Volume 72, Number 5, September-October 2020

Siriraj Medical Journal

SMJ

ISSN 2629-995XE-ISSN 2228-8082

ORIGINAL ARTICLE

371 A Randomised Controlled Trial of the Efficacy and Safety

of 0.25% Desoximetasone Cream (Topoxy) Compared with

0.25% Desoximetasone Cream (Topicorte) for the Treatment

of Scalp Psoriasis

Chanisada Wongpraparut, et al.

380 Evaluation of Hypotensive Prevention Effect of

Intramuscular Glycopyrrolate in Spinal Anaesthesia of

Elderly TURP Patients: A Randomized Control Trial

Kamoltip Prasopsuk, et al.

386 Incidence and Pattern of Nodal Metastasis in Colon and

Rectal Cancer: a Study of 1012 Cases from Thailand

Varut Lohsiriwat, et al.

391 Effect of Ultrafiltration Rate in Long Interdialytic

Interval Hemodialysis Session versus Average Weekly

Ultrafiltration Rate on Mortality Rate and Adverse

Cardiovascular Outcomes in Maintenance Hemodialysis

Patients

Kornchanok Vareesangthip, et al.

399 Mortality and Prevalence of Falls, and their Association

with Psychiatric Diagnoses and Psychotropic Medications

Nantawat Sitdhiraksa, et al.

407 Retrospective Cohort Study on Effect of Frenulotomy

Techniques on Breastfeeding

Chompoonoot Boonsopa, et al.

415 Active Learning Classes in a Preclinical Year May Help

Improving Some Soft Skills of Medical Students

Korakrit Imwattana, et al.

424 Public Awareness and Attitude toward Palliative Care in

Thailand

Wannapha Kunakornvong, et al.

REVIEW ARTICLE

431 Announcement of the Royal College of Surgeons of

Thailand on Guidance for Surgery in COVID-19 Patients

Paisit Siriwittayakorn

436 Performing Tracheostomy in Intensive Care Unit-

A Challenge during COVID-19 Pandemic

Santosh Kumar Swain

443 The effect of Myoma uteri on Infertility

Paweena Phaliwong

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International Association of Surgeons

Gastroenterologists & Oncologists

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Thai Association for Gastrointestinal

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Indexed by

By Paweena Phaliwong, et al.

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Christopher Khor (Singapore General Hospital, Singapore)

Yasushi Sano (Director of Gastrointestinal Center, Japan)

Mitsuhiro Kida (Kitasato University & Hospital, Japan)

Seigo Kitano (Oita University, Japan)

Ichizo Nishino (National Institute of Neuroscience NCNP, Japan)

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

Dong-Wan Seo (University of Ulsan College of Medicine, Korea)

George S. Baillie (University of Glasgow, UK)

G. Allen Finley (Delhousie University, Canada)

Sara Schwanke Khilji (Oregon Health & Science University, USA)

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Wikrom Karnsakul (Johns Hopkins Children’s Center, USA)

Frans Laurens Moll (University Medical Center Ultrecht, Netherlands)

James P. Dolan (Oregon Health & Science University, USA)

John Hunter (Oregon Health & Science University, USA)

Nima Rezaei (Tehran University of Medical Sciences, Iran)

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Intawat Nookaew (University of Arkansas for Medical Sciences, USA)

Victor Manuel Charoenrook de la Fuente 

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Nam H. CHO (University School of Medicine and Hospital, Korea)

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Vitoon Chinswangwatanakul

(Siriraj Hospital, Mahidol University, ailand)

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371

Original Article

SMJ

Leena Chularojanamontri, M.D., Narumol Silpa-archa, M.D., Pichanee Chaweekulrat, M.D., Chayanee

Likitwattananurak, M.D., Puncharas Weerasubpong, M.D., Natchaya Junsuwan, M.D., Norramon Charoenpipatsin,

M.D., Chanisada Wongpraparut, M.D.

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

A Randomised Controlled Trial of the Efcacy and

Safety of 0.25% Desoximetasone Cream (Topoxy)

Compared with 0.25% Desoximetasone Cream

(Topicorte) for the Treatment of Scalp Psoriasis

ABSTRACT

Objective: To compare the ecacy and safety of a generic desoximetasone cream (Topoxy) with the reference form,

Topicorte, for the treatment of scalp psoriasis.

Methods: A randomised, double-blind, controlled study was conducted. Altogether, 105 patients with psoriasis

lesions covering more than 10% of the scalp were randomised into three groups. e rst, second and third groups

received a placebo, Topoxy and Topicorte, respectively. e scalp psoriasis severities were assessed at weeks 0, 2, 4

and 8, using the Investigator Global Assessment (IGA) scale and Total Sign Score (TSS). e safety proles of the

products were assessed by the patients and physicians.

Results: Topoxy and Topicorte were signicantly more eective than the placebo in achieving at least a two-grade

improvement in the IGA score from baseline at weeks 2, 4 and 8, and there were no signicant dierences between

Topoxy and Topicorte. e TSS of both creams were signicantly lower than that of the placebo at weeks 2, 4 and

8. All patients tolerated well to the therapy.

Conclusion: Topoxy and Topicorte had comparable ecacies for scalp psoriasis. e medications were superior

to the placebo in all parameters, and had a good safety prole.

Keywords: Desoximetasone cream; scalp psoriasis; topicorte; topoxy (Siriraj Med J 2020; 72: 371-379)

Corresponding author: Chanisada Wongpraparut

E-mail: chanisada@hotmail.com

Received 30 August 2019 Revised 19 March 2020 Accepted 20 March 2020

ORCID ID: http://orcid.org/0000-0002-9014-3229

http://dx.doi.org/10.33192/Smj.2020.50

INTRODUCTION

Psoriasis is a chronic, immune-mediated, skin

condition that is caused by an abnormal proliferation

and dierentiation of the epidermis. It aects 2%–3%

of the global population, depending on the geographic

area being studied.

Scalp psoriasis is found in up to 80%

of psoriasis patients, and it proves to be troublesome

and frustrating to most patients.

It is characterised by

erythematous plaques with silvery scales that cause itching

and discomfort.

Scalp psoriasis is generally hard to treat

because the aected areas are mostly covered with hairs,

which act as a physical barrier to topical medications.

e medications currently used to treat scalp psoriasis are

topical corticosteroids, topical vitamin D analogues and

tar shampoo.

Monotherapy with a topical steroid has

proven to be acceptable for use as a short-term therapy

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372

Chularojanamontri et al.

for scalp psoriasis.

Topical moderate- to high-potency

corticosteroids such as 0.05% clobetasol propionate,

0.25% desoximetasone, 0.1% betamethasone valerate and

0.05% betamethasone dipropionate are recommended for

adult patients.

Cutaneous side eects of topical steroids

on the scalp are rare.

5-7

Some of the reported adverse

eects are skin discomfort, irritation, skin atrophy and

telangiectasia.

e topical corticosteroid desoximetasone is used for

scalp psoriasis because of it has high ecacy with limited

side eects.

9-11

Several formulations of the medication are

available in the market. Topical 0.25% desoximetasone

cream (Topicorte) is the reference form and is widely

used. Recently, a generic formulation of the 0.25%

desoximetasone cream, Topoxy, has been developed.

However, Topoxy is relatively new, and its ecacy and

safety have never been tested in a randomised control trial.

erefore, we conducted the present study to compare

the ecacy and safety of 0.25% desoximetasone cream,

Topoxy, with the reference form, Topicorte.

MATERIALS AND METHODS

Study design

A double-blinded, randomised, and placebo- and

active comparator-controlled drug trial was conducted

October 2016 to December 2018 at the Department of

Dermatology, Faculty of Medicine Siriraj Hospital, Mahidol

University. e trial was registered with ClinicalTrials.

gov identication number NCT02749656. Patients were

randomised into 3 groups using GraphPad Prism 5.00

for Windows (GraphPad Soware, San Diego, CA). e

rst group received a placebo with tar shampoo; the

second received Topoxy with tar shampoo; and the third

was given Topicorte with tar shampoo. Patients were

requested to apply the scalp cream twice daily with the

recommended dosage of 1 ml or 3.5 grams of product

per ten percent of total area of scalp aected and to use

the tar shampoo regularly.

Subjects

is study enrolled 105 scalp psoriasis patients. e

inclusion criteria were as follows: being over 18 years of

age; having had a dermatologist give a diagnosis of scalp

psoriasis with more than 10% of the scalp involved; and

having mild to severe scalp psoriasis, according to the

Investigator Global Assessment (IGA) scale, scoring a

moderate-to-severe severity for at least one parameter out

of redness, thickness or scaling.

e washout periods

were 2 weeks for topical therapy; 2 weeks for phototherapy

(narrow-band ultraviolet B or psoralen plus ultraviolet

A); 4 weeks for oral systemic agents (methotrexate,

acitretin and cyclosporine); and 6 months for biological

agents. e exclusion criteria consisted of having a skin

infection or skin atrophy on the scalp; currently receiving

medications that might aect psoriasis (such as beta-

blockers, antimalarial drugs or lithium); being pregnant

or lactating; being unable to attend follow-up visits;

having communication problems; or having a history of

an allergic reaction or hypersensitivity to desoximetasone.

e withdrawal or termination criteria comprised a patient

being unwilling to continue to participate, missing more

than 2 follow-up visits, or having an allergic reaction to

the Topoxy or Topicorte cream. All patients gave their

written informed consents prior to participating in the

study.

Assessments

e scalp lesions were assessed by two dermatologists

at weeks 0, 2, 4 and 8 using IGA, the Total Sign Score

(TSS) and the area of scalp involved. With the IGA

score, the following labels were assigned: 0, absence

of disease; 1, very mild disease with only mild redness;

2, mild disease with evident redness along with mild

thickness and scaling; 3, moderate disease with evident

redness, thickness and scaling; 4, severe disease with

inammatory erythematous plaques along with severe

thickness and scaling; and 5, very severe disease with

severe inammatory erythematous plaques.

e TSS

was derived from the summation of the scores for the

severity of redness, thickness and scaling.

Each parameter

was graded on a scale of 0 - 4, with 0 representing no

signs and 4 signifying severe signs. In cases of discordant

assessments by the 2 dermatologists, an assessment by

a third blinded dermatologist was requested to reach a

consensus. In addition patients assessed their disease

severity using the Patient Global Assessment (PGA) at

weeks 0, 2, 4 and 8.

e PGA score is graded using the

same scale as the IGA score (range, 0-4), but it diers in

that the PGA score is determined by patients rather than

medical sta. e ecacy of the results of the various

grading systems (IGA, PGA, redness score, thickness

score, and scaling score) were assessed based on the

percentage of patients achieving a response of at least a

2-grade improvement from week 0.

Safety was assessed by monitoring patients’ side eects,

such as skin discomfort and irritation. Skin atrophy and

telangiectasia were assessed by physicians. Photographs

were taken at weeks 0 and 8. Patients were asked to

bring their bottles of Topoxy or Topicorte cream to

each follow-up visit; the amount of cream that was le at

each visit was measured to assess the levels of treatment

compliance.

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373

Original Article

SMJ

Statistical analysis

Ecacy analysis

e patients’ baseline characteristics (gender, underlying

disease, family history of psoriasis, and smoking and

alcohol-drinking habits) and the percentage of patients

who achieved at least a 2-grade improvement in IGA,

PGA, redness, thickness and scaling were presented as

n (%) and were analysed using Fisher’s exact test or the

Chi-square test. e patients’ baseline characteristics

(age and duration of scalp psoriasis), TSS and area of

scalp involved were presented as medians (minimum,

maximum) and analysed using the Kruskal - Willis test.

Dierences were further analysed using the pairwise

comparison method, with signicance values adjusted

by the Bonferroni correction for multiple tests. A p value

of less than .05 was selected as the signicance level for

all statistical analyses.

Safety analysis

e safety parameter was described as the percentage

of patients who experienced side eects, and it was

analysed using Fisher’s exact test or the Chi-square test.

A p value of less than .05 was deemed to be statistically

signicant.

RESULTS

Patient disposition

In all, 105 scalp psoriasis patients were randomised

equally into three groups. e rst group received a

placebo with coal tar shampoo (n = 35), the second

group was given Topoxy with the tar shampoo (n = 35),

while the third group was administered Topicorte with

the tar shampoo (n = 35). Overall, 94.2% (n = 33) of the

patients in the rst group, 94.2% (n = 33) in the second

group and 94.2% (n = 33) in the third group completed

the study. Of the 99 patients who completed the study, 90

attended all four follow-up visits, while the remaining 9

patients had either two or three visits. Six patients (two

from each group) were lost to follow up. Fig 1 (the study

ow chart) illustrates the ow of participants through

the study.

Patient demographics and baseline characteristics

e demographic data were compared across the

three treatment arms (Table 1). Female was found in 66.7%,

51.5%, and 36.4% of patients in e topoxy-with-tar-

shampoo treatment group, the placebo-with-tar-shampoo

treatment group, and the Topicorte-with-tar-shampoo

treatment group respectively. e median ages of the three

groups ranged between 35 and 50 years. e durations

of the scalp psoriasis ranged from 4 to 5 years. e

most common underlying disease among each group

was hypertension. e baseline disease characteristics

(Table 2) were compared across the treatment arms.

Most patients in each group had a baseline IGA score

of either 3 or 4; a PGA score of either 3 or 4; a redness

score of either 2 or 3; a thickness score of either 2 or

3; and a scaling score of either 2 or 3. e median TSS

of each group ranged from 7 to 8 (range, 2-11). e

median of the percentage of the scalp involved was

50% (range, 10%-100%) for each group. ere were no

statistical dierences between any of the baseline disease

characteristics of the 3 groups.

Ecacy (Table 3)

IGA of disease severity: The Topoxy-with-tar-

shampoo treatment and the Topicorte-with-tar-shampoo

treatment were signicantly more eective than the

placebo-with-tar-shampoo therapy in achieving at least a

two-grade improvement from the baseline IGA score at

week 2 (p=.002) and week 4 (p=.007), with no dierences

between Topoxy and Topicorte. At week 8, Topoxy was

signicantly more eective than the placebo in achieving

at least a two-grade improvement from the baseline IGA

score (p=.013).

PGA of disease severity: e Topicorte-with-tar-

shampoo therapy was signicantly more eective than

the placebo-with-tar-shampoo treatment in achieving

at least a two-grade improvement from the baseline

PGA score at week 2 (p=.05). Topicorte and Topoxy

were signicantly more eective than the placebo in

achieving at least a two-grade improvement from the

baseline PGA score at week 4 (p=.004)

Redness score: The Topoxy-with-tar-shampoo

treatment and the Topicorte-with-tar-shampoo therapy

were signicantly more eective than the placebo-with-

tar-shampoo treatment in achieving at least a two-grade

improvement from the baseline redness score at week

2 (p=.014), with no dierences between Topoxy and

Topicorte.

ickness score: At week 2 and week 8, the Topoxy-

with-tar-shampoo therapy was significantly more

eective than the placebo-with-tar-shampoo therapy

in achieving at least a two-grade improvement from the

baseline thickness score (p=.018 for week 2, and .025

for week 8). At week 4, the Topoxy-with-tar-shampoo

treatment and the Topicorte-with-tar-shampoo therapy

were signicantly more eective than the placebo-with-

tar-shampoo treatment (p=.004), with no dierences

between Topoxy and Topicorte.

Scaling score: e Topoxy-with-tar-shampoo therapy

was signicantly more eective than the placebo-with-

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374

Chularojanamontri et al.

Fig 1. Flow of participants in a randomised clinical trial of 0.25% desoximetasone cream (Topoxy) compared with 0.25% desoximetasone

cream (Topicorte) and a placebo.

105 patients assessed for eligibility and randomized

35 randomized to received placebo

+ 35 randomized to receive Topoxy + 35 randomized to receive Topicorte +

tar shampoo tar shampoo tar shampoo

2 discontinued intervention after first 2 discontinued intervention after first 2 discontinued intervention after first

visit as lost to follow-up visit as lost to follow-up visit as lost to follow-up

33 included in efficacy and safety

33 included in efficacy and safety 33 included in efficacy and safety

ana

lysis analysis analysis

TABLE 1. Summary of patients’ baseline demographic characteristics.

Patient characteristics Placebo Topoxy Topicorte P-value

(n = 33) (n = 33) (n = 33)

Age, years 35 (19, 66) 50 (21, 90)* 46 (20, 72) .027

Female gender 17 (51.5%) 22 (66.7%)** 12 (36.4%) .048

Duration of scalp psoriasis, years 5 (0.25, 21) 5 (0.08, 37) 4 (0.08, 20) .739

Underlying disease

Hypertension 5 (15.2%) 9 (27.3%) 6 (18.2%) .443

Dyslipidemia 4 (12.1%) 7 (21.2%) 3 (9.1%) .445

Diabetes mellitus 5 (15.2%) 4 (12.1%) 0 (0%) .072

Obesity 1 (3.0%) 2 (6.1%) 4 (12.1%) .496

Renal disease 1 (3.0%) 0 (0%) 1 (3.0%) 1.000

Malignancy 0 (0%) 0 (0%) 1 (3.0%) 1.000

Family history of psoriasis 7 (21.2%) 6 (18.2%) 6 (18.2%) .937

Current smoker 2 (6.1%) 3 (9.1%) 3 (9.1%) 1.000

Current alcohol drinker 8 (24.2%) 4 (12.1%) 5 (15.2%) .397

*diered signicantly comparing to the placebo group; **diered signicantly comparing to the Topicorte group

p value for gender, underlying disease, family history of psoriasis, current smoker, and current alcohol drinker were analyzed using Fisher’s

exact test or the Chi-square test. p value for age and duration of scalp psoriasis were analyzed using Kruskal–Willis test. Dierences were

further analysed using the pairwise comparison method, with signicance values adjusted by the Bonferroni correction for multiple tests.

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Original Article

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TABLE 2. Summary of patients’ baseline disease characteristics.

