%CI 55.9-76.1 32.9-49.9 64.1-79.7 74.8-94.4 48.3-74.7 74.8-94.4

Specicity, % 97.4 99.7 97.4 90.2 99.3 90.2

95%CI 95.6-99.2 99.1-100 95.6-99.2 85.3-95.1 97.9-100 85.3-95.1

Silpasakorn et al.

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Original Article

SMJ

The results of this study confirmed that in the

acute phase of leptospirosis (less than 7 days of illness),

serological diagnosis using either IgM/IgG detection

is not sensitive. e antibody against Leptospira spp.

only become detectable in the late acute phase of the

disease.

Molecular diagnosis by either conventional or

real- time polymerase chain reaction is the most common

laboratory test for the conrmation of leptospirosis in

this early phase. e main use of serological testing is

for conrmation of a diagnosis of leptospirosis when the

convalescent sample is available. erefore, an ICT for

the detection of IgG/IgM against Leptospira spp. alone

might not be cost- eective for routine implementation.

us rapid point- of- care for antigen detection is urgently

needed for the early diagnosis of leptospirosis.

e assay demonstrated better sensitivity for the

diagnosis of scrub typhus than leptospirosis in the acute

phase of infection. O. tsutsugamushi re-infection is not

uncommon in endemic areas of scrub typhus.

The

pattern of antibody response to Orientia re-infection

mimics that found in those who have had re-infection

by dengue virus. erefore, the detection of both IgM

and IgG antibodies at the same time provided higher

sensitivity than the assays for IgM or IgG alone.

For the diagnosis of either leptospirosis or scrub

typhus, both IgM and IgG could be detected in more

than 80% of samples collected aer day 6 to day 14 of

fever. False- positives may be caused by many factors,

including cross-reactivity between antibodies among

O. tsutsugamushi, Leptospira spp., or other pathogens, such

as inuenza, or by the persistence of an antibody following

recovery from previous scrub typhus or leptospirosis. For

hantavirus infection, only IgM was detectable in 9 patients.

However, all of them were diagnosed with scrub typhus

by IFA and as all patients recovered aer doxycycline

treatment, further investigation at the ImmuneMed

laboratory, conrmed that all of these samples were not

hantavirus infection. us cross reaction of hantavirus

infection and scrub typhus was the most likely explanation

of results found in this study.

We did not calculate the positive and negative

predictive values for this ICT because we used the stored

samples collected from various hospitals, at dierent

periods of time. As a result, the proportion of samples

from patients with leptospirosis, scrub typhus, and

other diagnoses did not represent the true prevalence

of these diseases among patients with acute fever in

ailand. Overall, it would be more cost eective to

implement this ICT for the simultaneous diagnosis

of either leptospirosis or scrub typhus (or hantavirus

infection) than the application of individual ICTs for

these diseases sequentially. Although the determination

of the diagnostic performance of a newly developed assay

is commonly performed by using well stored samples,

prospective clinical studies are needed to determine the

more accurate diagnostic performance of the assay as

discrepancies between stored samples and prospective

studies with the same ICT assays may exist. More studies

are also needed to conrm that hantavirus infection is

rare in ailand.

CONCLUSION

For the syndromic approach to acute fever, this rapid

ICT for the simultaneous detection of IgM/IgG for the

diagnosis of leptospirosis, scrub typhus, and hantavirus

infection, demonstrated comparable sensitivity and

specicity to the previously reported individual ICTs for

either leptospirosis or scrub typhus in endemic areas.

However, we did not detect hantavirus infection in this

study, and a rapid test for the diagnosis of leptospirosis,

using antigen detection, is still needed.

ACKNOWLEDGMENTS

e authors thank ImmuneMed Inc, Korea for

their kind donation of ICT (ImmuneMed AFI Rapid®)

used in this study. e company played no role in the

study design, data collection and analysis, decision to

publish, or preparation of the manuscript.

Funding: YS was supported by a Siriraj Chalermphrakiat

Grant, Faculty of Medicine Siriraj Hospital, Mahidol

University, Bangkok, ailand. e funder had no role

in the study design, data collection and analysis, decision

to publish, or preparation of the manuscript

Conict of Interest: Professor Yoon-Won Kim advised

the scientic contribution when ImmuneMed AFI Rapid®

has been developed.

Abbreviations

HFRS: Hemorrhagic fever with renal syndrome,

ICT: Immunochromatographic test, IFA: Indirect

immunouorescent assay

REFERENCES

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Wuthiekanun W, Chierakul W, et al. Causes of acute undierentiated

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2. Bhargava A, Ralph R, Chatterjee B. Assessment and initial

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3. Abela-Ridder B, Sikkema R, Hartskeerl RA. Estimating the

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burden of human leptospirosis. Int J Antimicrob Agents

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5. Luce-Fedrow A, Lehman ML, Kelly DJ, Mullins K, Maina AN,

StewartR L, et al. A review of scrub typhus (Orientia tsutsugamushi

and Related Organisms): en, Now, and Tomorrow. Trop

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6. Suttinont C, Losuwanaluk K, Niwatayakul K, Hoontrakul S,

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undierentiated febrile illness in rural ailand: a prospective

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8. Suputthamongkol Y, Nitatpattana N, Chayakulkeeree M,

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9. Pattamadilok S, Lee B-H, Kumperasart S, Yoshimatsu K, Okumura

M, Nakamura I, et al. Geographical distribution of hantaviruses

in ailand and potential human health signicance of ailand

virus. Am J Trop Med Hyg 2006;75(5):994-1002.

10. Dahanayaka N, Agampodi S, Bandaranayaka A, Priyankara

S, Vinetz J. Hantavirus infection mimicking leptospirosis: how

long are we going to rely on clinical suspicion? J Infect Dev

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11. Suputtamongkol Y, Niwattayakul K, Suttinont C, Losuwanaluk

K, Limpaiboon R, W. Chierakul W, et al. An open, randomized,

controlled trial of penicillin, doxycycline, and cefotaxime for

patients with severe leptospirosis. Clin Infect Dis 2004;39:1417-

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12. ipmontree W, Suputtamongkol Y, Tantibhedhyangkul W,

Suttinont C, Wongsawat E, Silpasakorn S. Human leptospirosis

trends: northeast ailand, 2001-2012. Int J Environ Res Public

Health 2014;11(8):8542-51.

13. Lee JW, Park S, Kim SH, Christova I, Jacob P, Vanasco NB,

et al. Clinical Evaluation of Rapid Diagnostic Test Kit Using the

Polysaccharide as a Genus-Specic Diagnostic Antigen for

Leptospirosis in Korea, Bulgaria, and Argentina. J Korean Med

Sci 2016;31:183-9.

14. Kim YJ, Yeo SJ, Park, S, Woo Yj, Kim MW, Kim SH, et al.

Improvement of the diagnostic sensitivity of scrub typhus

using a mixture of recombinant antigens derived from Orientia

tsutsugamushi serotypes. J Korean Med Sci 2013;28:672-9.

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Med Med Sci 2017;6(12):316-9.

16. Suputtamongkol Y, Pongtavornpinyo W, Lubell Y, Suttinont C,

Hoontrakul S, Phimda K, et al. Strategies for diagnosis and

treatment of suspected leptospirosis: a cost-benet analysis.

PLoS Nleg Trop Med 2010;4:e610.

17. Maze MJ, Sharples KJ, Allan JK, Rubach MP, Crump JA. Diagnostic

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18. Saraswati K, Day N, Mukaka1 M, Blacksell SD. Scrub typhus

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259

Review Article

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.

Hepatitis E in Southeast Asia

ABSTRACT

Hepatitis E is a major cause of acute viral hepatitis in the world. e causative agent of hepatitis E is hepatitis

E virus (HEV). In Southeast Asia, the seroprevalence of HEV and the most prevalent genotype of HEV are largely

unclear and the available data is either limited or outdated. Aer a systematic review of literature, we found the

seroprevalence of HEV and the most prevalent genotype of HEV appear to vary greatly by countries. e seroprevalence

is likely between 17% to 42% and the prevalent genotypes across Southeast Asia are likely 1, 3, and 4, but not 2 as

no cases of genotype 2 have been reported in this region. As HEV remains widespread in Southeast Asia and the

clinical implications of HEV can be severe, surveillance programs for HEV should be implemented.

Keywords: Epidemiology; genotype; seroepidemiologic studies; vaccination; swine (Siriraj Med J 2020; 72: 259-264)

Corresponding author:Wikrom Karnsakul

E-mail: wkarnsa1@jhmi.edu

Received 7 October 2019 Revised 23 January 2020 Accepted 24 February 2020

ORCID ID: http://orcid.org/0000-0001-7288-5459

http://dx.doi.org/10.33192/Smj.2020.35

INTRODUCTION

Hepatitis E virus

Globally, hepatitis E is a major cause of acute viral

hepatitis.

1,2

e causative agent of this liver disease is

the hepatitis E virus (HEV).

HEV is a non-enveloped,

single-stranded, positive-sense RNA virus with similar

physical characteristics to the hepatitis A virus.

4,5

Similar

to the hepatitis A virus, HEV is transmitted via the

oral-fecal route through contaminated water and it

can also be transmitted via zoonosis.

6,7

ere are ve

genotypes of HEV known to infect humans, genotypes

1-4 and recently genotype 7 however, for those ve

genotypes, there is only one serotype.

8,9

HEV appears

to have genotype-specic complications. Infection by

genotype 1 and 2 can result in severe complications

such as death and stillbirth while infection by genotype

3 typically results in mild to non-existent complications

in immunocompetent individuals.

10-14

Genotypes 1 and 2 have only been reported in humans

while genotypes 3 and 4 are zoonotic and are known to

be carried by swine and other animals depending on the

regions. Transmission of HEV from infected swine can

be due to direct contact with the swine, consumption

of undercooked swine meat, or exposure to swine feces.