Baseline disease characteristics Placebo Topoxy Topicorte P-value

(n = 33) (n = 33) (n = 33)

IGA, n (%) .220

0 0 (0%) 0 (0%) 0 (0%)

1 0 (0%) 1 (3%) 2 (6.1%)

2 2 (6.1%) 5 (15.2%) 9 (27.3%)

3 16 (48.5%) 13 (39.4%) 11 (33.3%)

4 14 (42.4%) 14 (42.4%) 11 (33.3%)

5 1 (3%) 0 (0%) 0 (0%)

PGA, n (%) .437

0 0 (0%) 1 (3%) 0 (0%)

1 0 (0%) 1 (3%) 2 (6.1%)

2 3 (9.1%) 7 (21.2%) 4 (12.1%)

3 13 (39.4%) 15 (45.5%) 15 (45.5%)

4 14 (42.4%) 9 (27.3%) 10 (30.3%)

5 3 (9.1%) 0 (0%) 2 (6.1%)

Redness, n (%) .797

0 0 (0%) 0 (0%) 1 (3%)

1 8 (24.2%) 4 (12.1%) 7 (21.2%)

2 12 (36.4%) 16 (48.5%) 13 (39.4%)

3 12 (36.4%) 13 (39.4%) 11 (33.3%)

4 1 (3%) 0 (0%) 1 (3%)

Thickness, n (%) .139

0 0 (0%) 1 (3%) 0 (0%)

1 4 (12.1%) 6 (18.2%) 9 (27.3%)

2 17 (51.5%) 10 (30.3%) 16 (48.5%)

3 11 (33.3%) 16 (48.5%) 7 (21.2%)

4 1 (3%) 0 (0%) 1 (3%)

Scaling, n (%) .151

0 0 (0%) 0 (0%) 0 (0%)

1 2 (6.1%) 4 (12.1%) 5 (15.2%)

2 11 (33.3%) 5 (15.2%) 14 (42.4%)

3 17 (51.5%) 19 (57.6%) 10 (30.3%)

4 3 (9.1%) 5 (15.2%) 4 (12.1%)

Total sign score 7 (4, 11) 8 (2, 10) 7 (3, 11) .175

Area of scalp involvement (%) 50 (10, 100) 50 (10, 100) 50 (10, 100) .889

Abbreviations: IGA, Investigator Global Assessment; PGA, Patient Global Assessment

p value for IGA, PGA, Redness, ickness, and scaling were analyzed using Fisher’s exact test or the Chi-square test. p value for Total Sign

Score and Area of scalp involvement were analyzed using Kruskal–Willis test. Dierences were further analysed using the pairwise comparison

method, with signicance values adjusted by the Bonferroni correction for multiple tests.

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Chularojanamontri et al.

TABLE 3. Treatment ecacy shown by number and percentage of patients achieving a response of at least a 2-grade

improvement from week 0 for their IGA score, PGA score, and scalp psoriasis signs (redness, thickness and scaling),

and the median of the Total Sign Score and percentage of area of scalp involvement.

Week 2

Placebo Topoxy Topicorte P-value

(n = 32) (n= 32) (n = 33)

IGA 5 (15.6%) 17 (53.1%)* 17 (51.5%)* .002

PGA 8 (25.0%) 12 (37.5%) 18 (54.5%)* .050

Redness 1 (3.1%) 8 (25%)* 10 (30.3%)* .014

Thickness 4 (12.5%) 14 (43.8%)* 12 (36.4%) .018

Scaling 5 (15.6%) 16 (50.0%)* 13 (39.4%) .013

Total Sign Score 5 (1, 11) 3 (0, 8)* 3 (0, 8)* <.001

Area of scalp involvement (%) 40 (5, 100) 20 (0, 90)* 15 (0, 100)* .021

Week 4

Placebo Topoxy Topicorte P-value

(n = 32) (n= 32) (n = 33)

IGA 9 (28.1%) 20 (64.5%)* 19 (59.4%)* .007

PGA 11 (34.4%) 22 (71.0%)* 22 (68.8%)* .004

Redness 7 (21.9%) 15 (48.4%) 12 (37.5%) .087

Thickness 6 (18.8%) 18 (58.1%)* 16 (50.0%)* .004

Scaling 9 (28.1%) 18 (58.1%)* 16 (50.0%) .047

Total Sign Score 4.5 (1, 11) 2 (0, 7)* 2 (0, 9)* .001

Area of scalp involvement (%) 25 (1, 100) 9 (0, 90)* 10 (0, 95)* .001

Week 8

Placebo Topoxy Topicorte P-value

(n = 32) (n= 32) (n = 33)

IGA 10 (32.3%) 21 (70.0%)* 16 (50.0%) .013

PGA 15 (48.4%) 21 (70.0%) 23 (71.9%) .102

Redness 6 (19.4%) 13 (43.3%) 10 (31.3%) .130

Thickness 8 (25.8%) 18 (60.0%)* 13 (40.6%) .025

Scaling 10 (32.3%) 19 (63.3%) 15 (46.9%) .052

Total Sign Score 5 (1, 8) 2 (0, 9)* 2 (0, 9) .001

Area of scalp involvement (%) 20 (1, 100) 5 (0, 100)* 5 (0, 90)* <.001

Abbreviations: IGA, Investigator Global Assessment; PGA, Patient Global Assessment

*diered signicantly comparing to the placebo group

p value for IGA, PGA, redness, thickness, and scaling were analyzed using Fisher’s exact test or the Chi-square test. p value for Total Sign

Score and Area of scalp involvement were analyzed using Kruskal–Willis test. Dierences were further analysed using the pairwise comparison

method, with signicance values adjusted by the Bonferroni correction for multiple tests.

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tar-shampoo treatment in achieving at least a two-grade

improvement from the baseline scaling score at week 2

(p=.013), and at week 4 (p=.047)

Total Sign Score: At week 2 and week 4, the Topoxy-

with-tar-shampoo treatment and the Topicorte-with-

tar-shampoo treatment were signicantly more eective

than the placebo-with-tar-shampoo therapy in improving

the median TSS (p<.001 for week 2 and p=.001 for week

4), with no dierences between Topoxy and Topicorte.

At week 8, the Topoxy-with-tar-shampoo therapy was

signicantly more eective than the placebo in improving

the median TSS (p=.001)

Area of scalp involvement: e Topoxy-with-tar-

shampoo treatment and the Topicorte-with-tar-shampoo

treatment were signicantly more eective than the

placebo-with-tar-shampoo treatment in decreasing the

area of scalp involved at week 2 (p=.021), week 4 (p=.001)

and week 8 (p<.001), with no dierences between Topoxy

and Topicorte.

Pictures for each group of the scalp area at baseline

and aer eight weeks of treatment are presented in Fig 2.

Safety evaluation

Table 4 details the side eects experienced by each

treatment arm. In the placebo-with-tar-shampoo treatment

group, 3 (9.4%) patients at week 2 and week 4 and 2 (6.5%)

patients at week 8 reported of having skin discomfort with

no statistical dierence from other groups. Telangiectasia

was reported in 1 (3.3%) patient and 1 (3.1%) patient

from the Topoxy-with-tar-shampoo treatment group

and the Topicorte-with-tar-shampoo treatment group

respectively with no statistical dierence between two

groups and to the placebo-with-tar-shampoo treatment

group. No patients discontinued the treatment because

of the side eects.

Fig 2. Pictures comparing the scalp at baseline and aer eight weeks of treatment for each group. In the placebo group, minimal improvement

was seen aer treatment. In the case of the Topoxy and Topicorte groups, marked reductions in redness and scaling were observed.

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Chularojanamontri et al.

DISCUSSION

Topoxy was proved to be equally eective to the

reference form of desoximetasone cream, Topicorte,

in achieving treatment success by reducing all signs of

psoriasis (redness, thickness and scaling) throughout

the study. By the rst two weeks, all of the parameters

(IGA, PGA, redness, thickness, scaling, TSS and area of

scalp involved) had improved signicantly for both the

Topoxy and Topicorte groups, without any signicant

dierences between the two. Aer four weeks, Topoxy

and Topicorte were statistically signicantly superior to

the placebo for all parameters except the redness score.

ese results proved the ecacies of Topoxy and Topicorte

compared with the placebo. However, the PGA, redness

score and scaling score showed no signicant dierences

between the three groups by treatment week eight. is

might be because topical steroid could lose its ecacy

over time due to the down-regulation of receptor resulting

in the phenomenon called tachyphylaxis.

us, the

short course of corticosteroid treatment with no longer

than 2-4 weeks’ duration is recommended. If symptoms

persist, the re-evaluation of disease is needed.

Rajabi-Estarabadi et al. studied clobetasol lotion in

scalp psoriasis and showed that it could lead to improvement

of symptoms assessed by Psoriasis Severity Index and

decreasing of transepidermal water loss.

However,

because scalp is not the thick skin area such as palms

and soles, therefore, the super potent topical steroid

might not be needed.

Less potent topical steroid such as

desoximethasone was also proved to be eective.

Bagel

et al. studied the desoximetasone topical spray 0.25% in

patients with scalp psoriasis. e results showed that

it could lead to signicant improvement in scalp IGA

and PGA and decreasing of area of scalp involvement

at 4 and 16 weeks aer the product use.

Our results

were in line with previous studies. ese also showed

that several formulations of desoximethasone, whether

spray, or cream such as in our study worked well in scalp

psoriasis.

TABLE 4. Summary of reported side eects from week 2 to week 8 of treatment.

Week 2

Side effects Placebo Topoxy Topicorte P-value

(n = 32) (n = 32) (n = 33)

Skin discomfort, n (%) 3 (9.4%) 0 (0%) 2 (6.1%) .281

Skin atrophy, n (%) 0 (0%) 0 (0%) 0 (0%) –

Telangiectasia, n (%) 0 (0%) 0 (0%) 0 (0%) –

Week 4

Side effects Placebo Topoxy Topicorte P-value

(n = 32) (n = 32) (n = 33)

Skin discomfort, n (%) 3 (9.4%) 0 (0%) 0 (0%) .066

Skin atrophy, n (%) 0 (0%) 0 (0%) 0 (0%) –

Telangiectasia, n (%) 0 (0%) 0 (0%) 0 (0%) –

Week 2

Side effects Placebo Topoxy Topicorte P-value

(n = 32) (n = 32) (n = 33)

Skin discomfort, n (%) 2 (6.5%) 0 (0%) 0 (0%) .210

Skin atrophy, n (%) 0 (0%) 0 (0%) 0 (0%) –

Telangiectasia, n (%) 0 (0%) 1 (3.3%) 1 (3.1%) .768

p value were analyzed using Fisher’s exact test or the Chi-square test. Dierences were further analysed using the pairwise comparison

method, with signicance values adjusted by the Bonferroni correction for multiple tests.

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e Topoxy was found to be acceptable to, and

well-tolerated by, all patients, with none experiencing

skin discomfort. However, one patient in the Topoxy

group experienced telangiectasia, which is a common side

eect of topical steroid use. We also found telangiectasia

in one patient from the Topicorte group.

It should be noted that the ecacies of Topoxy

and Topicorte in our study might be higher than their

ecacies in a real-life situation for 2 reasons. Firstly, tar

shampoo was provided to all groups for ethical reasons.

is shampoo has anti-inammatory and antipruritic

properties that are benecial to the treatment of scalp

psoriasis. ese might have contributed to the relatively

high ecacies of the therapies based on Topoxy and

Topicorte in our study. Secondly, it is generally accepted

that most patients adhere well to treatment when they

are included in a research study. e limitation of this

study is it was conducted in a single centre with a limited

number of patients; the results may therefore not be

generalisable.

CONCLUSION

e ecacies of the Topoxy and Topicorte creams

were comparable, showing their treatment success through

improved results for the grading systems employed (IGA,

PGA, redness score, thickness score, scaling score and

TSS) as well as a decrease in the area of scalp involved

from treatment week 2 to week 8, compared to the

placebo. Both the Topoxy and Topicorte creams were

well tolerated by all patients and had a good safety prole.

ACKNOWLEDGMENTS

We gratefully thank Ms. Orawan Supapueng and

Mr. Suthipol Udompunthurak for their assistance with

the statistical analyses and manuscript preparation.

Funding/nancial support: is work was supported by

SPS Medical Co., Ltd. e funder paid for the expense of

the medication, data collection, and analysis. e funder

had no role in the study design, decision to publish, or

preparation of the manuscript.

Conicts of interest: All of the authors declare that

there are no conicts of interest.

REFERENCES

1. Pariser DM, Bagel J, Gelfand JM, Korman NJ, Ritchlin CT,

Strober BE, et al. National Psoriasis Foundation clinical consensus

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V. Clobetasol propionate shampoo 0.05%: a new option to treat

patients with moderate to severe scalp psoriasis. J Drugs

Dermatol 2004;3:367-73.

9. Kircik L, Lebwohl MG, Del Rosso JQ, Bagel J, Stein Gold L,

Weiss JS. Clinical study results of desoximetasone spray,

0.25% in moderate to severe plaque psoriasis. J Drugs Dermatol

2013;12:1404-10.

10. Cornell RC, Stoughton RB. Six-month controlled study of

eect of desoximetasone and betamethasone 17-valerate on

the pituitary-adrenal axis. Br J Dermatol 1981;105:91-95.

11. Kuokkanen K. Comparison of 0.25% desoxymethasone ointment

with 0.05% uocinonide ointment in psoriasis. Curr Med Res

Opin 1976;4:703-5.

12. Spuls PI, Lecluse LL, Poulsen ML, Bos JD, Stern RS, Nijsten T.

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psoriasis? quantitative evaluation in a systematic review. J

Invest Dermatol 2010;130:933-43.

13. Taheri A, Cantrell J, Feldman SR. Tachyphylaxis to topical

glucocorticoids; what is the evidence? Dermatol Online J 2013;

19:18954.

14. Rathi SK, D’Souza P. Rational and ethical use of topical

corticosteroids based on safety and ecacy. Indian J. Dermatol

2012;57:251-9.

15. Rajabi-Estarabadi A, Hasanzadeh H, Taheri A, Feldman SR,

Firooz A. e ecacy of short-term clobetasol lotion in the

treatment of scalp psoriasis. J Dermatolog Treat 2018;29:111-5.

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380

Kamoltip Prasopsuk, M.D.*, Songwut Prasopsuk, M.D.**, Suppadech Tunruttanakul, M.D.**

*Department of Anesthesiology, **Department of Surgery, Sawanpracharak Hospital, Nakhon Sawan 60000, ailand.

Evaluation of Hypotensive Prevention Effect of

Intramuscular Glycopyrrolate in Spinal Anaesthesia

of Elderly TURP Patients: A Randomized Control

Trial

ABSTRACT

Objective: Spinal anaesthesia is one of the options for patients who need transurethral resection of the prostate

(TURP). However, due to typical patient age, risk factors, and the procedure itself, hemodynamic instability is

common and hazardous. Glycopyrrolate, an anticholinergic drug, has been used in many indications, including in

hypotensive prevention in caesarean section patients undergoing spinal anaesthesia. e study aims to evaluate the

hypotensive prevention eect of the drug in elderly (> 60 years) spinal anaesthesia TURP patients.

Methods: A prospective randomized control trial of 62 elderly patients who needed TURP was conducted from

December 2019 to January 2020. Exclusion criteria were an American Society of Anesthesiologists classication

of more than three, contra-indication for glycopyrrolates, and an inability to take spinal anaesthesia. e primary

testing process was administration of 0.2 milligram (mg) intramuscular glycopyrrolate 15 minutes before spinal

anaesthesia. Data were collected concurrently with hemodynamic parameters, which were recorded as a baseline and

every 5 minutes up to 60 minutes. e analysis was done with both single-measure and repeated-measures analysis.

Results: Hypotensive incidence was signicantly reduced in the glycopyrrolate group (38.7 vs. 74.2%, p-value=0.01)

and showed signicantly decreased use of epinephrine [0.2 (±1.1) vs. 4.55 (±6.0) mg, p-value<0.01). Intravenous

uid and vasopressor requirements were also lower. All hemodynamic parameters were higher in the glycopyrrolate

group, except heart rate.

Conclusion: Intramuscular glycopyrrolate could prevent spinal anaesthesia-related hypotension without a dierence

in heart rate in elderly TURP patients.

Keywords: Glycopyrrolate; hypotensive prevention; TURP; spinal anaesthesia; elderly (Siriraj Med J 2020; 72: 380-385)

Corresponding author: Suppadech Tunruttanakul

E-mail: suppadech_t@spr.go.th

Received 5 April 2020 Revised 6 May 2020 Accepted 27 May 2020

ORCID ID: http://orcid.org/0000-0002-5418-682X

http://dx.doi.org/10.33192/Smj.2020.51

INTRODUCTION

Transurethral resection of the prostate (TURP)

is an eective therapeutic procedure for indication of

benign prostatic hyperplasia (BPH).

Although TURP is

technically a less invasive procedure, sometimes lethal

events can occur either by the process itself or by patient

risk factors. e latter is because BPH usually aicts elderly

patients.

us, the choice of anaesthesia is essential.

Spinal anaesthesia is an attractive option due to the ability

to monitor conscious patients directly. Nevertheless,

vital sign instability is a troublesome procedure-related

unwanted eect.

Hypotension is a frequent procedure-related

hemodynamic change and can lead to many adverse

Prasopsuk et al.

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consequences, even myocardial ischemia.

Sympathetic

blockade aer induction of spinal anaesthesia, which

sequentially decreases systemic vascular resistance and

cardiac output, is its pathophysiology.

4-6

Unintended and

uncorrected hypotension can cause serious consequences,

such as myocardial infarction and even death. Reported

hypotensive incidence among ageing patients was 65-

75%.

6-8

Several preventive strategies were intravenous

ﬂuid administration and vasopressors.

Nevertheless,

TURP-related volume overload can occur and worsen

the condition.

Anticholinergic drugs have been proven to be able

to prevent adverse cardiovascular eects and decrease

secretion during induction of general anaesthesia.

e anticholinergic drug glycopyrrolate has reportedly

high activity for these preventive eects.

Later studies

also showed that giving glycopyrrolate before spinal

anaesthesia could prevent hypotension and bradycardia

in caesarean section

13,14

and in hip arthroplasty patients.

Regarding these benecial eects, we decided to study

this drug in elderly TURP patients to determine whether

it can alleviate harmful hemodynamic eects. Previous

studies reported increased hemodynamic stability using

a combination of neostigmine and glycopyrrolate during

the reversal of anaesthesia.

16,17

We, however, excluded

patients with cardiovascular diseases because there were

also some published arrhythmic consequences of the

drug in this group of patients.

MATERIALS AND METHODS

is study was registered with the ai Clinical Trial

Registry (Identication number: TCTR20191105001)

and approved by the Sawanpracharak Hospital ethics

committee.

BPH patients, who were indicated as needing TURP,

were included if they were more than 60 years old and

decided to do spinal anaesthesia on an elective basis

between December 2019 and January 2020. Patients

were excluded if they had an American Society of

Anesthesiologists (ASA) classication of more than

three, had glycopyrrolate contra-indications (glaucoma,

hyperthyroid, morbid obesity, cardiovascular disease,

pulmonary disease, renal or hepatic dysfunction, and

neuromuscular disease), or were unable to take spinal

anaesthesia.

Eligible patients were randomly allocated in parallel

by computer-generated numbers and the allocations

were sealed in envelopes aer informed consent was

obtained. Both actions were done by a non-clinically

related official. The envelope content was revealed

before the beginning of intervention by another non-

clinically involved investigator. Before spinal anaesthesia

was administered in the intervention group (Group

G), 0.2 milligrams (mg) of glycopyrrolate was given

intramuscularly. e same volume of normal saline was

given as a placebo to the control group (Group C). Both

sets of injections were prepared by the investigator who

opened the envelopes. e anaesthesiologist team that

gave and recorded outcomes were blind to the group

identity during all of the procedures. e study ow is

illustrated in Fig 1.