Exposure to the swine feces can be either directly through

contact or indirectly through contaminated water or

contaminated shellsh.

6,7,15

Although swine are the most

commonly reported source of zoonotic transmission,

deer and other animal species have been reported to

transmit genotype 3 to humans as well.

Review methodology

We conducted a systematic search on PubMed and

Google Scholars for research articles with the main keywords

“hepatitis E,” “genotype,” and “seroprevalence.” ese

keywords were supplemented with the “Southeast Asia,”

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260

“Brunei,” “Burma,” “Myanmar,” “Cambodia,” “Timor-

Leste,” “Indonesia,” “Laos,” “Malaysia,” “Philippines,”

“Singapore,” “ailand,” and “Vietnam.” Non-English

research articles without English translations were not

reviewed. All relevant research articles found in the

search were reviewed. Recent publications were favored;

however, publication dates were not used as an exclusion

factor.

Epidemiology

In Southeast Asia, previous studies have reported

genotype 1 and 4 to be prevalent in humans.

17,18

However,

recent evidence found conicting results suggesting that

those previous studies may be outdated.

19-24

e prevalent

genotype of HEV is largely unclear and varies greatly by

countries.

In ailand, multiple studies have found that the

local swine carry HEV genotype 3, exclusively.

25-28

And

in humans, genotype 3 have also been found.

19-24

e

seroprevalence of HEV, dened in this paper as the

presence of anti-HEV immunoglobin G, was found to be

14% nationally in 2007-2008, but the seroprevalence was

not homogenous, varying greatly within the country.

e study found lower HEV seroprevalence in Muslim

dominated regions where pork consumption is relatively

scarce.

29,30

A decade later, a recently published study

found that the seroprevalence of HEV to be much higher,

29.7% in the general ai population.

is study also

found lower HEV seroprevalence in Muslim dominated

region.

Recent reports, including a recently published

national study, have only found genotype 3 in ailand.

20,21

Because of these consistent reports, the prevalent HEV

genotype that is circulating in ailand is almost certainly

genotype.

In Cambodia, studies have reported various genotypes

circulating in the country. In humans, genotypes 3 and

4 have been found.

22,32

And swine have been found to

carry HEV genotype 1, 3, and 4.

32,33

Genotype 3 has also

been found in the river water.

In a study in 2015, the

seroprevalence of HEV was found to be 18.4% in the

general population.

In Laos, the swine population has been found to

carry genotype 4.

35-37

However, there are currently no

genotyping studies of HEV in humans in Laos. e

seroprevalence in humans may be 17% based on controls

used in a study by Bounlu et al.

In Malaysia, a 1999 study reported the seroprevalence

of HEV to be only 2% in the general population, strangely

low.

Another study around the same time found the

seroprevalence to be 10% in a population of patients

infected by the human immunodeciency virus.

is

suggests that seroprevalence of HEV used to be very

low, however, these studies are outdated. Genotype

information for both humans and swine have not been

reported in the literature.

In Myanmar (previous known as Burma), the

predominant genotype appears to be genotype 1. A few

studies have reported nding genotype 1 in humans.

4,41

e statuses of other genotypes are unknown and swine

genotypes have not been studied. A study in 2001 found

the seroprevalence of HEV in Myanmar to be 31.5% in

humans and 24% in swine.

In Vietnam, studies have reported genotype 4 in

humans.

43,44

Genotype 1 has been suspected of being

prevalent in Vietnam due to waterborne outbreaks of

HEV, however, genotypic analysis to explicitly conrm

the presence of genotype 1 HEV does not exist.

Animal

reservoirs for HEV in Vietnam have not been reported

in the literature. is seroprevalence is unknown in the

whole country, but in the capital city of Ho Chi Minh

City, it is very high at 42%.

In Indonesia, genotype 4 has been found in humans.

Genotype 4 has also been reported in swine.

47,48

A study

in 2005 of 2,450 pregnant women found that the

seroprevalence of HEV was 18% in this population

nationally, and that in Muslim dominated areas, where

pork consumption is relatively scarce, the seroprevalence

was much lower at 2%.

ere have been no reports

of genotype 1, 2, or 3 in Indonesia suggesting that the

prevalent genotype may be genotype 4, likely due to

zoonotic transmission from swine.

In Singapore, studies on the seroprevalence or

genotype of HEV do not exist based on our search criteria.

However, the incidence rate of cases is very low at 0.92

per 100,000 people between 2009-2011.

Such a low

incidence rate is likely related to the fact that Singapore

is the most developed country in Southeast Asia, which

typically comes with good hygiene and well-funded

public health programs.

In the Philippines, a recent study found that the

swine carry genotype 3 exclusively.

In the river water,

HEV RNA was detected and samples were all found

to be genotype 3.

However, we could not nd any

seroprevalence or genotype reports on HEV in humans.

ere were no or very limited HEV epidemiology

data from Brunei and Timor-Leste. However, in Timor-

Leste, HEV is likely still endemic.