Collected outcomes were age, ASA classication,

bupivacaine dosage, spinal blockage level, total ephedrine

dosage, total intravenous (IV) volume, estimated blood loss

(EBL), and hemodynamic outcomes. e hemodynamic

outcomes included systolic blood pressure (SBP), diastolic

blood pressure (DBP), mean arterial pressure (MAP),

and heart rate. All hemodynamic parameters, which were

primary outcomes, were recorded as the baseline, every

minute aer spinal anaesthesia for 10 minutes, and then

every 5 minutes for up to 60 minutes. Hypotension was

dened as decreased SBP at least 20% below the patient’s

baseline level, SBP less than 90 mmHg, or DBP less than

60 mmHg.

Sixty-two of the included participants were calculated

to have experienced hypotension: 70% and 27.3% between

drug and placebo groups,

respectively, with adjusted

statistic power to 90% of the two-sided test. Statistical

analysis for single-measure data was calculated with

Fisher’s exact test for categorical data and t-test or Mann-

Whitney U test for continuous data. Repeated-measures

data were analysed with a multilevel mixed-eects linear

regression model. Statistical analysis was performed by

statistical soware. A p-value of <0.05 was considered

to be signicant statistically.

RESULTS

Aer application of the study design, no eligible patient

was excluded, and no patient refused to provide informed

consent. us, 31 patients were distributed equally in

both groups. Table 1 presents the baseline data and the

results of single-measure data. Hypotensive incidence was

signicantly lower in the glycopyrrolate group (38.7 vs.

74.2%, p-value=0.01). With less hypotension, epinephrine

use and the IV volume was also lower in the glycopyrrolate

group [0.2 (±1.1) vs. 4.55 (±6.0) mg, p-value<0.01, and

1.0 (±0.2) vs. 1.1 (±0.3) litre, p-value=0.03].

Regarding repeated-measures data, bar graphs with

standard error are illustrated in Fig 2, and the summary

of statistical analysis results is given in Table 2. e

glycopyrrolate group had signicantly higher values for

all blood pressure parameters. SBP, DBP, and MAP were

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382

Fig 1. Study ow in which 62 patients were assessed for eligibility and eligible subjects were randomized.

Abbreviations: Group G = glycopyrrolate group; Group C = control group; IM = intramuscular

TABLE 1. Baseline data and single-measure outcomes according to study group.

Characteristic Group C Group G P-value

Age (years), Mean (± SD) 69.68 (6.5) 70.9 (8.0) 0.97

Bupivacaine dosage (mg), 2.8 (2.6-3.2) 2.8 (2.6-4) 0.42

Median (Range)

Anaesthesia level, N (%)

T6 11 (35.5) 5 (16.1) 0.24

T8 9 (29.0) 10 (32.3)

T10 11 (35.5) 16 (51.6)

Operative time, Median (Range) 30 (25-55) 40 (25-85) 0.01

EBL (ml), Median (Range) 50 (20-150) 50 (20-100) 0.91

IV uid volume (ml), Mean (± SD) 1,140.3 (297.9) 1,000.0 (204.9) 0.03

Total epinephrine dosage (mg), 4.55 (6.0) 0.2 (1.1) <0.01

Mean (± SD)

Hypotensive incidence, N (%) 23 (74.2) 12 (38.7) 0.01

Abbreviations: Group G = glycopyrrolate group; Group C = control group; SD = standard deviation; mg = milligram; T = thoracic level;

EBL = estimated blood loss; ml = millilitre

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Fig 2. Bar charts with standard error for repeated-measures data.

Abbreviations: SBP = systolic blood pressure; DBP = diastolic blood pressure; MAP = mean arterial pressure; HR = heart rate; mmHg =

millimetre of mercury; beat/min = beats per minute

TABLE 2. Statistical analytic results of repeated-measures outcomes.

Outcome Differences from control 95% Condence interval P-value

Systolic blood pressure 7.4 mmHg higher 3.1 to 11.8 <0.01

Diastolic blood pressure 4.3 mmHg higher 1.7 to 6.9 <0.01

Mean arterial pressure 5.4 mmHg higher 2.6 to 8.1 <0.01

Heat rate 1.5 beats/min -3.8 to 6.7 0.59

higher, around 7.4 mmHg (95% CI: 3.1-11.8, p-value<0.01),

4.3 mmHg (95% CI: 1.7-6.9, p- value<0.01), and 5.4

mmHg (95% CI: 2.6-8.1, p-value<0.01), respectively. e

graph also shows that the values were maintained for

at least the entire 60-minute observation period. Heart

rate, however, was no dierent between the two groups

(p-value=0.59).

DISCUSSION

Spinal anaesthesia is the technique of choice for

TURP. It is oen preferred over general anaesthesia due to

more hemodynamic stability during induction,

a lower

post-operative analgesic requirement

, and less blood

loss.

is procedure also oers physicians the ability to

monitor patient consciousness, which can indicate early

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384

signs of TURP syndrome. ese warning signs (such as

dizziness, headache, and nausea)

, if unaddressed, can lead

to cyanosis, hypotension, or even cardiac arrest. TURP

patients are also particularly vulnerable to volume overload,

as most of them are elderly and have cardiopulmonary

disorders. Excessive absorption of irrigation solution

through open prostatic venous sinuses during the surgical

procedure

is the unique cause of this condition. ese

pose a challenge to the procedure, especially with regard

to hemodynamic parameters.

Glycopyrrolate, administered as glycopyrronium

bromide, is an anticholinergic drug. It does not cross

the blood-brain barrier,

has no central nervous system

eect, and has fewer chronotropic properties compared

to atropine.

In anaesthetic practice, glycopyrrolate is

commonly used to reverse non-depolarizing muscle

relaxants

17, 24

or to reduce oral secretions.

Some studies

have evaluated the eect of glycopyrrolate on hypotension

following spinal anaesthesia induction during caesarean

delivery.

26-28

According to the pharmacodynamics of

glycopyrrolate, it will take eect at about 16.1 minutes

and will be cleared about 75.4 minutes aer injection.

us, we decided to apply the drug 15 minutes before

performing the procedure. e intramuscular application

was chosen to avoid acute tachycardia from the drug’s

chronotropic eect.

Dosage was adjusted to be 0.2 mg

to prevent hypertension.

In ailand, the incidence of spinal anaesthesia-

associated hypotension was around 52.6% to 57.9%.

30,31

At age > 65 years, underlying hypertension and use of

high doses of bupivacaine were risk factors for TURP

patients.

Our patients were one of the high-risk groups.

With our results, the drug could signicantly suppress

hypotension. e IV uid requirement and vasopressor

usage were even more reduced, which are attractive for this

group of patients, who were vulnerable to uid overload.

Nevertheless, heart rate parameters were not dierent

between the two groups in our study. is nding was

partly compatible with the nding from a meta-analysis

of glycopyrrolate use in caesarean delivery, that although

the drug could maintain a higher heart rate, bradycardia

incidence was not dierent statistically.

There were, however, limitations in our study.

Patients with cardiovascular disease and ASA status

of more than three were excluded. Further studies are

required to evaluate the eectiveness and safety of the

drug in patients high ASA status, especially those with

cardiovascular disease.

CONCLUSION

In summary, intramuscular glycopyrrolate may be

able to prevent hypotension while decreasing vasopressor

and IV uid usage in elderly spinal anaesthesia TURP

patients. Heart rate, however, was not aected.

Disclosure: The authors declare that they have no

competing interests in this work.

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386

Varut Lohsiriwat, M.D., Ph.D.*, Chayudee Rungteeranont, M.D.*, Napat Saigosoom, M.D.**

*Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, **National Cancer Institute, Bangkok, ailand.

Incidence and Pattern of Nodal Metastasis in

Colon and Rectal Cancer: a Study of 1012 Cases

from Thailand

ABSTRACT

Objective: Lymph node (LN) metastasis is a key to determine prognosis and adjuvant treatment for resectable

colorectal cancer. is study aimed to determine and compare the incidence and pattern of LN metastasis between

colon cancer and rectal cancer.

Methods: Medical and pathological reports of patients with stage I-III colorectal adenocarcinoma undergoing

oncological resection between 2009 and 2013 at the Faculty of Medicine Siriraj Hospital were reviewed. e incidence

and pattern of LN metastasis related to tumor staging between colon cancer and rectal cancer were analyzed.

Results: is study included 1012 cases (502 colon cancer and 510 rectal cancer). Compared with rectal specimens,

colonic specimens had a larger tumor size (5.8 cm vs 5.0 cm; P<0.001), more T4 lesion (24% vs 6.3%; P<0.001) and

more LNs harvested (24 vs 18; P<0.001). Nodal metastases were found in 552 specimens (54.5%). e rate of LN

metastasis was 14.3% for T1 tumors, 25.6% for T2 tumors, 61.2% for T3 tumors, and 65.6% for T4 tumors. ere

was no signicant dierence in the overall rate of nodal metastasis between colon cancer and rectal cancer (52.6%

vs 56.5%; P=0.22), but rectal cancer had more N2 staging (31% vs 22.5%; P=0.002). Rectal cancer yielded more

median number of positive LN (4 vs 3; P=0.002) with a greater LN ratio (0.22 vs 0.12; P<0.001) than colon cancer.

Based on the depth of tumor invasion, T3 rectal cancer had a signicantly higher rate of LN metastasis (66.8% vs

55.7%; P=0.004) and a greater LN ratio (0.23 vs 0.10; P<0.001) than T3 colon cancer.

Conclusion: Although colon cancer had a larger tumor size and a higher percentage of deeper invasion, rectal cancer

were associated with a higher number of positive LN, more N2 status and a greater LN ratio - especially T3 lesion.

Keywords: Colon cancer; rectal cancer; nodal metastasis; lymph node ratio; ailand (Siriraj Med J 2020; 72: 386-390)

Corresponding author: Varut Lohsiriwat

E-mail: bolloon@hotmail.com

Received 25 May 2020 Revised 3 July 2020 Accepted 6 July 2020

ORCID ID: http://orcid.org/0000-0002-2252-9509

http://dx.doi.org/10.33192/Smj.2020.52

INTRODUCTION

e incidence of colorectal cancer (CRC) is rapidly

increasing in Asia including ailand. At present, CRC

is the third common malignancy in ai males and the

fourth in ai females, and accounts for 11% of cancer

burden in ailand.

Oncological resection remains a

mainstay treatment of non-metastatic CRC. Meanwhile,

the status of lymph node (LN) metastasis determines

the prognosis of CRC and the need of adjuvant therapy.

Negative resection margin and adequate LN harvested

(more than 12 LNs) indicate the quality of surgical

specimens. erefore, many surgeons advocate extensive

operations including complete mesocolic excision with

central vascular ligation and D3 lymphadenectomy for

Lohsiriwat et al.

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colon cancer to achieve utmost removal of potentially

cancer-harboring LN.

Apart from surgical extent, it was

evident that the number of LN harvested was dependent

on the length of surgical specimen, tumor size, depth of

CRC invasion, and location of the tumor.

Another interesting aspect of LN removal and nodal

metastasis is that lymph nodes ratio (LNR), dened

as the ratio of metastatic LN to the total number of

LN harvested, is predictive of disease-free survival and

overall survival in stage III CRC.

e LNR may provide

an additional value to the N-stage of TMN classication

for CRC. However, histopathology and nodal status of

CRC could be various among tumor location and may

be dierent among ethnics.

3,5

In Asian countries, most

studies examining these subjects were based on the East

Asia population.

6-10

It would be interesting to have this

information form other regions of Asia including Southeast

Asia. e objective of this study was to determine and

compare the incidence and pattern of nodal metastasis

between colon cancer and rectal cancer using a database

from the largest hospital in ailand.

MATERIALS AND METHODS

Aer obtaining ethics approval from the Institution’s

Ethics Committee (Si 122/2014), medical records and

pathological reports of patients undergoing elective and

emergency colectomy and/or proctectomy for stage I-III

colorectal adenocarcinoma between 2009 and 2013in

the Department of Surgery, Faculty of Medicine Siriraj

Hospital, Mahidol University, Bangkok, were reviewed.

Our oncological principles of CRC resection included a

resection margin at least 5 cm from colon cancer with

the removal of node-baring mesentery and proximal

ligation of the feeding vessels, and adequate or total

mesorectal excision for rectal cancer.

e clinicopathological records were identied

from the hospital’s prospectively-collected database.

Pathological reports were excluded from this review if

patients had local excision or palliative resection, and those

underwent an operation for recurrent CRC, carcinoma

in situ, synchronous CRC, or familial adenomatous

polyposis. Patients having neoadjuvant therapy were

also excluded. Rectal cancer was dened as a tumor

locating within 15 cm from the anal verge measured by an

endoscopy. High-grade tumors were poorly dierentiated

adenocarcinoma, mucin-producing tumors, signet ring

cells. Notably, pathologists would identify LNs by careful

palpation a surgical specimen aer proper formalin

xation. e seventh edition of UICC TNM staging

system for colorectal cancer was used in this study. e

primary outcomes measured were the incidence and

pattern of nodal metastasis between colon cancer and

rectal cancer. is study was performed in accordance

with the Declaration of Helsinki.

All data were prepared and compiled using SPSS

computer soware (version 15.0 for Windows). Mean

and standard deviation are presented for continuous

data. e Kolmogorov-Smirnov test was used to test for

the pattern of data distribution. Student unpaired t-tests

were used to compare data between the two groups when

they showed normal distribution. e Mann-Whitney U

tests were used when data were not normally distributed.

e Pearson χ 2 tests or Fisher’s exact tests were used

for categorical data. A P-value of less than 0.05 was

considered statistically signicant.

RESULTS

is study included 1012 cases (502 colon cancer

and 510 rectal cancer). Patients with colon cancer was

about 2-year older than those with rectal cancer (average

age 64.7 years vs 62.6 years, P=0.011). Compared with

rectal specimens, colonic specimens had a larger tumor

size (5.8 cm vs 5.0 cm; P <0.001), more T4 lesion (24% vs

6.3%; P<0.001) and more harvested lymph nodes (24 vs

18; P<0.001) - but a comparable percentage of high-grade

histology (5.4% vs 3.7%; P=0.21). Clinicopathological

characteristics between colon cancer and rectal cancer

are shown in Table 1.

Nodal metastases were found in 552 specimens

(54.5%). e rate of nodal involvement was 14.3% for T1

tumors, 25.6% for T2 tumors, 61.2% for T3 tumors, and

65.6% for T4 tumors. ere was no signicant dierence in

the overall rate of nodal metastasis between colon cancer

and rectal cancer (52.6% vs 56.5%; P=0.22), but rectal

cancer had more N2 staging (31% vs 22.5%; P=0.002).

Rectal cancer yielded more median number of positive

LN (4 vs 3; P=0.002) with a greater LNR (0.22 vs 0.12;

P<0.001) than colon cancer. Based on the depth of tumor

invasion, T3 rectal cancer had a signicantly higher rate

of nodal metastasis (66.8% vs 55.7%; P=0.004) (Table 2)

and a greater LNR (0.23 vs 0.10; P<0.001) than T3 colon

cancer (Table 3).

DISCUSSION

This study examining 1012 surgical specimens

of colorectal cancer in ailand demonstrated that,

although colon cancer had a larger tumor size and a

higher percentage of deeper invasion, rectal cancer were

associated with a higher number of LN metastasis, more

N2 status and a greater lymph node ratio - especially T3

lesion. Rectal cancer appeared to be more aggressive

than colon cancer.

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388

TABLE 1. Clinicopathological characteristics between colon cancer and rectal cancer. Data are presented as mean ±

standard deviation, median [interquartile range], or number (percentage).

Characteristics Colon cancer Rectal cancer P-value

(n=502) (n=510)

Age (years) 64.7 ± 13.3 62.6 ± 12.4 0.011

Male 265 (52.8) 278 (54.5) 0.58

Tumor size (cm) 5.8 ± 2.9 5.0 ± 1.8 <0.001*

High-grade tumor

27 (5.4) 19 (3.7) 0.21

Tumor stage <0.001*

T1 16 (3.2) 19 (3.7)

T2 68 (13.5) 104 (20.4)

T3 296 (59.0) 355 (69.6)

T4 122 (24.3) 32 (6.3)

Harvested lymph node 24 [17-36] 18 [13-25] <0.001*

≥ 12 lymph node removal 453 (90.2) 424 (83.1) 0.001*

Node stage 0.008*

N0 238 (47.4) 222 (43.5)

N1 151 (30.1) 130 (25.5)

N2 113 (22.5) 158 (31.0)

Of patients with nodal metastasis

Positive lymph node 3 [1-6] 4 [2-7] 0.002*

Lymph node ratio (%) 0.12 [0.06-0.29] 0.22 [0.10-0.41] <0.001*

*P-value <0.05

Note:

High-grade tumors were poorly dierentiated adenocarcinoma, mucin-producing tumors, signet ring cells.

TABLE 2. Comparison between tumor stage and nodal stage in colon cancer and rectal cancer. Data are presented

as number (percentage).

T stage Proportion of nodal metastasis (%) P-value

Colorectal cancer Colon cancer Rectal cancer

(n=1012) (n=502) (n=510)

T1 5/35 (14.3) 4/16 (25.0) 1/19 (5.3) 0.16

T2 44/172 (25.6) 18/68 (26.5) 26/104 (25.0) 0.83

T3 402/651 (61.2) 165/296 (55.7) 237/355 (66.8) 0.004*

T4 101/154 (65.6) 77/122 (63.1) 24/32 (75.0) 0.21

*P-value <0.05

Lohsiriwat et al.

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TABLE 3. Comparison between tumor stage and lymph node ratio (LNR) in colon cancer and rectal cancer. Data

are presented as median [interquartile range].

T stage Lymph node ratio P-value

Colon cancer (n=264) Rectal cancer (n=288)

T1 0.24 [0.08-0.84] - n/a

T2 0.10 [0.07-0.22] 0.17 [0.07-0.31] 0.54

T3 0.10 [0.05-0.25] 0.23 [0.10-0.44] <0.001*

T4 0.16 [0.07-0.33] 0.20 [0.11-0.39] 0.19

*P-value <0.05

Abbreviation: n/a = not available

Surgical specimens of colon cancer in this study

yielded more median number of LN harvested than

those of rectal cancer (24 LNs vs 18 LNs). e number

of colonic specimens containing adequate LN removal

(at least 12 LNs) was also signicantly higher than that

of rectal specimens (90.2% vs 83.1%). ese nding

were consistent with those reported from Austria

and

China

– where right-sided colon specimen had the

highest number of LN harvested followed by le-sided

colon and rectal specimens. Other factors inuencing the

number of LNs harvested included patient’s age, tumor

size, tumor staging, type of operation, and technique to

identify LN in a surgical specimen.

e presence of at

least 12 LNs in a CRC specimen is widely regarded as one

of quality assurances for appropriate CRC operations. It

is associated with proper staging, subsequent treatment,

surveillance protocol and CRC prognosis.