The seroprevalence of HEV in humans is still unknown in

most areas of Southeast Asian countries. e seroprevalence

in the region may be between 17% in Laos to 42% in

Ho Chi Minh City, Vietnam (Figs 1, 2, and 3).

Wasuwanich et al.

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261

Review Article

SMJ

Fig 1. Map of hepatitis E virus genotype distribution

found in humans in Southeast Asia.

Fig 3. Seroprevalence of hepatitis E virus in humans

in Southeast Asia.

Fig 2. Map of hepatitis E virus genotype distribution

found in swine in Southeast Asia.

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262

Complications and consequences

In the general population, the complications of HEV

are typically moderate such as fatigue, vomiting, and

jaundice.

However, in certain groups, the complications

can be severe. In people with chronic liver diseases, acute-

on-chronic liver failure, a serious condition with high

short-term mortality, can occur as a result of genotype

1 HEV infection.

In pregnant women, high morbidity

and mortality for both the mother and the fetus have

been reported. A study in 2007 on pregnant women in

India reported a mortality rate of 41% of those infected

with HEV compared to 7% of those non-infected.

at study also reported 54% of births from women

infected with HEV were stillbirths compared to 1% in

non-infected women.

Hepatitis E is generally an acute

disease, however, in populations with a compromised

immune system such as organ transplant recipients or

HIV populations, the disease can become chronic.

54-56

In Southeast Asia, studies on the eects of HEV on

these vulnerable groups are lacking. A study by Rein et

al. estimated the burden of HEV in one year, 2005, in

Southeast Asia to be 1,984,235 incident infections, 357,086

symptomatic cases, 7,347 deaths, and 148 stillbirths.

Rein

et al., however, only explored genotypes 1 and 2 of HEV,

thus, their report of burden are likely underestimates.

Diagnosis

Clinically, hepatitis E is practically indistinguishable

from infection from other hepatitis virus such as

hepatitis B and C. us, condent diagnosis of hepatitis

E requires serological tests. Antibody assays for anti-

HEV immunoglobin M and anti-HEV immunoglobin

G and nucleic acid assays for HEV RNA in blood are

commonly used in hepatitis E diagnosis.

Ideally, all

three tests are done for a comprehensive evaluation,

however, resources in many Southeast Asian countries

may be too scarce to permit this. e reverse transcriptase

polymerase chain reaction for HEV RNA is the most

resource intensive, but it is a direct method for detecting

HEV and can provide information on whether a patient

has a current infection. HEV RNA can be detected in

feces as well, but this method is not commonly used.

Antibody assays for anti-HEV immunoglobin M and

anti-HEV immunoglobin G, such as the Wantai assays by

Beijing Wantai Pharmacy Enterprise Co., Ltd. (Beijing,

China), are relatively inexpensive, simple to use, and

both high in sensitivity and specicity.

59,60

Anti-HEV

immunoglobin M and anti-HEV immunoglobin G are

indirect methods for detecting HEV. e presence of

anti-HEV immunoglobin M indicates either current

or recent infection of up to approximately 5 months

prior.

61,62

e presence of anti-HEV immunoglobin G

indicates a distant past infection of up to 14 years prior

in some reports.

One of the facilities able to test for

HEV, both the antibody and the RNA, is the Armed

Forces Research Institute of Medical Sciences (AFRIMS)

which have centers in many Southeast Asian countries,

especially ailand.

Recently, new assays were developed by Pisanic et

al. for detecting anti-HEV immunoglobin A (for current

or recent infection) and anti-HEV immunoglobin G in

saliva. e study showed high sensitivity and specicity

for anti-HEV immunoglobin G and low sensitivity but

high specicity for anti-HEV immunoglobin A.

Because

these assays are non-invasive and also inexpensive and

rapid like the Wantai assays, they have the potential to

be useful for HEV screening.

Vaccination

Since 2012, there exists an approved recombinant

HEV vaccine called HEV 239 or Hecolin developed

by Xiamen Innovax Biotech in China.

However, it is

currently only approved for use in China. e vaccine was

designed to protect against HEV genotype 1; however,

a phase 3 clinical trial demonstrated its eectiveness

in protecting against genotype 4 as well.

e study

reported an ecacy of 100% against HEV genotypes 1

and 4 over a 12-month period.

However, there is no

data on Hecolin’s eectiveness in protecting against

genotypes 2 and 3. e vaccine has been shown to be

eective for at least 4.5 years for 87% of healthy adults.

Because the burden of HEV across Southeast Asia is

unclear, the need to evaluate Hecolin for domestic use

is also unclear.

CONCLUSION

HEV genotype 1, which has been typically associated

with South Asian countries, does not appear to be prevalent

in Southeast Asia based on genotyping studies. All genotypes

except for genotype 2 have been reported in Southeast

Asia. However, this data and the data on seroprevalences

were not ideal as the studies were oen outdated or had

limited populations of study. Large, national studies or

surveillance programs are few. As the seroprevalence

of HEV remains high throughout Southeast Asia and

the impact of HEV could be signicant, surveillance

programs for HEV should be implemented.

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Mathuwan Srikong, M.S.*, Panita Wannapiroon, Ph.D.*

*Medical Education Technology Center, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, **Division of Information and Communication

Technology for Education, Faculty of Technical Education, King Mongkut’s University of Technology North Bangkok, ailand.

Immersive Technology for Medical Education:

Technology Enhance Immersive Learning

Experiences

ABSTRACT

Immersive Technology was a trend of the interesting technology in presentation, demonstration, imitation.

ese techniques could be used in medical education. is article would present immersive technology knowledge

which consisted of Augmented Reality (AR), Virtual Reality (VR) and Mixed Reality (MR). Immersive technology

could also be applied to medical education in 5 parts such as Treatment, Education, Rehabilitation, Training,

Surgery, and equipment for medical education media development.

Keywords: Immersive technology; virtual reality; augmented reality; mixed reality; immersive learning experience

(Siriraj Med J 2020; 72: 265-271)

Corresponding author: Mathuwan Srikong

E-mail: mathuwan.sri@mahidol.edu

Received 13 November 2019 Revised 27 March 2020 Accepted 30 March 2020

ORCID ID: http://orcid.org/0000-0003-0150-596X

http://dx.doi.org/10.33192/Smj.2020.36

INTRODUCTION

e rapid development of technology takes part in

the daily life and technology for changes, opportunities,

a new relationship (is article will tell about immersive

technology.), the development of assessment, connection,

imitation of 3-dimensional graphics to classroom to

promote the virtual learning by using many instruments.

Applying the virtual technology to education urges learners

to analyze, solve problems and enhance skills especially

for; Immersive Technology for Medical Education. is

technology can increase eciency in learning such as

anatomy which is dicult and complicated. Learners can

understand and decide eectively which can decrease the

mistakes and boost prociency in learning. Immersive

technology for medical education is an application of

wireless network in classroom or laboratory. Learners

can gain experience, urge their attention in virtual

condition. is technology is also the creative design

for the development of medical education.

Meaning of immersive technology

Immersive Technology means experiences and

reactions of Virtual Reality (VR). is technology is an

important approach that takes parts in the publication

of knowledge in science for nonscientists and motivates

students to the laboratory. It can change the processes

of working in the laboratory and urge development in

science.

Impression in technology (immersive technology),

this technology can apply technology to 3-dimensional

dierent data such as Virtual Reality (VR) and Augmented

Reality (AR) for providing 3-dimensional conditions on

the computer. Learners can understand the immersive

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266

objects in the real world.

Impression in the attention

of technology in real-world and virtual conditions.

Impression of technology consists of Virtual Reality

(VR), Augmented Reality (AR) and Mixed Reality (MR).

Learners can apply this technology to react and control.

e continuity of immersive and physical condition

depends on the levels of immersive condition. Learners

can learn through virtual digital content to practice risky

situations in the classroom and laboratory under safe

conditions.

Instruments for immersive technology can

train basic knowledge automatically without pressures

from patients.

In conclusion, immersive technology means imitation

the virtual instruments in a real situation that can show

on the computer. is technology applies Virtual Reality

(VR), Augmented Reality (AR) to Mixed Reality (MR).

It can create an impressive experience to urge attention

which can react and control this immersive situation.

Immersive technology

Immersive technology is a technology in the virtual

world that is quite similar to the real world. Immersive

Technology cover to AR, VR and Mixed Reality (MR).

Kinds of immersive technology

Augmented Reality (AR)

Augmented Reality is a form of Virtual Environment

(VE) in the synthesized condition. Augmented Reality

(AR) is the increase of realistic things more than virtual

reality. AR will imitate the virtual objects then overlap

them to the real objects which are in the same area.

e

activation of technology in real-world and immersive

world purposes to create the perfect new condition

from computer.

e view of physical condition and the

real world can be edited by adding more information

about the reality of each person from the computer.

is information may be applied to create experience

for each person in real condition.

It is the modern

technology that has various displays such as message,

number, alphabets, symbol or graphic as well as the view

of users in the real world. e augmented reality has the

real-time relationship to the immersive condition.

As a result, In AR objects are enhanced in the

interactive experience compared to in standard virtual

reality.

Virtual Reality (VR)

Virtual Reality is a condition that is created by

soware then present to users. is kind of reality will

imitate the steps of operation in real-time processes.

Virtual Reality (VR) can be used to demonstrate the

steps of operation by using the computer to train, show

the models of anatomy and many processes of operation

from stereo laparoscopy. e forms of Virtual Reality –

Internet of ing (VR-IoT) will increase in the future

because they can apply the capacities in the real world.

Virtual reality can be created by 3-dimensional computers.

It consists of reection of real-world to make objects to

be similar to real objects and it also improves processes

then applies to the teaching materials, learning as well

as medical training.

Virtual Reality is a model in the

synthesized condition to create a real-time virtual world

by using computer graphics. is system can react in

many ports in censor perception then react to users

in gestures and commands. e important factor of

virtual reality is to record the data of users then create

the virtual world immediately. It is the reacted graphic

connection.