It is known that the possibility of nodal metastasis

is related to the depth of tumor invasion. For example,

using the Surveillance, Epidemiology, and End Results

(SEER) cancer registry, the rate of nodal involvement

for CRC was approximately 10% for T1 tumors, 20% for

T2 tumors, 40% for T3 tumors, and 50% for T4 tumors.

Moreover, nodal metastasis was more prominent in rectal

cancer and poorly dierentiated cancer.

Our ndings

conrmed this correlation and were in line with the results

of this US population-based study as we found that the

proportion of nodal metastasis increased by advanced

T-staging and rectal cancer had more percentage of LN

involvement than colon cancer – especially T3 lesions.

In addition, rectal cancer also had more median number

of positive LN, more N2 staging and a greater LNR than

colon cancer.

A higher rate of nodal metastasis and greater LNR

in rectal cancer shown in our study was supported by a

review of population-based studies

and hospital-based

cohorts.

For instance, a study of 2340 Chinese surgical

patients with stage I-III CRC found that patients with

rectal cancer had signicantly more LNs involved and

higher LNR than those with colon cancer.

ere is

no clear rationale why rectal cancer has more nodal

involvement than colon cancer, but some possible

explanation includes their dierences in anatomical

and oncological characteristics. Although LNR could

be a signicant prognostic factor for stage III CRC, its

optimal cut-o point remains debatable for determining

the regimen of adjuvant treatment and CRC survival.

It is interesting that the rates of nodal metastasis

based on T-staging in our study appeared to be slightly

higher than those reported in other studies

11,12

– ours

ranged from 14.3% for T1 tumors to 65.6% for T4 tumors.

One possible explanation for these ndings is that the

average size of the tumor was quite large (about 5-6 cm)

in our study and a tumor with large diameter (especially

more than 4.5 cm) could increase the risk of nodal

involvement.

Also, some T1 tumors in our institute

were treated by endoscopic removal or transanal excision

thus resulting in those with large tumor or high-risk for

nodal metastasis underwent oncological resection with

LN-bearing area. Moreover, 50% of our cases were rectal

cancer which was more prone to have LN metastasis.

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390

Our study beneted from a review of a prospectively-

collected database of the largest hospitality in ailand

– which could be a good representative of real-world

practice and overall clinicopathological characteristics of

CRC in ailand. However, there are some limitations of

this observational study. First, the number of patient with

T1 tumor was small - which represented a real picture

of CRC in ailand where the incidence of stage I CRC

was less than 10% due to the lack of CRC screening

and cancer awareness.

erefore the incidence of LN

metastasis in T1 lesion may be dicult to interpretate

especially for T1 colon cancer. Specically, there were 4

cases with LN metastasis out of 16 cases with T1 colon

cancer (accounting for 25%). is should not be perceived

as a true incidence of nodal involvement for T1 lesion

because a majority of malignant colonic polyps were

removed endoscopically in our institute thus leaving only

high-risk T1 lesions for oncological resection. Second, the

comparison of LNR in T1 tumors between colon cancer

and rectal cancer cannot be performed because the rectal

cancer group had only one case with LN metastasis.

Hence, future studies with large sample size especially

for early CRC are needed from ailand. ird, the

correlation between nodal status including LNR and

oncological outcomes was beyond the scope of this study.

However, several population-based prospective studies

have shown a strong correlation between a high number

of LNs harvested and better survival, and a prognostic

indicator of LNR for stage III CRC.

In summary, this single-center study demonstrated

that the incidence of LN metastasis in CRC increased

by the depth of tumor invasion. Although the overall

rate of nodal metastasis between colon cancer and rectal

cancer was comparable, rectal cancer had more median

number of positive LN, more N2 staging and a greater

LNR – especially T3 rectal cancer.

Conict of Interests: e authors declare that we have

no conict of interest.

Funding Statement: ere was no funding or grant

support.

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11. Akagi Y, Adachi Y, Kinugasa T, Oka Y, Mizobe T, Shirouzu K.

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12. Ricciardi R, Mado RD, Rothenberger DA, Baxter NN. Population-

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13. Balta AZ, Ozdemir Y, Sucullu I, Derici ST, Bagci M, Demirel

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predict prognosis? Ulus Cerrahi Derg. 2014;30:115-9.

Lohsiriwat et al.

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Kornchanok Vareesangthip, M.D., awee Chanchairujira, M.D., Kriengsak Vareesangthip, M.D.

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

Effect of Ultraltration Rate in Long Interdialytic

Interval Hemodialysis Session versus Average

Weekly Ultraltration Rate on Mortality Rate and

Adverse Cardiovascular Outcomes in Maintenance

Hemodialysis Patients

ABSTRACT

Objective: Cardiovascular events are more commonly observed during hemodialysis sessions aer a long interdialytic

interval compared to average weekly hemodialysis sessions, and ultraltration rate (UFR) was reported to be

associated with cardiovascular outcomes. Whether the UFR during hemodialysis sessions aer a long interdialytic

interval is a better predictor of cardiovascular outcome than the average weekly UFR is unknown.

Methods: e charts of patients aged >18 years with end-stage renal disease that received hemodialysis treatment

Siriraj Hospital during January 2008 to December 2017 were retrospectively reviewed.

Results: Two hundred and forty-one patients (52.8% females) were included. During the median time follow-up of

54 months, the rate of adverse cardiovascular outcomes was 7.26 events/100-patient-years, and the mortality rate

was 8.40 deaths/100-patient-years. Mean UFR was signicantly higher in the long interdialytic interval hemodialysis

sessions than in the average weekly UFR sessions (14.07±5.29 vs. 13.13±5.14 ml/h/kg, p<0.001). Compared with

UFR of ≤10 ml/h/kg, the adjusted hazard ratio (HR) for mortality in the UFR >13 ml/h/kg subgroup was 1.29 (95%

CI: 0.65-2.56) and 1.05 (95% CI: 0.55-2.03) in the long interdialytic interval hemodialysis sessions and the average

weekly UFR, respectively. e adjusted HR for adverse cardiovascular outcome in the UFR >13 ml/h/kg subgroup

was 1.32 (95% CI: 0.64-2.80) and 0.72 (95% CI: 0.36-1.35) in the long interdialytic interval hemodialysis sessions

and the average weekly UFR, respectively.

Conclusion: is study revealed that the UFR in long interdialytic hemodialysis sessions has the trend to be associated

with more adverse cardiovascular outcomes and all-cause mortality than the average weekly UFR. A larger population

is needed to further elucidate the relationship between UFR and outcomes in ai hemodialysis population.

Keywords: Ultraltration rate; cardiovascular outcomes; mortality, maintenance hemodialysis patients; long

interdialytic interval hemodialysis; weekly hemodialysis (Siriraj Med J 2020; 72: 391-398)

Corresponding author: Kriengsak Vareesangthip

E-mail: kriengsak.war@mahidol.ac.th

Received 30 August 2019 Revised 17 February 2020 Accepted 19 February 2020

ORCID ID: http://orcid.org/0000-0002-8750-8071

http://dx.doi.org/10.33192/Smj.2020.53

INTRODUCTION

Volume management in maintenance hemodialysis

(HD) patients is challenging. An increasing body of

evidence points to association between uid-related

factors and treatment outcomes in these patients.

Moreover, fluid retention or excessive interdialytic

weight gain (IDWG) was found to be associated with

adverse cardiovascular outcomes.

1-3

Experts suggest that

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Vareesangthip et al.

normalization of extracellular uid volume should be

added to the traditional goals of dialysis that include

molecule clearance and patient well-being.

Rapid uid

removal was also found to be associated with adverse

cardiovascular outcomes and mortality in maintenance

hemodialysis patients.

5-8

In addition, long interdialytic

interval was found to be associated with cardiovascular

morbidity, mortality, and higher risk of sudden death

9,10

which further suggests that volume abnormalities may

be complicit. IDWG is commonly observed to be higher

during dialysis aer long interdialytic intervals compared

to midweek dialysis, and this leads to a need for a higher

ultraltration rate (UFR). Whether the UFR used during

a long interdialytic interval hemodialysis session is a

better predictor of patient outcomes compared to the

UFR used during average weekly HD is still unclear.

Accordingly, the aim of this study was to investigate the

eect of ultraltration rate in long interdialytic interval

hemodialysis session versus average weekly ultraltration

rate on mortality rate and adverse cardiovascular outcomes

in maintenance hemodialysis patients.

MATERIALS AND METHODS

Study design

The electronic medical charts of patients aged

greater than 18 years with end-stage renal disease (ESRD)

that received hemodialysis treatment at the Division

of Nephrology, Department of Medicine, Faculty of

Medicine Siriraj Hospital, Mahidol University, Bangkok,

ailand during 1 January 2008 to 31 December 2017

were retrospectively reviewed. Patients were enrolled

in the following phases: phase 1 – starting on 1 January

2008; phase 2 – starting on 1 January 2010; phase 3 –

starting on 1 January 2012; and, phase 4 – starting on

1 January 2014. Each patient’s baseline characteristics

were considered at the time of enrollment. Baseline

demographic characteristics and comorbidity data were

collected. Baseline laboratory measurements were collected

and calculated for dierence in predialysis serum sodium

(pre-HD SNa) and dialysate sodium (DNa), urea reduction

ratio (URR), dialysis adequacy (single pool Kt/V), and

normalized protein catabolic rate (nPCR). Hemodialysis

data, including access type [arteriovenous stula (AVF),

arteriovenous gra (AVG), permanent catheter (PC), or

double lumen catheter (DLC)], DNa, dry weight, IDWG,

UFR, pre-hemodialysis (pre-HD) and post-hemodialysis

(post-HD) blood pressures, were also collected at baseline.

e estimation of baseline mean average weekly UFR

was calculated from average UFR of the rst 2 weeks of

consecutive hemodialysis sessions at the time of enrollment

for each phase. e UFR in the long interdialytic interval

was calculated from the mean UFR in the beginning of

week of hemodialysis sessions aer the longest interdialytic

period in the rst 2 weeks at the time of enrollment.

Pre-HD and post-HD blood pressure data were collected

in the same way that average UFR data were collected.

Patients were followed forward in the historical timeline

until death or until the end of the study (31 December

2017). e protocol for this study was approved by the

Siriraj Institutional Review Board (Si 043/2019). e

requirement to obtain written informed consent was

waived due to this study’s retrospective design.

Data collection

All data were retrieved from an electronic medical

records search of our hospital database. Demographic and

comorbidity data were recorded at the time of admission

to the dialysis unit, and that information was updated

based on the patient’s clinical status during the follow-

up period. Laboratory data were measured monthly

according to the standard protocol of the dialysis unit.

Hemodialysis details were recorded during each dialysis

session.

Exposures and outcomes

Prescribed UFR was calculated from net ultraltration

estimated from IDWG (milliliters, ml) divided by

duration of prescribed dialysis session in hours (h) of

each hemodialysis session. UFR normalized for body

weight is expressed as ml/h/kg. We assumed that the

prescribed UFR was constant during the study period,

and the HD sessions in the rst 14 days of each phase

was used for calculations.

The primary outcome was all-cause mortality.

Patients were considered at risk for the study outcome

during the exposure period until death or censoring for

loss to follow-up or end of study (31 December 2017).

e secondary outcomes were adverse cardiovascular

outcomes (myocardial infarction, stroke or death from

cardiovascular cause) and hospitalization rate. e eect

of the average UFR and the UFR at the beginning of

weekly hemodialysis sessions on mortality and adverse

cardiovascular outcomes was also compared.

Statistical analysis

Cross-sectional data at baseline is presented as

descriptive data using percentage for categorical

variables, mean ± SD for continuous variables with

normal distribution, and median and range (minimum,

maximum) for continuous variables with non-normal

distribution. Patients were categorized into 1 of the 3

following UFR subgroups: ≤10, 10-13, or >13 ml/h/kg.

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e UFR of ≤10 ml/h/kg was used as a reference for

comparison with the other 2 UFR subgroups relative

to clinical outcomes. e UFR cuto of 13 ml/h/kg,

which was used in previous studies, is equivalent to 3

kg of IDWG in a post-HD body weight of 60 kg.

7,8,11

Association between UFR and outcomes was analyzed

using log rank test and survival analysis, while overall

survival was analyzed using Kaplan-Meier survival analysis.

Cox proportional hazard analysis was used to identify

association between dierent factors and survival. e

results of that analysis are presented as hazard ratio

(HR) and 95% condence interval (CI). All statistical

analyses were performed using SPSS Statistics soware

version 18 (SPSS, Inc., Chicago, IL, USA). A p-value of

less than 0.05 was considered statistically signicant.

RESULTS

Baseline patient characteristics

Baseline demographic, clinical, and laboratory data

were stratied by UFR category, as shown in Tables

1 and 2. A total of 241 ai patients (52.8% females)

were included. e median time of follow-up was 54.05

months (min: 1.77, max: 118.77). e number of patients

recruited in phase 1, 2, 3, and 4 was 121, 47, 37, and 43,

respectively. e prescribed dialysis treatment was 2

sessions per week in 19%, and 3 sessions per week in 81%

of all patients. Compared with the group of patients with

UFR <10 ml/h/kg, patients in the higher UFR groups (10-

13 and >13 ml/h/kg) were signicantly younger and had

a lower percentage of DM, hypertension, dyslipidemia,

and cardiovascular disease; however, they had more

IDWG, longer dialysis vintage, lower body weight, and

a lower percentage of preserved residual renal function.

Association between average weekly UFR and outcomes

All-cause mortality and cardiovascular events in

each UFR subgroup of average weekly UFR are presented

in Table 3. Median time to all-cause mortality was 98.6

months, with a 5-year survival rate of 68.08%. Median

time to adverse cardiovascular outcome was 108.33

months. Outcomes were adjusted for age, gender, history

of cardiovascular disease (CVD), history of diabetes,

underlying diseases, dialysis vintage duration, number of

dialysis sessions per week, phase, dry weight, pre-HD blood

pressure, post-HD blood pressure, Kt/V, and normalized

protein catabolic rate (nPCR). Mean UFR in the long

interdialytic interval hemodialysis group was signicantly

higher than in the average weekly UFR group (14.07±5.29

TABLE 1. Patient demographic and clinical characteristics.

Characteristics UFR (ml/h/kg)

P-value

≤10 (n=64) 10-13 (n=69) >13 (n=108)

Age (years) 68.3±12.7 60.2±14.1 50.9±14.5 <0.001

Female gender 54.7% 50.7% 50.9% 0.87

Duration of follow-up (months) 45.67 59.97 58.98 0.04

(1.77, 118.77) (1.87, 118.73) (3.73, 118.77)

Residual urine 36.0% 15.9% 12.0% <0.001

No. of anti-HT drugs 1 (0, 5) 1 (0, 5) 1 (0, 6) 0.37

Underlying disease

Coronary artery disease 25.0% 17.4% 11.1% 0.06

Stroke 7.8% 5.8% 3.7% 0.51

Peripheral artery disease 3.1% 1.4% 0.0% 0.21

Hypertension 54.7% 49.3% 35.2% 0.11

Diabetes mellitus 37.5% 20.3% 14.8% 0.02

Dyslipidemia 43.8% 39.1% 25.0% 0.02

Data presented as mean ± standard deviation, percentage, or median (minimum, maximum)

A p-value<0.05 indicates statistical signicance

Abbreviations: UFR, ultraltration rate; HT, hypertension

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Vareesangthip et al.

TABLE 2. Hemodialysis factors at baseline.

Factors UFR (ml/hr/kg)

P-value

≤10 (n=64) 10-13 (n=69) >13 (n=108)

Dialysis vintage (months) 20.7 (0.2, 139.6) 39.7 (0.2, 255.5) 60.7 (0.2, 282.7) 0.001

HD sessions 0.14

2 per week 15.6% 27.5% 16.7%

3 per week 84.4% 72.5% 83.3%

Access 0.28

AVF 55.2% 63.0% 67.9%

AVBG 5.2% 9.3% 9.0%

Permanent catheter 32.8% 20.4% 15.4%

Double lumen catheter 6.9% 7.4% 7.7%

Dry weight (kg) 60.63±13.22 59.46±11.22 52.80±10.83 <0.001

Dry weight 0.001

≤50 kg 25.0% 18.8% 41.7%

50-60 kg 26.6% 39.1% 33.3%

>60 kg 48.4% 42.0% 25.0%

UF (L) 1.78±0.66 2.71±0.54 3.67±0.76 <0.001

UFR (ml/h/kg) 7.33±2.09 11.4±0.77 17.67±3.67 <0.001

IDWG (%DW) 2.93±0.84 4.56±0.31 7.07±1.47 <0.001

Pre-HD SBP (mmHg) 148.0±20.0 149.0±18.0 152.0±16.0 0.34

Pre-HD DBP (mmHg) 76.0±11.0 78.0±9.0 80.0±11.0 0.07

Post-HD SBP (mmHg) 150.0±23.0 145.0±18.0 150.0±17.0 0.18

Post-HD DBP (mmHg) 77.0±9.0 78.0±9.0 80.0±9.0 0.20

Pre-HD SNa (mmol/L) 139.0±4.0 139.0±3.0 138.0±3.0 0.20

Delta SNa - DNa (mmol/L) 1 (-10, 8) 1 (-8, 5) 0 (-7, 5) 0.78

Serum albumin (g/dl) 3.84±0.36 3.98±0.36 4.00±0.30 0.06

Pre-HD BUN (mg/dl) 64.12±22.80 71.01±19.08 76.79±20.17 0.06

URR 70.4±29.8 74.9±22.7 79.7±15.5 0.11

Kt/V

HD 2 times per week 2.12±0.45 2.05±0.48 2.08±0.28 0.89

HD 3 times per week 2.05±0.40 2.12±0.39 2.22±0.38 0.53

nPCR (g/kg/day) 1.0±0.25 1.05±0.27 1.11±0.32 0.06

Data presented as median (minimum, maximum), percentage, or mean ± standard deviation

A p-value <0.05 indicates statistical signicance

Abbreviations: UFR, ultraltration rate; HD, hemodialysis; AVF, arteriovenous stula; AVBG, arterioveneous bridge gra; UF, ultraltration;

UFR, ultraltration rate; IDWG, interdialytic weight gain; DW, dry weight; SBP, systolic blood pressure; DBP, diastolic blood pressure;

SNa, serum sodium; DNa, dialysate sodium; BUN, blood urea nitrogen; URR, urea reduction ratio; Kt/V, dialysis adequacy

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vs. 13.13±5.14 ml/h/kg, p<0.001). e median unadjusted

HR for all-cause mortality and adverse cardiovascular

outcome for patients in the average weekly UFR >13

ml/h/kg subgroup was 0.62 (0.39-1.01) and 0.67 (0.39-

1.15), respectively. Aer adjusting for relevant factors,

the higher average weekly UFR subgroups (UFR 10-13

and >13 ml/h/kg) were not found to be associated with

increased all-cause mortality or adverse cardiovascular

outcomes.