Mixed Reality (MR)

Mix reality is the combination of elements and

perception between the physical and digital worlds.

is

reality will be impressive when it combines Augmented

Reality (AR) and Virtual Reality (VR). AR is the combination

of synthesis and realism then blends the physical world

to data in the computer. Users can know, react to the

condition. Virtual Reality (VR) is the immersive reality

from the computer which may not related to the real

world.

e combination of reality will combine the

Augmented Reality (AR) and Virtual Reality (VR) in

application which can be edited in the real world. ere are

many ways of combination between Augmented Reality

(AR) and Virtual Reality (VR) in an application.

Mix

Reality (MR) is the combination of 2 kinds of technology:

Augmented Reality (AR) can add more information to

the experience in real-world and Virtual Reality (VR)

will imitate the situation from computer to urge users

to experience.

In conclusion, Mixed Reality (MR) combines 2

realities such as Augmented Reality (AR) and Virtual

Reality (VR). It imitates the condition which is overlaps

by synthesized objects in the same area.

Elements of Immersive Technology

Immersive technology consists of these elements.

Immersion is an impressive experience. Users will wear

a headphone kit which is designed to protect the light

outside the room. Stereoscopic vision will imitate 3D

vision. Motion capture, this feature will capture the

users’ motion accurately.

e virtual world will imitate

the area by using the computer to be similar to the

situation in the real-world then imitate the physical and

Srikong et al.

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267

Review Article

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Fig 1. Simplied representation of the Augmented Reality (AR),

Virtual Reality (VR) and Mixed Reality (MR)

By: Mathuwan Srikong

mental condition of being in the virtual world. Sensory

feedback, this feature will give feedback according to

physical positions. Interactivity will work when the system

reacts to users.

is part will work when the system

connects Head Mounted Display (HMD), Headphones

for sound to the system for headphones and decreasing

noise. Applying immersive technology in 3D condition

will experience users to impress in the virtual world.

Elements of soware will be dierent in the virtual

environment and the real environment.

Immersive Learning Experience

Technology in education began to focus on the

Augmented reality (AR) and Virtual Reality (VR) because

of the ability to support immersive learning teamwork and

teaching through treatment to interact with the computer.

It is used in various types of training programs and is

especially useful for the participation and motivation of

learners. It is an eective technology to support learning.

To enhance the learning experience can be applied to

medicine from a study of Immersive Learning Experiences:

Technology-Enhanced Instruction. Users report increased

engagement with informal learning environments.

the study of immersive learning for enhanced organic

chemistry instruction, the system design and development

with immersive and immersive virtual reality technology for

teaching organic chemistry in the environment encourage

participation, motivation and high interest within an

immersive environment, users are disengaged from

physical disturbances and systems and can, therefore,

be useful for resolving important problems of student

participation.

In the study of caregiving between careers

and the development of communication abilities in the

healthcare professional curriculum through realistic,

realistic experiences participants have learned positively,

feel their status and show empathy through immersive

experiences. Understand technology and want to learn in

an environment that is updated with technology. ere

is an increased awareness of learning through virtual

reality.

erefore, Immersive technology learning is the

application of technology to create immersive learning

experiences for future studies.

Applying Immersive Technology to Medical Science

is part will tell about the latest development and

challenges in the future of Mix Reality (MR) which is

interesting to medical science development. ere are

5 forms of applying immersive technology to medical

science

as following;

Treatment

e advantage in medical science: Educational

virtual reality videos in improving bowel preparation

quality and satisfaction of outpatients undergoing

colonoscopy: protocol of a randomized controlled trial.

e protocol of research was randomized experiment.

e result found that virtual reality video could imitate

the experience of intestine preparation improvement

to patients. Virtual Reality (VR) could enhance their

concentration and result. Moreover, it reduced the

patients’ anxiety before operation.

but its ecacy is

closely related to the quality of bowel preparation. Poor

patient compliance is a major risk factor for inadequate

bowel preparation likely due to poor patient education.

Such an education is usually provided via either oral or

written instructions by clinicians. However, multiple

education methods, such as smartphone applications,

have been proved useful in aiding patients through

bowel preparation. Also, it was reported that a large

proportion of patients feel anxious before colonoscopy.

Virtual reality (VR Mix reality (MR) usually applied to the

operating system. However, there were some complicated

medical instruments. is limitation could decrease the

prociency and it is not suitable for the operation in real

situations. Doctors identied the position of wounds

from virtual reality which was the combination of the

operation by virtual images from recording data and

operation in real situations. is approach analyzed the

position of wounds before operation. It reduced the risk

and improved the security in operation.

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Education

The advantage in medical education: Applying

the virtual reality in medical education. is project

was successful in applying the invention for physical

therapists and nursing curriculum. e result found

that Virtual Reality (VR) was a part that could help

students to understand some symptoms related to age

and it could increase the attention to elderly persons in

vision and Alzheimer’s disease.