Association between UFR in long interdialytic hemodialysis

session and outcomes

All-cause mortality and adverse cardiovascular

events in each subgroup of UFR in the long interdialytic

interval hemodialysis group are presented in Table 4.

e mean IDWG of the hemodialysis sessions aer the

longest interval was 3.08±1.04 kg, and the mean UFR

was 14.07±5.29 ml/h/kg. e two higher UFR (10-13 and

>13 ml/h/kg) subgroups showed an increasing trend in

all-cause mortality and adverse cardiovascular outcomes

aer adjustment for all relevant factors. A subgroup

analysis in patients with 3 hemodialysis sessions per week

was also performed, and a similar result was observed.

DISCUSSION

Previous studies have examined the association

between mean UFR and mortality. Kim, et al. examined

a US cohort of 110,800 patients who started hemodialysis

and found a linear association between UFR and both

all-cause and CV mortality, and UFR of more than 10

ml/h/kg was found to have the highest risk.

From the

international Dialysis Outcomes and Practice Patterns

Study (DOPPS) cohort of 21,919 participants, Wong,

et al. reported an elevated risk of mortality with relative

IDWG of greater than 5.7%.

Using DOPPS cohort data,

Saran, et al. found longer treatment time and slower

UFR to be associated with lower mortality rate, and that

UFR of >10 ml/h/kg was associated with more episodes

of hypotension and higher mortality.

Assimon, et al.

reported higher mortality in hemodialysis patients with

higher UFR aer being normalized for body weight,

body mass index, and body surface area.

In the present study, unadjusted HR for mortality

and adverse cardiovascular outcomes tended to be

higher in the UFR ≤10 ml/min group. This may be

due to several confounding factors, including older

age and more underlying diseases (diabetes, CAD, and

TABLE 3. Association between UFR and all-cause mortality and cardiovascular events in each UFR subgroup of

patients that received average weekly UFR.

Factors

Number of Unadjusted HR Adjusted HR

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

All-cause mortality

UFR >13 ml/h/kg 41 (38.0%) 0.62 (0.39-1.01) 1.05 (0.55-2.03)

UFR 10-13 ml/h/kg 28 (40.6%) 0.77 (0.46-1.29) 0.97 (0.53-1.79)

UFR ≤10 ml/h/kg 29 (45.3%) Reference Reference

Cardiovascular events

UFR >13 ml/h/kg 33 (30.6%) 0.67 (0.39-1.15) 0.72 (0.36-1.35)

UFR 10-13 ml/h/kg 24 (34.8%) 1.14 (0.64-2.02) 0.72 (0.38-1.35)

UFR ≤10 ml/h/kg 31 (48.4%) Reference Reference

Adjusted for age, gender, history of CVD, DM, underlying diseases, dialysis vintage duration, number of dialysis sessions per week, phase,

dry weight, pre-HD BP, post-HD BP, Kt/V, nPCR

Abbreviations: UFR, ultraltration rate; HD, hemodialysis; HR, hazard ratio; CI, condence interval

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Vareesangthip et al.

Fig 1. Kaplan-Meier survival analysis. UFR was categorized into 3 groups, as follows: ≤10 ml/h/kg shown in blue, 10-13 ml/h/kg shown in

green, and >13 ml/h/kg shown in red. e associations between subgroup of UFR and outcomes are shown. Association between UFR aer

the longest interval and mortality (A), and between UFR aer the longest interval and adverse cardiovascular outcomes (B). Association

between average weekly UFR and mortality (C), and adverse cardiovascular outcomes (D).

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TABLE 4. Association between UFR and all-cause mortality and cardiovascular events in each UFR subgroup of long

interdialytic interval HD.

Factors

Number of Unadjusted HR Adjusted HR

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

All-cause mortality

UFR >13 ml/h/kg 47 (37.0%) 0.76 (0.45-1.27) 1.29 (0.65-2.56)

UFR 10-13 ml/h/kg 30 (48.4%) 1.05 (0.60-1.83) 1.31 (0.66-2.59)

UFR ≤10 ml/h/kg 21 (40.4%) Reference Reference

Cardiovascular events

UFR >13 ml/h/kg 39 (30.7%) 0.47 (0.28-0.78) 1.32 (0.64-2.80)

UFR 10-13 ml/h/kg 29 (46.8%) 0.62 (0.37-1.03) 1.43 (0.70-2.89)

UFR ≤10 ml/h/kg 20 (38.5%) Reference Reference

Adjusted for age, gender, history of CVD, DM, underlying diseases, dialysis vintage duration, number of dialysis sessions per week, phase,

dry weight, pre-HD BP, post-HD BP, Kt/V, nPCR

Abbreviations: UFR, ultraltration rate; HD, hemodialysis; HR, hazard ratio; CI, condence interval

dyslipidemia), whereas patients in the UFR >10 ml/hr/kg

group were signicantly younger. Aer adjusting for the

relevant confounding factors, high average weekly UFR

was not found to be associated with increased all-cause

mortality (HR: 1.05) or adverse cardiovascular outcomes

(HR: 0.97). In contrast, high UFR in the long interval

hemodialysis sessions showed a trend of increasing risk

for both all-cause mortality (HR: 1.29-1.31) and adverse

cardiovascular outcomes (HR: 1.32-1.43). Our study

found that higher UFR in long interdialytic hemodialysis

session is a better predictor of all-cause mortality and

adverse cardiovascular outcomes than average weekly

UFR.

Limitations

e limitations of this study include its retrospective

design and the small size of the study population. Moreover,

we only observed the UFR over a short period, so it is

possible that all UFRs that were prescribed in these

patients were not included in our analysis, and this could

mean that all statistical dierences and associations

between UFR and outcomes were not identied. To our

knowledge, no previous study has compared the eects

of UFR between long interdialytic hemodialysis sessions

and average weekly UFR relative to all-cause mortality

and cardiovascular outcome.

CONCLUSION

e results of this study showed that the UFR in

long interdialytic hemodialysis sessions has the trend to

be more strongly associated with adverse cardiovascular

outcomes and all-cause mortality than the average weekly

UFR. A larger study population is needed to conrm these

ndings, and to further elucidate the relationship between

UFR and outcomes in ai hemodialysis population.

ACKNOWLEDGMENTS

e authors gratefully acknowledge Ms.Khemajira

Karaketklang of the Department of Medicine, Faculty of

Medicine Siriraj Hospital, Mahidol University, Bangkok,

ailand for assistance with statistical analysis.

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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Nantawat Sitdhiraksa, M.D., Ph.D.*,**, Nattawut Apiwannarat, M.D.*, Wichian Boonyaprapa, MS*, Naratip

Sanguanpanich, B.Sc.*, Wandee Wansrisuthon, MBA*, Pakaratee Chaiyawat, Ph.D.***, Woraphat Ratta-Apha,

M.D., Ph.D.*, Jingswat Sirikunchoat, M.D.*, Pornjira Pariwatcharakul, M.D.*

*Department of Psychiatry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, **ASEAN Institute for Health Development, Mahidol

University, Nakon Pathom, ***Faculty of Physical erapy, Mahidol University, Salaya, Nakhon Prathom, ailand.

Mortality and Prevalence of Falls, and Their

Association with Psychiatric Diagnoses and

Psychotropic Medications

ABSTRACT

Objective: Falls are a signicant health problem that can aect the quality of life of older adults. is study was

undertaken to study the mortality and prevalence of falls, and their associations with psychiatric diagnoses and

psychotropic medications.

Methods: e study was a retrospective 10-year data analysis of a general hospital database from 2006-2015. e

prevalence, odds ratio, hazard ratio, and survival analysis were analyzed to study the association with falls.

Results: e overall prevalence of falls was 3.6%. Subjects with a psychiatric diagnosis had a 3.28 times greater

chance of falls. Subjects taking prescribed psychotropic medication had a 1.76 times greater chance of falls. Survival

analysis revealed a mean survival of 6.84 years aer falls. e average survival years aer falls was age-related.

Subjects with a history of falls and carrying a psychiatric diagnosis had a mean survival of 6.55 years and a hazard

ratio of 0.84. Subjects with a history of falls and taking prescribed psychotropic medication had a mean survival of

6.15 years and a hazard ratio of 1.27.

Conclusion: A psychiatric diagnosis and psychotropic medication prescriptions were associated with a greater chance

of falls. Subjects with a history of taking prescribed psychotropic medication had a higher risk of mortality from falls.

Keywords: Falls; prevalence; psychiatric diagnosis; psychotropic medication; survival (Siriraj Med J 2020; 72: 399-406)

Corresponding author: Pornjira Pariwatcharakul

E-mail: pornjira.par@mahidol.edu

Received 3 December 2019 Revised 25 February 2020 Accepted 26 February 2020

ORCID ID: http://orcid.org/0000-0003-0228-3043

http://dx.doi.org/10.33192/Smj.2020.54

INTRODUCTION

Falls are a very signicant health problem for the

elderly. Falls are associated with disability, death, increased

medical resources utilization,

1,2

and a limited sense of

well-being and reduced quality of life in the elderly.

3,4

ailand, from the Annual Epidemiological Surveillance

Report 2015, falls, according to the 10

revision of the

International Statistical Classication of Diseases and

Related Health Problems (ICD-10): W00–W19, were

the second most common cause of injury, second only

to trac accidents, with an increasing risk of mortality

associated with falls.

In falls studies, the causes of falls are mainly divided

into two major categories: internal and external. One

of the most signicant internal causes of falls is related

to the medication prescribed by physicians. Although

with dierent methodologies, populations of study, and

denitions of falls, the research ndings in this eld indicate

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400

that prescribed medications are associated with a higher

risk of falls, especially psychotropic medications. e

most common psychotropic medications reported to be

associated with falls are antipsychotics, antidepressants,

antimanics, and anxiolytic-hypnotics.

6-9

Centrally-acting

psychotropic medications have been reported to have side-

eects of drowsiness, dizziness, orthostatic hypotension,

blurred vision, gait and balance diculties, and also

abnormal movements, which are all associated with

falls.

Besides the studies of the association between falls

and psychotropic medications, a psychiatric diagnosis has

also been reported to be related with a history of injuries,

falls, and accidents more than physical diagnoses,

which

might be explained by the nature of psychiatric illnesses.

Psychiatric disorders can aect a person’s behavior and

judgment and might cause injuries unable to be explained

only from the side-eects of psychotropic medications.

In addition, mental disorders, psychotropic medications,

polypharmacy, and multiple psychotropic drug use have

also been reported to be associated with accidental death

and all-cause mortality.

12-14

Many newer psychotropic medications have been

launched on the market over the past 20 years. In ailand,

there has been an increasing evaluation of new psychiatric

cases yearly, and the trend in prescribing psychotropic

medication has also been escalating. is study aimed

to look into the current situation of falls in a psychiatric

context; in particular, to study the prevalence of falls in

a general hospital setting, the association between falls

and psychotropic medications and psychiatric diagnoses,

and also the survival in subjects with a history of falls.

MATERIALS AND METHODS

Study design and population

e study involved a retrospective 10-year data

analysis. e protocol was approved by Siriraj Hospital

IRB (Si 375/2015). e study population consisted of all

subjects included in Siriraj Hospital’s database during

the 10-year period from 2006 to 2015 as well as cases in

the Siriraj Hospital Death Registry, which was updated

and matched with the ai National Death Registry

(Fig 1).

Fig 1. Diagram of the study process.

Sitdhiraksa et al.

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Procedure and data

e authors retrieved and classied data into four

main groups: (1) subjects with and without a history

of falls (ICD 10 codes: W00-W19), (2) subjects with

and without a history of psychiatric diagnoses (ICD 10

codes: F00-F99), (3) subjects with and without a history

of receiving any psychotropic medication before falls,

including antidepressants, mood stabilizers, antipsychotics,

hypnotics-anxiolytics, and cognitive enhancing agents

groups, and 4) subjects with and without hospital death

registration (Fig 1). We studied the association by comparing

the data in each group.

Statistical analyses

Statistical analyses were performed with the Statistical

Package for Social Sciences (SPSS; version 18.0). We

compared dependent variables, subjects with/without a

history of falls, and independent variables, such as age, sex,

psychiatric diagnosis, and psychotropic medications, by

using chi-square tests. Multiple logistic regression analysis,

adjusted for age, was performed to assess the associations

of falls with psychiatric diagnoses and psychotropic

medications. Kaplan–Meier (K-M) survival curves were

calculated to determine survival years aer falls for

subjects with a history of psychiatric diagnoses and

subjects with a history of taking psychotropic medication.

Signicances of the log-rank tests were interpreted at a

two-sided alpha value of 0.05. Multivariate comparisons

were performed with the adjusted Cox proportional

hazards (PH) model. Signicances of the hazard ratios

(HR) estimates were based on a two-sided alpha value

of 0.05, and condence intervals at 95% were obtained

for the estimations. Unadjusted and adjusted-for-age

Cox PH models were tested for dierences in survival

years aer falls in subjects with a psychiatric diagnosis

and taking psychotropic medication.

RESULTS

Study population

e number and gender of the population in the

study are shown in Fig. 1. ere was a total of 1,855,887

subjects in the hospital database from 2006 to 2015. e

mean age was 39.21±21.419 years. eir age ranged from

0-117 years. 39.8% were male. ere were 66,174 falls,

and 50,192 deaths recorded.

Association between falls and psychiatric diagnoses

and psychotropic medications

Regarding subjects with a history of psychiatric

diagnoses, there were 9,326 cases (11.2%) with a history

of falls, whereas this gure was only 3.2% in subjects with

no psychiatric diagnosis. Falls were age-related and more

common in males. Subjects with a psychiatric diagnosis

had a 3.28 (adjusted OR, 95%CI 3.20-3.37) greater chance

of falls. e chances of falls, aer adjusting for age, sex,

marital status, and employment status, were the greatest

in patients with organic mental disorders (F00-F09) and

mental and behavioral disorders due to psychoactive

substance use (F10-F19) (Table 1).

Regarding subjects with a history of previous

psychotropic medication prescriptions, there were

14,850 cases (4.9%) with a history of falls, whereas this

gure was only 2.6% in subjects without a history of

receiving psychotropic medication prescriptions. Subjects

with psychotropic medication prescriptions had a 1.76

(adjusted OR, 95%CI 1.73-1.80) times greater chance

of falls. e strongest association between psychotropic

medications and falls, aer adjusting for age, sex, marital

status, and employment status, was found in patients

taking hypnotics-anxiolytics, mood stabilizers, cognitive

enhancing agents, antidepressants, and antipsychotics,

respectively (Table 1).

Survival in subjects with a history of falls and a history of

psychiatric diagnoses and psychotropic medication use

ere was a total of 66,174 recorded cases of falls,

and a total of 50,192 deaths recorded in the 10-year

hospital database, of which 6,537 deaths (9.9%) were

patients with a history of falls.

ere were 2,082 (22.3%) deaths recorded of subjects

with a history of falls and having a psychiatric diagnosis,

whereas 7.8% of deaths recorded were in subjects with

a history of falls but who had no psychiatric diagnosis.

Psychiatric diagnoses were predictive of decreased survival

in subjects with a history of falls (HR 1.15; 95%CI 1.10-

1.22). However, when adjusted for age, sex, marital status,

and employment status, psychiatric diagnoses were not

predictive of decreased survival (adjusted HR 0.84; 95%CI

0.79-0.89). e only decrease in survival chances was

found in subjects with mental and behavioral disorders

due to psychoactive substance use (adjusted HR 1.43;

95%CI 1.26-1.63) (Table 1).

ere were 2,300 (15.5%) deaths recorded in subjects

with a history of falls aer receiving psychotropic medications,

whereas 8.3% of deaths were recorded in subjects with

a history of falls but who had no previous history of

psychotropic medication prescriptions. Psychotropic

medication prescriptions were predictive factors for decreased

survival in subjects with a history of falls (adjusted HR

1.27; 95%CI 1.20-1.34). e largest decrease in survival

was found in subjects with antipsychotics (adjusted

HR 1.49; 95%CI 1.35-1.65), cognitive enhancing agents

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TABLE 1. Logistic regression assessing the risk and Cox proportional hazards analysis of falls.

Total Fall

Risk of falls Risk of Death

Variables

N N (%)

Unadjusted OR Adjusted OR

Death after falls

Unadjusted HR Adjusted HR

(95%CI) (95%CI)

N (%)

(95%CI) (95%CI)

Total 1,855,887 66,174 (3.6) 6,537 (9.9)

Male 739,344 27,987 (3.8) 1.11 (1.09-1.13)

1.13 (1.11-1.15)

3,063 (10.9) 1.50 (1.43-1.57)

2.01 (1.95-2.19)

Age 60-79 years 307,491 16,592 (5.4) 1.91 (1.87-1.94)

2.03 (1.99-2.08)

3,009 (18.1) 3.53 (3.31-3.76)

2.94 (2.71-3.19)

Age ≥80 years 44,129 5,858 (13.3) 5.11 (4.97-5.26)

4.95 (4.77-5.14)

2,106 (36.0) 6.35 (5.94-6.79)

4.87 (4.44-5.34)

Employment status

Employed 941,806 30,805 (3.3) 1 1 2,101 (6.8) 1 1

Non-employed 402,876 21,755 (5.4) 1.69 (1.66-1.72)

1.43 (1.41-1.46)

3,381 (15.5) 1.91 (1.81-2.01)

1.06 (0.99-1.13)

Marital status

Never married 799,037 28,157 (3.5) 1 1 987 (3.5) 1 1

Married 832,049 27,290 (3.3) 0.93 (0.91-0.94)

0.58 (0.57-0.60)

3,588 (13.1) 2.61 (2.44-2.80)

1.44 (1.32-1.57)

Divorced/Widowed 153,031 7,979 (5.2) 1.51 (1.47-1.54)

0.73 (0.71-0.76)

1,779 (22.3) 4.03 (3.73-4.35)

2.03 (1.83-2.24)

Psychiatric diagnoses

F00-F09: Organic, including symptomatic, 19,706 4,403 (22.3) 8.27 (7.98-8.56)

5.17 (4.96-5.38)

1,593 (36.2) 1.86 (1.75-1.96)

0.92 (0.86-0.98)

mental disorders

F10-F19: Mental and behavioral disorders due 9,196 1,247 (13.6) 4.31 (4.05-4.57)

3.98 (3.72-4.26)

283 (22.7) 1.29 (1.14-1.45)

1.43 (1.26-1.63)

to psychoactive substance use

F20-F29: Schizophrenia, schizotypal, and 6,357 630 (9.9) 2.99 (2.76-3.25)

2.40 (2.19-2.64)

102 (16.2) 0.76 (0.62-0.92)

0.81 (0.65-1.01)

delusional disorders

F30-F39: Mood [affective] disorders 22,009 2,692 (12.2) 3.89 (3.73-4.05)

3.20 (3.06-3.36)

441 (16.4) 0.72 (0.65-0.79)

0.64 (0.58-0.71)

F40-F48: Neurotic, stress-related, and 24,452 2,161 (8.8) 2.68 (2.56-2.80)

2.52 (2.40-2.65)

190 (8.8) 0.40 (0.35-0.46)

0.48 (0.41-0.56)

Statistically signiﬁcant at p < 0.05,

Adjusted for age, sex, marital status, and employment status

Abbreviations: OR = Odds Ratio; HR = Hazard Ratio; CI = Condence Interval

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TABLE 1. Logistic regression assessing the risk and Cox proportional hazards analysis of falls. (continued)

Total Fall

Risk of falls Risk of Death

Variables

N N (%)

Unadjusted OR Adjusted OR

Death after falls

Unadjusted HR Adjusted HR

(95%CI) (95%CI)

N (%)

(95%CI) (95%CI)

F50-F59: Behavioral syndromes associated with 4,499 605 (13.4) 4.23 (3.88-4.61)

3.54 (3.22-3.89)

88 (14.5) 0.63 (0.51-0.78)

0.52 (0.42-0.66)

physiological disturbances and physical factors

F60-F69: Disorders of adult personality and behavior 2,466 255 (10.3) 3.13 (2.75-3.56)

3.06 (2.63-3.55)

32 (12.5) 0.54 (0.38-0.77)

0.77 (0.53-1.12)

F70-F79: Mental retardation 3,602 280 (7.8) 2.29 (2.02-2.58)

2.68 (2.33-3.08)

21 (7.5) 0.32 (0.21-0.49)

1.12 (0.72-1.74)

F80-F89: Disorders of psychological development 9,571 550 (5.7) 1.65 (1.52-1.80)

2.32 (2.10-2.56)

14 (2.5) 0.12 (0.07-0.21)

0.41 (0.23-0.71)

F90-F98: Behavioral and emotional disorders with 8,356 541 (6.5) 1.88 (1.72-2.05)

2.53 (2.28-2.81)

10 (1.8) 0.08 (0.04-0.14)

0.40 (0.21-0.77)

onset usually occurring in childhood and adolescence

All psychiatric diagnoses 83,309 9,326 (11.2) 3.80 (3.72-3.89)

3.28 (3.20-3.37)

2,082 (22.3) 1.15 (1.10-1.22)

0.84 (0.79-0.89)

Psychotropic medications

Antidepressants 127,249 5,662 (4.4) 1.51 (1.47-1.56)

1.36 (1.31-1.40)

753 (13.3) 1.24 (1.15-1.34)

1.12 (1.03-1.21)

Mood stabilizers 14,036 819 (5.8) 1.83 (1.71-1.97)

1.60 (1.48-1.73)

134 (16.4) 1.19 (1.01-1.42)

1.09 (0.91-1.31)

Antipsychotics 42,751 2,111 (4.9) 1.62 (1.55-1.70)

1.30 (1.23-1.36)

461 (21.8) 1.83 (1.66-2.01)

1.49 (1.35-1.65)

Central nervous system stimulants 5,322 135 (2.5) 0.73 (0.62-0.87)

0.97 (0.79-1.19) 3 (2.2) 0.17 (0.06-0.54)

0.64 (0.20-1.97)

Cognitive enhancing agents 7,048 516 (7.3) 2.56 (2.34-2.80)

1.45 (1.32-1.61)

180 (34.9) 2.55 (2.19-2.95)

1.43 (1.22-1.67)

Drugs used in substance dependence 26,319 1,029 (3.9) 1.19 (1.12-1.27)

1.06 (0.99-1.14) 98 (9.5) 1.05 (0.86-1.28) 0.99 (0.80-1.23)

Hypnotics and anxiolytics 225,234 11,280 (5.0) 1.93 (1.89-1.97)

1.71 (1.67-1.76)

1,774 (15.7) 1.52 (1.44-1.61)

1.32 (1.25-1.40)

All psychotropic medications 310,667 14,850 (4.8) 1.92 (1.89-1.96)

1.76 (1.73-1.80)

2,300 (15.5) 1.48 (1.41-1.56)

1.27 (1.20-1.34)

Statistically signiﬁcant at p < 0.05,

Adjusted for age, sex, marital status, and employment status

Abbreviations: OR = Odds Ratio; HR = Hazard Ratio; CI = Condence Interval

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(adjusted HR 1.36; 95%CI 1.17-1.58), and hypnotics-

anxiolytics prescriptions (adjusted HR 1.24; 95%CI

1.17-1.31) (Table 1).

Survival analysis revealed an average mean survival

of 6.84 (SE = 0.03; 95%CI 6.77–6.90) years aer falls. e

average survival years aer falls was age related, whereby

the survival was 8.53 (SE = 0.04; 95%CI 8.45–8.61) years

in subjects aged under 60 years old, 5.92 (SE = 0.05;

95%CI 5.82–6.02) years in subjects aged 60–79 years

old, and 3.88 (SE = 0.06; 95%CI 3.75–4.00) years in

subjects aged 80 years old or more. Survival years were

signicantly shorter in subjects with a history of falls

and having psychiatric diagnoses (mean survival = 6.55;

SE = 0.06; p < 0.0001), and in subjects with a history of

falls and having psychotropic medication prescriptions

(mean survival = 6.15; SE = 0.07; p =< 0.0001) (Fig 2).

DISCUSSION

e prevalence of falls was higher in subjects with

psychiatric diagnoses, 11.2%, with a 3.28-times greater

chance of falls compared to subjects without a psychiatric

diagnosis. e highest psychiatric diagnoses associated

with falls were organic mental disorders (F00-09) (adjusted

OR 5.17), and mental and behavioral disorders due

to psychoactive substance use (F10-19) (adjusted OR

3.98). Subjects with a history of psychotropic medication

prescriptions had a 1.76 greater chance of falls. e most

common psychotropic medication associated with falls

was hypnotics-anxiolytics (adjusted OR 1.71). Aer

adjusting for age, sex, marital status, and employment

status, the only psychiatric diagnosis associated with

death aer falls was mental and behavioral disorders

due to psychoactive substance use (F10-19) (adjusted

HR 1.43). e psychotropic medications associated with

an increased risk of death aer falls were antipsychotics,

cognitive enhancing agents, hypnotics-anxiolytics, and

antidepressants. Survival analysis revealed an average

mean survival of 6.84 years aer falls. e average survival

years aer falls was age related.

Mental disorders were reported to be associated with

accidental death in a Swedish national cohort study,

with the three highest disorders stated as alcohol use

disorder, other substance use disorders, and dementia.

e hazard ratios of accidental death due to falls (ICD

10 W00-19) in subjects with a history of any psychiatric

disorders were associated more with the male gender,

6.2 in men versus 4.6 in women.

e present study

showed that the male gender (adjusted HR 2.01) and

subjects with a history of falls and having mental and

behavioral disorders due to psychoactive substance

use had an increased risk of death (adjusted HR 1.43).

However, psychiatric diagnoses were not associated with

an increased risk of death aer adjusting for age, sex,

marital status, and employment status. is dierence

might be explained by the dierences in population

studied and the denition of fall-related deaths.

From the results of this study, psychotropic

medication prescriptions; hypnotics-anxiolytics, mood

stabilizers, cognitive enhancing agents, antidepressants,

and antipsychotics were signicantly associated with

falls, which was in line with meta-analyses showing that

psychotropic medications and falls in the elderly are

signicantly correlated.

15,16

Benzodiazepines, antidepressants,

and antipsychotics have all been shown to be signicantly

associated with falls injuries and hospitalization.

14-16

the present study, hypnotics-anxiolytics showed the

Fig 2. Time from fall to death (A) subjects with psychiatric diagnoses, and (B) subjects with history of psychotropic medication prescriptions

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highest risk associated with falls, which is similar to

the results from the meta-analyses.

Benzodiazepines

are one of the most widely prescribed psychotropic

medications and hypnotics-anxiolytics.

Benzodiazepines

have been reported to increase postural sway and a loss

of balance.

Besides the side-eects of benzodiazepines,

dierences in the duration of the half-life and the dosage

of benzodiazepines are also related with a greater chance

of falls.

e association between mood stabilizers and falls

is not well established. Since some anti-epileptics are

classied as mood stabilizers and as most fall-related

studies have been done on the elderly, their subjects were

less likely to be prescribed anti-epileptics. However, in

the present study, mood stabilizers were the psychotropic

medications second most associated with falls. Anti-

epileptics were reported to be associated with falls in

emergency room visits by the elderly.

Further studies

of falls and mood stabilizers might be needed.

In the present study, cognitive enhancing agents

were the other psychotropic medications associated with

falls. e detrimental eects of dementia medications

may outweigh the benets of dementia treatment in the

elderly; for instance, side-eects, including syncope,

dizziness, vertigo, nausea, and fatigue, were 2–5 times

more common in patients who received dementia

medications compared to a placebo.

Moreover, falls

in the elderly were multifactorial. Besides psychiatric

diagnoses and cognitive enhancing agent prescriptions,

other causes, such as physiological changes, autonomic

nervous system function, visibility, hearing, muscle

strength, reaction time, a change in pharmacokinetics

and pharmacodynamics,

multiple medical diagnoses,

and polypharmacy,

were also associated with falls.

is study showed that psychotropic medication

prescriptions, antipsychotics, cognitive enhancing agents,

hypnotics-anxiolytics, and antidepressants, aer adjusting

for age, sex, marital status, and employment status, were

associated with falls and death, which was consistent with

the study of mortality in a population-based cohort of

older hip fracture patients.

Antipsychotics prescriptions

had the highest association with death aer falls, followed

by cognitive enhancing agents, and hypnotics-anxiolytics,

which was consistent with a nationwide study among

older adults in Sweden.

A retrospective study and a

meta-analysis from randomized controlled trials revealed

that dementia medications might increase the risk of

syncope; however, with no eects on falls, fracture, or

accidental injury in dementia treatment in the elderly,

25,26

which was in contrast with the present study, which

showed that aer adjusting for age, cognitive enhancing

agents were signicantly associated with both falls and

death aer falls, but not the diagnosis of organic mental

disorders. e dose, total number of medications, and

the co-administration of medications for other physical

disorders were also related with a risk of falls in the

elderly,

27-29

but the data were not available in this study.

In a study of falls aer spinal cord injury, the mean

survival was 7.4 years.

In the present study, subjects

with a history of falls and having a psychiatric diagnosis

had a shorter mean survival of 6.55 years.

Psychiatric diagnoses and psychotropic medication

prescriptions were clearly associated with falls in the

present study. Subjects with a history of being prescribed

psychotropic medications were associated with a higher

risk of mortality. Patients with psychiatric diagnoses

and patients with a history of psychotropic medication

prescriptions should benet from fall-prevention measures.

e key strengths of this study were the use of

a 10-year hospital database of all subjects, including

outpatients, inpatients, and a death registry that was

updated with the National Death Registry, and the fact

all age groups were included. e limitations of this

study were that the data were obtained only from one

big university general hospital in Bangkok, ailand,

the retrospective nature of the study, and the fact that

other clinical- and medication-related factors were not

included in the study. Physical disorders, disease severity,

medication adherence, use of over-the-counter drugs as

well as non-psychotropic medications and total number

of medications merit studying in future researches.

Our study may be confounded by other physical

diagnoses and other medications besides psychotropic

medications and central nervous system-acting medications.

Furthermore, an ascertainment of falls diagnosis was

obtained from computerized coding in the hospital

database, not directly from a review of the medical records,

and might possibly underrepresent the exact prevalence

of falls.

In conclusion, our study demonstrates that psychiatric

diagnoses and psychotropic medication prescriptions were

signicantly associated with 3.28-times and 1.76-times

increased risks of falls, respectively. Furthermore, patients

with a history of being prescribed psychotropic drugs were

associated with a 1.92-times higher risk of mortality. Fall

monitoring should be considered for patients with psychiatric

diagnoses and for patients with a history of psychotropic

medication prescriptions. In addition, physicians

should consider prescribing psychotropic medication

according to individuals’ clinical needs and obviates

unnecessary psychotropic drug use, especially in the elderly.

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406

ACKNOWLEDGMENTS

We acknowledge Lakana Thongchot for her

coordination in this study, Pratoom Nuanming at the

Medical Record Department for his help in retrieving the

data from the database, and Tumrongsak Pajareeyanont

at the Department of Information Technology Siriraj

Hospital for help in the data processing.

Conicts of Interest: None

REFERENCES

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15. Bloch F, ibaud M, Dugue B, Breque C, Rigaud AS, Kemoun G.

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Sitdhiraksa et al.

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Original Article

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Chompoonoot Boonsopa, M.D., Yasinee Apiraknapanon, M.D.

Division of Neonatology, Department of Pediatrics, Faculty of Medicine, Naresuan University, Phitsanulok 65000, ailand.

Retrospective Cohort Study on Effect of

Frenulotomy Techniques on Breastfeeding

ABSTRACT

Objective: e primary objective of this study was to compare the outcomes between frenulotomy by bedside

technique and surgery under general anesthesia to successful breastfeeding in ankyloglossia infants. e secondary

objective was to compare the dierences in the infants’ body weight, length of hospital stay and overall maternal

satisfaction.

Methods: A quantitative research of retrospective cohort study was conducted in Naresuan University Hospital,

ailand between July 2012 and June 2017. We enrolled all infants born and identied the infants diagnosed with

ankyloglossia. e severity of ankyloglossia was assessed at birth. Age of infants at the time of frenulotomy was on

the second day of life. e outcomes of two types of frenulotomy were compared.

Results: Ankyloglossia was diagnosed in 187 (6.3%) of 2,968 infants born. e main breastfeeding problems in

both groups were maternal sore nipples, cracked nipples and poor latch on. e infants in the bedside technique

group had more successful rate of exclusive breastfeeding at day 7 when compared with the surgical group (87.3%

and 39% respectively, p<0.001). More percent increment of infant’s body weight at day 7 in the bedside technique

group than the surgical group (60% and 20.8% respectively, p<0.001). Overall maternal satisfaction in the bedside

technique group was notably higher than that in the surgical group (96.4% and 59.7% respectively, p< 0.001). e

length of hospital stay was less in the bedside group for 1.2 days. More weight gain was found in the bedside group.

Conclusion: Frenulotomy is the procedure that should be performed in indicated ankyloglossia infants. is study

found that bedside technique frenulotmy had association to a more satisfactory outcome than surgery under general

anesthesia to successful breastfeeding.

Keywords: Ankyloglossia; tongue-tie; frenulotomy; breastfeeding (Siriraj Med J 2020; 72: 407-414)

Corresponding author: Chompoonoot Boonsopa

E-mail: chompoonoot_pednu@outlook.com

Received 2 March 2020 Revised 15 June 2020 Accepted 17 June 2020

ORCID ID: http://orcid.org/0000-0003-2179-1561

http://dx.doi.org/10.33192/Smj.2020.55

INTRODUCTION

Breastfeeding benets include immunity, decreased

risk of allergy, greater intellectual quotient than formula-

fed infants especially in exclusive breastfeeding for over 6

months.

1,2

Generally, mother and newborn are evaluated

immediately during the postnatal period concerning

breastfeeding position, latching technique, and sucking

eciency of the newborn. e correct latch-on technique

displays peristaltic tongue movements. Infants with

ankyloglossia or tongue-tie limit the range of motion of

the tongue due to the tight lingual frenulum.

is causes

severe discomfort to the mother having sore and cracked

nipples and eventually fails to exclusively breastfeed.

4-7

A frenulotomy is a surgical intervention usually

done when the indications include latch-on problems,

maternal sore nipples and substantial weight loss in

infants.

8-16

e benets aer frenulotomy such as better

latching, maternal nipple pain reduction, and maintenance

of breastfeeding practices have been reported.

11,15,17,18

e conventional technique is the surgical frenulotomy

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408

done by the surgeons in the operating room under

general anesthesia. An alternative way is the frenulotomy

performed on the bedside by experienced neonatologists.

is technique eliminates risks of general anesthesia

and the infants are able to latch on immediately aer

the procedure.

14,19

e primary objective of this study was to compare

the outcome of two frenulotomy procedures for successful

breastfeeding in ankyloglossia infants. In addition, the

secondary objective was to compare the dierences in

the infants’ body weight, length of hospital stay and

overall maternal satisfaction.

MATERIALS AND METHODS

A quantitative research of retrospective cohort study

was conducted. Data were collected from all infants born

in Naresuan University Hospital, Phitsanulok, ailand,

whom were diagnosed with ankyloglossia and undergone

frenulotomy between July 2012 and June 2017. e

medical records of all included infants were reviewed.

is study was approved by the Institutional Review

Board of Naresuan University (COA No.539/2016). e

assessment for a severity of ankyloglossia was done by

using a quantitative tool. e inclusion criteria were the

infants with ankyloglossia and undergone frenulotomy.

e exclusion criteria were the infants with ankyloglossia

who had a conservative treatment, incomplete follow up,

missing data records or ankyloglossic infants who were

unable to breastfed since birth according to any infant

or maternal reason. e contents of all enrolled medical

records included the assessment of ankyloglossia by using

a quantitative tool, called “Siriraj Tongue Tie score; STT

score”

20-22

(Fig 1), which scores both the appearance of

tongue tie and the function of the tongue in attaching

the maternal nipples. e indication for frenulotomy

was the STT score of less than 8.

20,21

e included infants were divided into 2 groups of

frenulotomy types according to attending physician’s

consideration. e rst group comprised infants with

ankyloglossia who underwent frenulotomy by a bedside

technique done by one neonatologist. e technical

procedures

5,10,23,24

were as follows: First, the neonatologist

applied a 2% Xylocaine Viscous topical anesthetic at

the frenulum. e arterial clamps were used to stop the

blood supply and hold the frenulum in place. en, the

frenulum was immediately snipped using the Metzenbaum

scissors. Next, cotton buds were utilized to divide any

attached residual frenulum at the base of tongue. Lastly,

pressure was applied at the incision site using sterile-

gauze in order to stop the bleeding.

e second group consisted of those who underwent

frenulotomy by one surgeon.

25,26

The infants with

ankyloglossia were transported to the operating room.

Aer administering the general anesthesia, the surgeon

used the electrocautery to cut the frenulum to prevent

bleeding. e infants had to stay in the recovery room

before sending them back to their mothers.

Data records collected contains birth weight, sex,

gestational age, LATCH score

9,10,14,27-29

before frenulotomy,

maternal nipple pain score (visual analog scale : VAS for

nipple pain severity)

28,30-32

before frenulotomy, overall

maternal satisfaction aer each frenulotomy procedure,

complications aer frenulotomy and the length of hospital

stay.

Fig 1. Siriraj Tongue Tie score (STT score)

20,21

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Aer hospital discharge, the information of follow

up data records at 7 days and 6 months were reviewed and

statistically analyzed as for the results of the increment

of body weight in 7 days and exclusive breastfeeding

success rate in 7 days and 6 months.

Statistical analysis

Data were analyzed using SPSS version 22 (IBM

Corp., Armonk, NY). Continuous data were shown as

mean+standard deviation (SD). Categorical data were

shown as frequency and percentage. Independent T-test

and Chi-square test were used to compare continuous

and categorical data, respectively. e absolute dierences

between the two types of frenulotomy procedure with

the p-values of <0.05 are considered to be statistically

signicant.