Rehabilitation

e advantage in rehabilitation for medical science:

Connection in medical science to Virtual Reality (VR) and

Augmented Reality (AR). is work was a combination

of Augmented Reality (AR) and Virtual Reality (VR).

Specialists used 2D and 3D data for analyzing the operation

and communicating between specialists and patients.

Case study: Planning for dental implantation by using

Augmented Reality (AR) in mobile phones and tablets

for dental students. e processes was shown in a display

above the patient’s head. Endoscopy operation could

combine the surgeries’ hands to show the positions in

anatomy and Augmented Reality (AR) could restore

patients in therapy by physical therapists. Patients could

give comments to this system.

Designing the virtual

system to enhance the emotional skill for autism spectrum

disorder children purposed to check whether their faces

were appropriate to each situation. ese children would

be evaluated skills which they practiced in Virtual Reality

(VR) to the real world. e result found that skills which

they practiced in Virtual Reality (VR) could transfer to

the real world and their progression was developed when

they did not use Virtual Reality (VR).

Training

Study of eect of cataract operation to the errors aer

cataract operation by the rst- and second-year trainees.

is research studied the error in the capsule aer lens

during operation which might cause complications; for

example, Retinal detachment during operation which

caused the rate of vision for patients decreased. e result

found that virtual reality in ophthalmology was ecient

to the patients who were done cataract operation. e

rate of complication aer cataract operation decreased

by 38%.

Application of virtual reality in clinical medical

science in training some approaches to manage the

patients’ painfulness and mind symptoms. Virtual Reality

(VR) could increase the patients’ obsession which was

similar to the virtual hypnosis to make patients endure

the painfulness.

e eciency of virtual reality training

in orthopedic surgery approved that Virtual Reality (VR)

was an instrument for the development of orthopedic

surgery techniques.

Surgery

Doctors could use Augmented Reality (AR) as the

instruments for training the surgery which showed the

patients’ view. It was benecial to medical science in the

operation room. ey could check some qualications

by their bared eyes which could not look in MRI or

CT scanning. On the other hand, doctors could use

Augmented Reality (AR) to access data.

e trend of

applying virtual reality and imitating situation was to

use in the operation in the virtual situation from the

computer then transferred it to patients by using Virtual

Reality (VR). Every situation was created by calculating

and Augmented Reality (AR) to overlap the virtual

objects from the computer to give alternative views of

operation. It enhanced the eciency of the operation.

In conclusion, applying immersive technology to

medical science had 5 categories: treatment, education,

rehabilitation, training, and surgery. is technology

could create the virtual situation in dierent contexts.

Instruments for developing immersive in medical

science

At this time, the development of soware in medical

science recognized to the combination of medical

photographing to a more realistic image. 3D structured

objects are important to solving clinical problems. Complex

imitations can be create to show how 3D objects are in

a given situation. In processing, doctors need to have

knowledge of anatomy and physiology as well as relational

and physical qualications. e 3D graphic is the main

element in the accuracy of imitating a 3D image. e

important things for medical science focus on reality and

real-time reaction. Soware package for these calculations

is ANSYS soware kit (Ansys Inc., Canonsburg, PA, United

States). Creating 3D models are done by SOLIDWORKS

soware (Dassault Systems, Concord, MA., United States)

and creating mechanical objects and imitation (Materialize

NV, Leuven, Belgium) for anatomy virtual model.

e most famous instruments for developers for

creating applications are Unity 3D and Unreal engine.

ey can create the immersive model like Virtual Reality

(VR) and Augmented Reality (AR) as following; Unity

3D (Unity Technologies, San Francisco, CA, United

States) e platform which is exible for calculating 3D

graphic is Unity. is application has various instruments

for editing and showing examples in real-time. It is

available ON Windows Mac and Linux for a virtual

experience. is application can use script to develop

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content which can reach each other.

Unreal Engine

(Epic Games, Cary, NC, United States) is a well-known

graphic application. It is not complicated. Moreover, this

application is available for free which is a good thing for

3D graphic development. Basis of this application can

apply to solve the complicated reasoning, presenting

anatomy data in 2D and 3D to help the users to understand

the overall condition while the real-time 3D graphic is

appropriate to the anatomy.

Planning, pre-analysis, advising on the operation and

aer the operation, caring can be seen by 3D microscope

in Augmented Reality (AR) and Virtual Reality (VR) to

encourage the surgeons who purpose to the operation

and anatomy by applying optical navigating system

or electrical magnet to follow the real-time operation

as following; Dextoscope (Braco): processing about

planning the operation and applying AR in 3D objects

and it can react to users. e database will be registered

automatically for creating images. e surface will be

divided to categorize the structure to determine the

relationship in anatomy. Immersive control is easy to

use. It can adjust to display each object to get the best

images. e system uses controller and stylus which

overlap keyboard and mouse which cause the reaction

and management of images to work more accurate.