RESULTS

Of 2,968 infants born between July 2012 and June

2017, 187 infants were identied and diagnosed as having

a signicant ankyloglossia and met the inclusion criteria.

Of these, 110 ankyloglossia infants were identied as

to be in the rst group of whom underwent bedside

frenulotomy and 77 in the second group of whom underwent

surgical frenulotomy under general anesthesia. Table 1

provides the demographic details and information of each

frenulotomy group. e main breastfeeding problems

in the rst group were maternal nipple sore (76 from

110, 69.1%), cracked nipple (47 from 110, 42.7%) and

poor latch on (20 from 110, 18.2%). e LATCH score

was less than 7 (78.2%, mean+SD 6.2+1.5). e average

maternal nipple pain score was 1.2±0.7. In the second

group, there were similar breastfeeding problems as

in the rst group. ere were maternal nipple sore (58

from 77, 75.3%), cracked nipple (53 from 77, 68.8%) and

poor latch on (17 from 77, 22.1%). e LATCH score

was less than 7 (90.9%, mean+SD 5.9±1.3). e average

maternal nipple pain score was 1.5±0.7.

Although the indication for frenulotomy was the

STT score less than 8, there were 6 infants that undergone

frenulotomy despite the STT score more than 8. e

reasons were parental concern about feeding problems,

speech articulation problems. erefore, the doctor had

to do the frenulotomy aer their discussion.

Data shown in Table 2 are follow-up records in each

frenulotomy group. e infants in the rst group had

the mean body weight of 3,083.5±358.9 grams on day

7. eir increment of body weight was 60%, 39.6±14.4

grams. e mean percentage of body weight dierence

at birth and on day 7 was1.4±0.5 grams. e success

rate of exclusive breastfeeding on day 7 and 6 months

were 87.3%and 70.0%, respectively. On the contrary,

the infants in the second group had the mean body

weight of 3,028.2±361.3 grams on day 7. e increase

of body weight was 20.8%, -24.6±13.7 grams. e mean

percentage of body weight dierence at birth and on

day 7 was -0.7±0.5 grams. e success rate of exclusive

breastfeeding on day 7 and 6 month were 39.0% and1.3%,

respectively.

Analysis between the two types of frenulotomy

procedures showed that infants who had the bedside

technique (the rst group) of frenulotomy had a signicantly

higher success rate of exclusive breastfeeding on day 7

than those who had surgery under general anesthesia

(the second group)(87.3% and 39.0%, respectively, p <

0.001).When using Risk ratio, the infants in the rst group

had greater chances of successful exclusive breastfeeding

on day 7 when compared with the second group. (RR

=2.23; 95%CI: 1.68 to 2.99) as shown in Table 3.

In addition, the types of frenulotomy procedures were

associated with overall maternal satisfaction (p<0.001).

e satisfaction rate in the rst group was 96.4% while

the second group was 59.7%. When using Risk ratio, the

rst group had greater chances (1.62) of overall maternal

satisfaction aer frenulotomy (RR=1.62; 95%CI: 1.34 to

1.94).e types of frenulotomy procedures were also

associated with the increment of infant’s body weight

on day 7 (p<0.001). Increase of infant’s body weight on

day 7 for the rst and second groups was recorded at

60.0%and 20.8%, respectively. e Risk ratio result was

2.89 higher in the rst group (RR=2.89; 95%CI:1.82 to

4.58) as shown in Table 3.

e mean nipple pain scores for the groups undergoing

bedside technique and surgical technique were 1.2±0.1 and

1.5±0.1, respectively. is was not statistically signicant

(p = 0.012). e mean dierence was -0.3 (95%CI: -0.5

to -0.1).

The infants in the first group had a significant

shorter length of hospital stay than the infants in the

second group (4.4±0.2 vs 5.6±0.2, p< 0.001). e rst

group had lesser length of hospital stay than the second

group with the mean dierence of 1.2 days (95%CI: -1.8

to -0.7).

e infants in the rst group had the average mean

dierence in infant’s body weight of 39.6 ±14.4 grams while

in the second group had the average mean dierence of

-24.6±13.7 grams. When compared, there was a statistical

signicance (p =0.002) in the weight dierence between

the two groups.e results also found that infants in the

rst group had more weight gain (64.3 grams) when

compared to the second group (95%CI: 23.5-105.1) as

shown in Table 4.

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TABLE 1. Participant Demographics.

Characteristics

Bedside technique Surgical technique P-value

(n=110) (%) (n=77) (%)

Sex

Male 63 (57.3) 48 (62.3) 0.488

Gestational age (weeks)

> 37 106 (96.4) 74 (96.1)

Birth weight (grams)

< 3,000 45 (40.9) 34 (44.2) 0.658

Mode of delivery

Vaginal 47 (42.7) 34 (44.2) 0.464

Cesarean section 58 (52.7) 42 (54.5)

Vacuum extraction 5 (4.6) 1 (1.3)

STT score (Siriraj Tongue tie score)

> 8 4 (3.6) 2 (2.6)

Mean (± S.D.) 6.4 (0.9) 6.5 (0.8)

Breast feeding problems (may be >1 problems)

Cracked nipple 47 (42.7) 53 (68.8) <0.001

Sore nipple 76 (69.1) 58 (75.3) 0.352

Inadequate milk ow 35 (31.8) 17 (22.1) 0.143

Short nipple 14 (12.7) 9 (11.7) 0.831

Poor latch on 20 (18.2) 17 (22.1) 0.510

Signicant infant’s weight loss 2 (1.8) 2 (2.6) 0.717

LATCH score 0.021

< 7 86 (78.2) 70 (90.9)

>7 24 (21.8) 7 (9.1)

Mean (± SD) 6.16 (1.5) 5.9 (1.3)

Nipple pain score (VAS) 0.012

Mean (±SD) 1.2 (0.7) 1.5 (0.7)

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TABLE 2. Outcome aer Frenulotomy.

TABLE 3. Outcome Comparison between two types aer frenulotomy.

Outcome

Bedside technique Surgical technique P-value

(n=110) (%) (n=77) (%)

Body weight on day 7 (grams) 0.303

Mean (± SD) 3,083.5 (358.9) 3,028.2 (361.3)

Body weight difference (grams) <0.001

Increase 66 (60.0) 16 (20.8)

Decrease 44 (40.0) 61 (79.2)

Mean (± SD) 39.6 (14.4) -24.6 (13.7)

Percentage of body weight difference 0.003

Mean (± SD) 1.4 (0.5) -0.7 (0.5)

Exclusive breastfeeding on day 7 <0.001

Yes 96 (87.3) 30 (39.0)

Exclusive breastfeeding on the 6

month <0.001

Yes 77 (70.0) 1 (1.3)

Bedside Surgical Risk ratio (RR) P-value

Outcome technique technique (95 % CI)

(n=110) (%) (n=77) (%)

Successful rate of exclusive breastfeeding on day 7

Success 96 (87.3) 30 (39.0) 2.23 (1.68-2.99) <0.001

Not success 14 (2.7) 47 (61.0)

Overall maternal satisfaction

Satisfy 106 (96.4) 46 (59.7) 1.62 (1.34-1.94) <0.001

Unsatised 4 (3.6) 31 (40.3)

Increment of infant’s body weight on day 7

Increase 66 (60.0) 16 (20.8) 2.89 (1.82-4.58) <0.001

Decrease 44 (40.0) 61 (79.2)

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DISCUSSION

Ankyloglossia is the condition that leads to limitation

of tongue movement by the attachment of lingual frenulum

to oor of mouth. is can lead to maternal sore and

cracked nipples, and eventually a failure of exclusive

breastfeeding.

1,6

Several studies have shown the association

between ankyloglossia and unsuccessful breastfeeding. ey

found that predominant cause that brings the mothers

to the hospitals is sore nipples but aer the surgical

release, the nipple pain score has considerably improved

with a signicant correlation of the average score point

of the nipple pain before and aer the surgery.

5,9,13,34,35

However, the nipple sore that occurs in the rst 3 weeks

of breastfeeding causes 10-26% of the mothers to stop

breastfeeding.

Schlomer et al. have reported that 64-

84% of infants are diagnosed with ankyloglossia. In fact,

dicult latch on can be found in 25% of infants with

ankyloglossia compared with only 3% in normal infants.

In their study, using an infant breastfeeding assessment

tool, signicant dierence in scores between pre and

post frenulectomy has been found among ankyloglossia

infants.

e denition of ankyloglossia in our current study

was based on Siriraj Tongue Tie Score (STT Score), which

is a standard quantitative assessment tool for ankyloglossia

evaluation in ailand.

20,21

e STT score is used to evaluate

the appearance of frenulum, nipple function and sensation

of tongue when infants was latching on. e benet of

this assessment tool is that physicians and nurses can

accurately detect ankyloglossia and provide indication

for treatment.

Surgical frenulotomy performed in the

operating room with general anesthesia is a conventional

treatment for ankyloglossia. In contrast, the bedside

technique, which is currently used, is advantageous on both

the mother and the infants. is method is conveniently

performed at bedside or outpatient department without

anesthesia complications and infants can be breastfed

immediately aer the procedure.

19,39,40

However, only

few studies were conducted regarding the advantages of

bedside technique and data on the comparison between

the two types of procedures are insucient.

Our study found that the incidence of ankyloglossia

was 6.3%. e main breastfeeding problems are nipples

sore, cracked nipple and poor latch on, which are similar

to the previous studies.

5,13,34

Aer we analyzed the data

from two groups of frenulotomy procedures, we found

that infants who underwent bedside technique had a

signicant success rate of exclusive breastfeeding at day

7 as compared with the surgical procedure with general

anesthesia. e types of frenulotomy procedures are

associated with the increment of infant’s body weight

on day 7, with the bedside technique outperforming the

surgical technique. e overall maternal satisfaction rate

aer frenulotomy is higher and the length of hospital

stay is signicantly shorter in the bedside technique

than in the surgical technique. e factors that aected

dierent outcomes between the two techniques were the

mode of anesthesia. In bedside technique, we used the

TABLE 4. Comparison of nipple pain score, length of hospital stay and the dierence of infant’s body weight.

Procedure N Mean S.D.

Mean

95 %CI P-value

Difference

Nipple pain score 0.012

Bedside technique 110 1.2 0.1

Surgical technique 77 1.5 0.1 -0.3 -0.5 to -0.1

Length of hospital stay (days) <0.001

Bedside technique 110 4.4 0.2

Surgical technique 77 5.6 0.2 -1.2 -1.8 to -0.7

Difference of infant’s body weight 0.002

Bedside technique 110 39.6 14.4

Surgical technique 77 -24.6 13.7 64.3 23.5 to 105.1

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local anesthesia so the infants can immediately return to

breast fed. While we were using the general anesthesia

in surgical technique that need longer time to return to

breastfeeding aer surgery. e types of equipment we

used for frenulotomy also aected dierent outcomes. e

electrocauterization that we used in surgical technique can

cause the complication such as wound swelling more than

the scissor in bedside technique. erefore, the infants

had more length of hospital stay and the overall successful

in breastfeeding was less in the surgical technique. In

our study, we did not found the complication such as

massive blood loss, wound infection or any damage

to the tongue or salivary glands aer each procedures.

e limitation of this study is its retrospectivity where

the randomization between groups could not be done

and there is a lack of control group without undergoing

frenulotomy.

e expected benet of our research is to encourage

the physicians charge with the care of breastfeeding mothers

of infants with ankyloglossia on how to eectively select

the appropriate frenulotomy procedures. However, the

characteristics of ankyloglossia such as the thickness and

the muscular type ankyloglossia, the surgical technique

with electrocautery should be considered to minimize

the risk of active bleeding.

CONCLUSION

Ankyloglossia is one of the major issues aecting

breastfeeding of infants. The significant problems

associated with ankyloglossia are maternal nipple sore,

cracked nipples and poor infant latch on which may

cause early cessation of breastfeeding. Frenulotomy is

the procedure that should be performed in indicated

ankyloglossia infants. is study found that bedside

technique frenulotmy had association to a more satisfactory

outcome to successful breastfeeding, more increment of

infant’s body weight, higher maternal satisfaction and

also shorten duration of hospitalization than surgical

technique. Further randomized, prospective, and long-

term follow-up studies are also needed to determine

whether the types of frenulotomy is appropriate to any

infants.

ACKNOWLEDGMENTS

is work was supported in part by a service grant

from the Faculty of Medicine, Naresuan University,

ailand. We gratefully acknowledge Assoc.Prof. Dr.

Sutatip Pongchareon, Dr. Mahippathorn Chinnapha and

Judely Marish C. Canete for review of the manuscript and

Kornthip Jeephet for assistance with statistical analysis.

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Boonsopa et al.

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Original Article

SMJ

Korakrit Imwattana, M.D.*, Yodying Dangprapai, M.D., Ph.D.**, Popchai Ngamskulrungroj, M.D., Ph.D.*

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

Active Learning Classes in a Preclinical Year May

Help Improving Some Soft Skills of Medical Students

ABSTRACT

Objective: Active learning methods are an eective way to improve essential so skills, such as critical thinking

and social skills, and so medical educators frequently implement active learning approaches as a means to improve

the so skills of medical students. is study reports an improvement in the so skills of medical students aer the

implementation of an active learning curriculum.

Methods: More active learning activities were implemented in 2016 in the 3

year medical class, involving 330

students. Overall, the number of hours devoted to active learning classes was increased from 340 hours (38.2%) in

2015 to 481 hours (59.98%) in 2016. To evaluate whether this led to any improvements in the so skills of medical

students, students undertaking the 3

year course in the 2015 and 2016 academic years were asked to complete

questionnaires to evaluate themselves (self-evaluation) as well as four other students in their same study group

(peer-evaluation) at the end of the academic year. e questionnaire responses from the 2015 and the 2016 groups

were compared.

Results: Most students believed there was no improvement in most of the evaluated so skills during the year.

However, students in the 2016 class showed improvements in eleven outcomes in the peer-evaluation: presentation,

information, technology, creativity, communication, leadership, life planning, adaptability, self-suciency, courtesy,

and punctuality (p < 0.05). e dierences were not due to the students’ dierent background skills as the initial

scores of most outcomes were identical between the two student groups (p > 0.05).

Conclusion: Even without a proper design for teaching so skills, active learning classes in a preclinical year of the

medical curriculum may help improve some of the essential so skills that medical practitioners need and, therefore,

should be implemented in the medical curriculum.

Keywords: Active learning; small group discussion; medical curriculum; preclinical teaching; so skills (Siriraj

Med J 2020; 72: 415-423)

Corresponding author: Popchai Ngamskulrungroj

E-mail: popchai.nga@mahidol.ac.th

Received 2 October 2019 Revised 25 December 2019 Accepted 27 December 2019

ORCID ID: http://orcid.org/0000-0001-5162-5498

http://dx.doi.org/10.33192/Smj.2020.56

INTRODUCTION

In order to be fully prepared for the medical profession,

medical students must acquire knowledge in medicine

and master essential procedural skills, for which they

must engage in a long period of extensive higher level

learning.

But besides medical knowledge and procedural

skills, medical students also need to possess other essential

skills to function as medical professionals, including

critical thinking and communication skills, teamwork

and collaboration skills, information assessment skills,

and other life skills.

ese skills are collectively termed

‘so skills.’ However, in contrast to medical knowledge

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416

and procedural skills, so skills are hardly directly taught

or evaluated in the 6-year medical curriculum taught in

ai medical schools.

e preclinical curriculum comprises the second and

third year of the medical curriculum. Traditionally, the

preclinical curriculum in ailand is based on large-group

teaching with occasional laboratory classes. Large-group

teaching, such as lectures, are considered appropriate

for the delivery of a large amount of knowledge from the

lecturer to the students in a limited time.

4,5

However, in

this approach students passively take in knowledge with

little or no class participation, and as such, they hardly

develop any high-level learning or essential so skills

during the process.

1,6

In order for high-level learning to

be achieved and so skills to be taught, other teaching

methods are needed. We hypothesized that active learning

classes might have some eects on so skills development

or improvement in medical students.

Active learning is dened as “a teaching method that

involves students’ active participation in class.” In this

approach, instead of receiving one-way information from

lecturers, the students contribute and gain knowledge

through taking part in various activities, such as group

discussions, debates, and presentations.

Active learning has

been proven to improve students’ academic performance

and satisfaction.

8,9

Also, as students get to communicate

in class and express their ideas, active learning also

improves students’ team cooperation, critical thinking,

and presentation skills, all of which are essential so

skills.

is study tested whether there was an improvement

in the so skills outcomes of medical students aer the

implementation of an active learning curriculum, using

self- and peer-evaluation questionnaires to gather the

research data.

11,12

Although the number of hours devoted to

active learning activities was increased, the activities were

not specically designed to teach such skills. We evaluated

improvements in 14 expected so skills outcomes based

on 4 essential skills, namely medical professionalism,

learning and innovation skills, life and career skills, and

information literacy. We gathered data from students

in the modied class in 2016, which included a higher

number of hours devoted to active learning, and from

students who took the traditional class in 2015 before the

curriculum changes, and compared their results.

MATERIALS AND METHODS

Structure of the medical curriculum

Our medical curriculum structure has been described

previously in the literature.

Briey, ai medical students

enter medical school promptly aer nishing high school

and then follow a 6-year medical curriculum. e second

and third years of the curriculum, termed the “preclinical

years,” focus on the teaching of basic medical sciences

related to the normality and abnormality of human bodies,

respectively. Both preclinical years are divided into two

parts: ‘general concepts’ and ‘organ systems.’ e general

concepts and organ system parts focus on introductory

subjects and the applications of those introductory subjects

to human organ systems, respectively. No real patients

are involved in these preclinical years. e expected

knowledge outcomes of both parts of the training are

based on the Medical Competency Assessment Criteria

for National License 2012 established by the Medical

Council of ailand.

Implementation of more active learning hours in the

medical curriculum

In 2016, a change was made to the third-year medical

curriculum structure taught at the Faculty of Medicine

Siriraj Hospital, Mahidol University, ailand, to include

various active learning methods in the medical curriculum,

including both large- and small-group teaching, as shown

in Table 1. Team-based learning

, ipped classrooms

and formative evaluations were also introduced.

Creation of a tool for evaluating the so skills outcomes

As part of the new curriculum evaluation and

development, an online questionnaire was created to

assess selected so skills outcomes based on the “21

century skills” needed by modern medical practitioners

including medical professionalism, learning and innovation

skills, life and career skills, and information literacy. e

online questionnaire was critically amended and nally

approved by the medical education expert committee

of the Undergraduate Education Division, Faculty of

Medicine Siriraj Hospital. Table 2 presents an example

of the questionnaire used to evaluate 14 soft skills

outcomes of the medical students in 4 main categories:

(1) information literacy (presentation, information, and

technology), (2) learning and innovation skills (creativity

and communication), (3) life and career skills (leadership,

life planning, adaptability, and self-suciency) and

(4) medical professionalism (courtesy, responsibility,

punctuality, kindness, and honesty).