Interface of image shows the relationship of complicated

anatomy. Dextoscope can create AR stereoscopic in the

3D world by overlapping the 3D analysis image to the

correct position of skin and bones and it can also nd

the position of diseases. HoloSurgical (Chicago, Illinois,

USA): e navigation system for AR and AI operation.

is application can correct the limitations about the

navigation system for operation and AI system. ARAI

uses AR-state-of-the-art to overlap the 3D image in

hologram type for the patients’ anatomy. Doctors can

understand the 3D anatomy structures and complete

patients’ anatomy structures. is system decreases

the complexity of operation. e navigation system

HoloSurgical ARAI will scan before operating with

AI and its algorithm of this application to know the

anatomy structure. VPI Reveal is the 3D creating kit

for medical science data. VPI presents the real-time

volume analysis for CT and MR data in a 3D monitor.

is application is also available on desktop platforms

and mobile phone which is easy to use. VPI Reveal can

work on the dierent processes for 3D scanning by using

any input which doctors use such as the keyboard and

touchscreen mouse. e navigation system and processes

in the 3D monitors are supported by various display

systems then present the patients’ hologram to scan the

data and model. Synaptive Medical (Synaptive Medical

Inc., Toronto, Ontario, Canada) is a platform for applying

to neurosurgery. Neurosurgeons can understand clearly

when they look at the images and nd the possible ways

for neurosurgery. is platform has many ways to work

according to the hand-free combination of accurate MR

images and it shows the real-time structures. It also has a

function that solves the complex reasoning for surgeons

by using 3D images with automatic evaluation and 3D

graphic rendering. As a result, they can plan before the

operation.

Instruments that apply immersive technology in medical

science for medical practitioners

Augmented Reality is the technology which users can

interact between virtual objects and real life. e applications

can provide real experience and virtual objects to users

such as Google Glass, Microso HoloLens because these

objects can overlap to the immersive world. Augmented

Reality (AR) is dierent from Virtual Reality (VR) which

facilitates users to experience a virtual experience such as

Oculus Ri, HTC Vive. e instruments for Augmented

Reality (AR) and Virtual Reality (VR) have the monitors

which have headphones. Headphones can interact between

users and the computer. Microsoft HoloLens is the

headphone kit which will overlap virtual objects to the real

condition of users to have various experiences. According

to the research “Study of Eect for immersive technology

by using Microso HoloLens Anatomical Pathology”,

specialists in this area investigated by wearing HoloLens

kit and command them in the far distance. is program

also provided a real-time diagram, description and voice-

command. 3D primary sample in pathology could be

viewed in hologram. Users could access to the pathologist

for asking advice in their interesting area such as advice

during operation. is advice could apply to improve the

searching in pathology and the slides navigation would

evaluate in pathology.

Another research was “Study of

Result in anatomy in learning to the achievement of the

medical practitioners in the topic: neuroanatomy”. is

research collected virtual objects and approved users to

interact by using mobile phones. Learning via mobile

phones could facilitate students to learn and they could

also access media in every time they wanted to access.

Instruments that apply immersive technology in medical

science for patients

e instrument will present the virtual model of the

laboratory which is developed for patients. Patients will be

operated in angiogram which will use the photographing

system to investigate patients’ blood heart vessels. ey

can know about the processes of operation in virtual

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270

condition, so their fear is decreased. e patients can

interact with the virtual object via the wireless controller.

Doctors introduce patients by using the recorded script.

When patients follow the processes, they will describe

some side eects to patients. Aer that, doctors will ask

patients to put their hand up. Interaction part: is part

will facilitate patients to respond easier by using the

button “trigger” to interact. It is their natural movement

to grab and move objects according to the processes by

doctors. Patients will focus on processes which happen

in the virtual world instead of focusing on the real world.

Design part: Patients will in the virtual condition to see

what they want to interact with. It needs a limited area.

Technique part: e Imitated situation in the laboratory

is developed by Unity game engine, C# programming,

and Autodesk Maya. ey can produce a 3D model in

medical science and there is some equipment to create

a soundtrack.

Example of applying immersive technology to medical

science in ophthalmology

Applying immersive technology to medical science

in ophthalmology, virtual reality (VR) instruments in

retinal surgery and cataract surgery proceeds by using

the 3D microscope in operation. During the imitation

process of the microscope, instruments will be controlled

by a pedal with a virtual interface platform that imitates

retinal surgery and cataract surgery. It starts from basic

surgery to complicated surgery until solving side eects.

Doctors can evaluate, analyze the results of students’

skills according to many indicators then summarize to

scores and announce to them to show their achievement.

ese results can improve the skills according to students’

dierence.

CONCLUSION

Virtual technology is a new strategy in medical science.

is technology will imitate situations that rarely happen

in a clinical experiment. It is a complicated skill which

needs to practice a lot of time until users will be expert

and solve problems according to medical ethics. Doctors

will be more condent in operation. By the way, rapid

development of hardware, soware and programming

skill for immersive media can facilitate doctors to work.

Patients can respond in real-time method and doctors

can apply these responses to the studying in each branch

in medical science.

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