Comparison of so skills outcomes

A total of 234 third-year medical students in the class

of 2015 (before the curriculum change, thus representing

a traditional learning group) and 294 third-year medical

students in the class of 2016 (rst year of the change,

Imwattana et al.

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Original Article

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TABLE 1. Comparison of the teaching hours in the traditional (2015) and active (2016) learning curricula.

Teaching Description Teaching hours (%)

methods 2015 2016

Total number of classes 890 (100) 802 (100)

Large-group teaching (330 students per class with 1–5 instructors per class) 550 (61.80) 409 (51.00)

Traditional - Passive one-way lectures

lectures - Giving basic knowledge of the designated knowledge outcomes

430 (48.31) 170 (21.20)

Case-based - Passive one-way lectures

lectures - Giving applications of basic knowledge based on simple 120 (13.48) 151 (18.83)

clinical cases

Large active- - Interactive lectures with quizzes and instructors’ feedback

learning* - Giving applications of basic knowledge based on simple clinical 0 (0.00) 88 (10.97)

cases

Small-group teaching (5 small-groups of 5-6 students per room facilitated by 1–3

340 (38.20) 393 (49.00)

instructors and a total of 12 rooms were run simultaneously)

Traditional - Group discussions based on assigned worksheets of selected topics

group discussions* - Giving basic knowledge of the designated knowledge outcomes 24 (2.70) 14 (1.75)

- Students’ reections and instructors’ feedback

Case-based - Group discussions based on assigned worksheets of clinical cases

group discussions* - Giving applications of basic knowledge based on simple clinical 180 (20.22) 223 (27.81)

cases

- Students’ reections and instructors’ feedback

Laboratory skills* - Hands-on laboratory practice

- Students’ reections and instructors’ feedback

45 (5.06) 28 (3.49)

Demonstrative - Demonstration of laboratory results, followed by

laboratory* - Students’ reections and instructor feedback

91 (10.22) 46 (5.74)

Flipped - Pre-class assignments given 1 week in advance, followed by

classroom* - In-class students’ reections and instructor feedback

0 (0.00) 26 (3.24)

- Individual readiness assurance test (iRAT), followed by

Team-based - Group RAT (gRAT), then instructor feedback, followed by 0 (0.00) 26 (3.24)

learning* - Application exercises on clinical cases, followed by

- Students’ reections and instructors’ feedback

Formative - MCQs or short answer questions at the end of each study section

evaluations* - Students’ reections and instructors’ feedback

0 (0.00) 27 (3.37)

Project-based - A project is chosen based on student–instructor discussions

learning* - Students conduct the project over a period of 1–2 months 0 (0.00) 3 (0.37)

- Students’ reections and instructors’ feedback during the activity

*Active learning classes

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TABLE 2. Example of the questionnaire used to evaluate the 14 so skill outcomes.

Give scores representing your ability or behavior in the following aspects

5 = very good; 4 = good; 3 = neutral; 2 = bad; 1 = very bad

Soft skills

outcomes

Information literacy

1. Presentation

2. Information

3. Technology

Learning and innovation skills

4. Creativity

5. Communication

Life and career skills

6. Leadership

7. Life planning

8. Adaptability

9. Self-sufciency

Medical professionalism

10. Courtesy

11. Responsibility

12. Punctuality

13. Kindness

14. Honesty

day of year 3

At present

day of year 3

At present

day of year 3

At present

day of year 3

At present

day of year 3

At present

Lab partner 4

Lab partner 3

Lab partner 2

Lab Partner 1

Yourself

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Original Article

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thus representing an active learning group) were asked to

complete the web-based questionnaire at the end of their

respective academic year. Briey, each student received

a username and password to log in to the questionnaire.

Each student was then asked to score him or herself

(self-evaluation) and to score other four members of

his/her study group (peer-evaluation) according to the

list of so skills (Table 2). e students were asked to

score by using a Likert scale ranging from 1 (very bad)

to 5 (very good) at two time points: at the beginning

of the academic year and at the end of the academic

year. Aer excluding controversial results, including

partially lled questionnaires and questionnaires with

the same scores for all the responses, the results for each

question scored at the beginning and at the end of the

academic year were compared. To eliminate response

bias in the use of the Likert scale, the results were only

categorized as either an improvement (positive change)

or no improvement (no change). It was noteworthy,

however, that a negative change was not found in this

study.

Statistical analysis

e improvement rate of each outcome was evaluated

using the chi-square test. Scores at the beginning of the

academic year were compared between the two groups

using the Mann–Whitney U test. All the analyses were

performed using Statistical Package for the Social Sciences

(SPSS®) for Windows 18.0. Statistical signicance was

achieved at p < 0.05.

RESULTS

e number of hours involving active learning was

markedly increased in the active learning group (2016)

All the active learning classes were mainly designed

for teaching medical knowledge or procedural skills.

None of them were specically designed for teaching

so skills. Overall, the number of hours devoted to active

learning was increased in the active learning group (2016;

481 hours, 59.98%) compared to the traditional learning

group (2015; 340 hours, 38.2%). Also, the amount of

hours devoted to large-group teaching decreased (550

hours to 409 hours) while small-group teaching increased

(340 hours to 393 hours). For the large-group teaching,

the traditional lecture classes decreased (430 hours to

170 hours) while the time devoted to case-based lecture

classes increased (120 hours to 151 hours) and more large

active-learning-activities classes were introduced (88

hours). For the small-group teaching, the number of hours

devoted to traditional group discussion classes decreased

(24 hours to 14 hours) while case-based group discussion

classes increased (180 hours to 223 hours). However,

the time devoted to both hands-on and demonstrative

laboratory classes decreased (45 and 91 hours to 28 and

46 hours, respectively).

Students in the 2016 group reported more improvement

in most so skills outcomes in the peer-evaluation

Aer excluding the controversial results, there were

119 and 187 self-evaluation responses and 527 and 820

peer-evaluation responses returned from the 2015 and

2016 groups, respectively. According to the self-evaluation

results (Table 3), most students (58-100%) in both 2015

and 2016 groups believed there was no improvement in

each of their so skill outcomes. e number of those

who believed there was an improvement of these skills

were not statistically dierent comparing between the

two groups. Similarly found in the peer-evaluation results

(Table 4), as most students in both groups (65-100%)

believed there was no improvement in each so skill

outcomes of their peers. However, there were signicantly

higher numbers of the students in the 2016 group who

believed there was an improvement in these skills of

their peers. Specically, the improvement was detected

in 11 outcomes (presentation, information, technology,

creativity, communication, leadership, life planning,

adaptability, self-suciency, courtesy, and punctuality).

Both student groups had similar improvement rates

in terms of responsibility and kindness. ere was no

improvement in the honesty outcome in both groups.

Students in both the traditional (2015) and active

learning groups (2016) had similar initial scores in

most outcomes

One possible reason for the higher improvements

of the students in the 2016 group in 11 out of the 14

so skills outcomes evaluated may be that the 2016

class might have started with lower rating scores at the

beginning of the academic year, or initial scores, which

would then have allowed more room for improvement

when compared to the 2015 group. erefore, we tested

if this was such a case. e initial scores of the 11 so

skills outcomes between the two academic years were

compared. e initial scores of nine outcomes were

similar in both academic years (Table 5). e initial score

for punctuality of the 2016 class was not lower, but the

initial scores for the presentation skills of the 2016 class

were signicantly lower. Interestingly, the initial scores of

the three outcomes with similar improvements between

the two groups (namely, responsibility, kindness, and

honesty) of the 2016 class were signicantly higher in

both the self- and peer-evaluations.

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TABLE 3. Number of students showing improvements in so skills outcomes as evaluated by self-evaluation.

Outcomes Groups No improvement (%) Improvement (%) P-value

Presentation 2015 69 (58%) 50 (42%)

0.740

2016 112 (60%) 75 (40%)

Information 2015 80 (67%) 39 (33%)

0.196

2016 111 (60%) 75 (40%)

Technology 2015 84 (71%) 35 (29%)

0.150

2016 117 (63%) 70 (37%)

Creativity 2015 82 (69%) 37 (31%)

0.448

2016 121 (65%) 66 (35%)

Communication 2015 78 (66%) 41 (34%)

0.597

2016 117 (63%) 70 (37%)

Leadership 2015 79 (66%) 40 (34%)

0.338

2016 114 (61%) 73 (39%)

Life planning 2015 86 (72%) 33 (28%)

0.168

2016 121 (65%) 66 (35%)

Adaptability 2015 91 (76%) 28 (24%)

0.088

2016 126 (67%) 61 (33%)

Self-sufciency 2015 99 (83%) 20 (17%)

0.325

2016 147 (79%) 40 (21%)

Courtesy 2015 89 (75%) 30 (25%)

0.198

2016 127 (68%) 60 (32%)

Responsibility 2015 82 (69%) 37 (31%)

0.344

2016 119 (63%) 68 (37%)

Punctuality 2015 94 (79%) 25 (21%)

0.125

2016 133 (71%) 54 (29%)

Kindness 2015 92 (77%) 27 (23%)

0.789

2016 147 (79%) 40 (21%)

Honesty 2015 119 (100%) 0 (0%)

2016 187 (100%) 0 (0%)

Note: U = incalculable by Chi-square test; p-value calculated by Chi-square test.

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TABLE 4. Number of students showing improvements in so skills outcomes as evaluated by peer-evaluation.

Outcomes Groups No improvement (%) Improvement (%) P-value

Presentation* 2015 383 (73%) 144 (27%)

0.004

2016 534 (65%) 286 (35%)

Information* 2015 421 (80%) 106 (20%)

< 0.001

2016 530 (65%) 290 (35%)

Technology* 2015 421 (80%) 106 (20%)

< 0.001

2016 574 (70%) 246 (30%)

Creativity* 2015 415 (79%) 112 (21%)

0.02

2016 600 (73%) 220 (27%)

Communication* 2015 417 (79%) 110 (21%)

0.004

2016 592 (72%) 228 (28%)

Leadership* 2015 424 (80%) 103 (20%)

< 0.001

2016 546 (67%) 274 (33%)

Life planning* 2015 413 (78%) 114 (22%)

0.002

2016 579 (71%) 241 (29%)

Adaptability* 2015 429 (81%) 98 (19%)

< 0.001

2016 591 (72%) 229 (28%)

Self-sufciency* 2015 452 (86%) 75 (14%)

0.045

2016 669 (82%) 151 (18%)

Courtesy* 2015 418 (79%) 109 (21%)

0.001

2016 587 (72%) 233 (28%)

Responsibility 2015 401 (76%) 126 (24%)

0.251

2016 601 (73%) 219 (27%)

Punctuality* 2015 431 (82%) 96 (18%)

< 0.001

2016 588 (72%) 232 (28%)

Kindness 2015 438 (83%) 89 (17%)

0.702

2016 688 (84%) 132 (16%)

Honesty 2015 527 (100%) 0 (0%)

2016 820 (100%) 0 (0%)

*Statistically signicant; U = incalculable by Chi-square test; p values were calculated by Chi-square test.

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TABLE 5. Comparison of the average initial scores between the traditional (2015) and active learning (2016) groups.

Outcomes Self-evaluation Peer-evaluation

2015 2016 P-value 2015 2016 P-value

Presentation* 3.96 3.88 0.268 4.19 4.12 0.030

Information 4.18 4.18 0.751 4.35 4.29 0.053

Technology 4.21 4.26 0.692 4.41 4.43 0.381

Creativity 4.04 4.12 0.469 4.26 4.25 0.511

Communication 4.15 4.19 0.760 4.36 4.37 0.550

Leadership 3.90 3.87 0.656 4.06 4.02 0.199

Life planning 4.18 4.22 0.977 4.38 4.37 0.832

Adaptability 4.24 4.36 0.236 4.39 4.39 0.909

Self-sufciency 4.31 4.42 0.263 4.49 4.50 0.547

Courtesy 4.08 4.21 0.177 4.27 4.35 0.052

Responsibility** 3.98 4.26 0.001 4.30 4.48 < 0.001

Punctuality* 4.34 4.43 0.169 4.34 4.41 0.029

Kindness** 4.38 4.60 0.014 4.49 4.68 < 0.001

Honesty** 4.75 4.84 0.031 4.72 4.83 < 0.001

*Statistical signicance for the peer evaluation; **Statistical signicance for both the self- and peer-evaluation; p-values were calculated by

Mann–Whitney U test.

DISCUSSION

e active learning method was implemented in

the third-year medical curriculum in 2016 for teaching

medical students at the Faculty of Medicine Siriraj Hospital,

Mahidol University, ailand, as it has been proven

to enhance academic performance and independent

learning.

8,9

It has also been reported to improve many

essential so skills.

Despite the lack of a specic design

for teaching so skills, students in the active learning

group (the 2016 group) had higher improvement rates

in 11 out of the 14 so skills outcomes evaluated based

on peer-evaluation compared to the traditional group,

namely students in the 2015 class prior to the curriculum

change. is implies that the active learning method is

potentially superior to the traditional learning method

in developing some so skill outcomes. is result is

similar to that reported in a recent systematic review

of problem-based learning in China, which reported

that such improvement came from the nature of group

discussion, where students need to express their ideas

and exchange their opinions with their peers.

It should be rst noted that despite some statistical

dierence in the peer-evaluation outcomes, most of the

students in both groups believe there was no dierence in

the performances both of themselves and of their peers.

is is likely due to the short study duration as these so

skills need to be developed over a longer period of time.

A follow-up study at the end of the 6-year curriculum

may be useful to clarify this point.

e similar initial scores of nine of the outcomes

in both groups justied the higher improvement rates

of those so skills. e 2016 class even had a higher

initial score for punctuality, in which they also showed

greater improvements. The lower initial score for

presentation skills was very minimal (4.19 vs. 4.12).

However, whether the higher initial scores in the 2016

group for responsibility and kindness would result in the

no dierence in improvement between the two groups

is controversial and requires further study. Finally, no

improvement was detected in the honesty outcome.

Among the tested outcomes, the honesty outcome had

the highest initial scores in both student groups (4.72 and

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4.84 in the 2015 and 2016 classes, respectively), leaving

only a small gap for improvement. To further evaluate

the honesty outcome, a study with higher discriminatory

power is needed.

It should be noted that there was no signicant

dierence in improvement rates of any of the tested

outcomes observed in the self-evaluation responses. It is

possible that the small sample size could account for the

insignicant results from the self-evaluation questionnaires.

However, other possible factors should also be considered.

For instance, self-evaluation questionnaires are potentially

subject to bias, which may lead to obscure data, especially

in non-grade-associated outcomes, such as so skills.

Moreover, one study reported that only peer-evaluation

had a signicant correlation with educator evaluation.

ere were two major limitations to this study. Firstly,

there were higher proportions of relevant responses from

both self- and peer- evaluation in the 2016 group which

might have skewed the results. Secondly, all students

were asked to complete the questionnaire at the end

of their academic years and, therefore, had to recall

their performances at the beginning of the year. is

might lead to somewhat over- or underestimate of the

performances. However, as the two groups were treated

in the same manner, we believe these biases would be

minimal.

CONCLUSION

In conclusion, even without applying a specic

design for teaching so skill outcomes, the active learning

classes in a preclinical year of the medical curriculum

may help improve some of the so skills of medical

students. However, as self- and peer-evaluation could

be subject to bias and the Hawthorne eect, a standard

in-depth method for the measurement of the quality

of each so skill is needed. Additionally, further study

may include the study of number of time comsuming

(in hours) outside the classroom in order to prepare for

the active learning classes.

ACKNOWLEDGMENTS

is work was supported by the Faculty of Medicine

Siriraj Hospital under Grant No. R016161012. We would like

to thank Rungnirand Praditsuwan, Cherdsak Iramaneerat,

Chantacha Sitticharoon, Wanchai Dejsomritrutai,

Weerawadee Chandranipapongse, and Ananya Pongpaiboon,

Undergraduate Education Division, Faculty of Medicine

Siriraj Hospital, as members of a medical education

expert committee for their help in developing the self-

and peer-questionnaires.

Conicts of interest: None to declare

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Kunakornvong et al.

Wannapha Kunakornvong, M.Sc., Kanyapak Ngoasri, M. Econ

ailand Development Research Institute, Bangkok, ailand.

Public Awareness and Attitude toward Palliative

Care in Thailand

ABSTRACT

Objective: is study aims to examine the ai public’s awareness and attitude toward the end of life and palliative

care.

Methods: We surveyed between February and April 2018. e sampling was framed by the ailand National

Statistical Oce and used a stratied four-stage sampling. A total of 2,394 adults aged 20 to 80 years who had lived

in one of nine provinces across all of ailand for at least 3 months were interviewed with a questionnaire, which

consisted of four parts.

Results: ai culture and tradition were the main barriers to discuss the end of life preparation. Only 43% of the

respondents, most of whom were elderly with chronic diseases, had concerned about the end of life. Most elderly

respondents preferred to receive end-of-life care at home. Only 24% of respondents knew of palliative care. Most

respondents believed that palliative care was provided in public hospitals. Most respondents (92%) were familiar with

section 12 of the National Health Act., B.E. 2550, which states that a person has the right to refuse medical treatment;

however, majority (79%) had never heard of a living will and only 14% had experience of advance care planning.

Conclusion: Public awareness on the end of life preparation of ai people was challenged and limited. e main

barriers to concerns about it are attitude and knowledge. Promoting and educating palliative care is necessary as

well as improve the availability of palliative care, both institutional and home-based care.

Keywords: End of life; palliative care; advance care planning; living will (Siriraj Med J 2020; 72: 424-430)

Corresponding author: Wannapha Kunakornvong

E-mail: wannapha@tdri.or.th

Received 1 April 2020 Revised 8 June 2020 Accepted 17 July 2020

ORCID ID: http://orcid.org/0000-0002-6438-4029

http://dx.doi.org/10.33192/Smj.2020.57

INTRODUCTION

Many countries are experiencing rapid population

ageing. Because of age-related increases in cancer and non-

communicable diseases (NCDs), the need for palliative

care is also increasing. According to the World Health

Organization (WHO) Global Health Estimates, there were

approximately 54.6 million deaths in 2011, the majority

of which were caused by NCDs (66%). Moreover, over

29 million deaths were the result of diseases requiring

palliative care, and approximately 20.4 million patients,

most of whom were adults aged over 60 years (69%),

were reportedly in need of palliative care at the end of

life.

As people age, they live and die with increasingly

complex medical conditions, which in turn leads to an

increasing demand for palliative care. e WHO has

advocated that palliative care be made a public health

service because it can substantially improve the quality of

life of patients and families.

Moreover, the Worldwide

Palliative Care Alliance (WPCA) recommends in 2014

that palliative care be integrated into health systems

alongside curative care. In fact, palliative care should

be provided even when curative care is unavailable.

Unfortunately, the World Health Assembly has

noted that the availability of palliative care services is

limited worldwide-more than 40 million people globally

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were in need of palliative care in 2016, most of whom

live in low and middle income countries; only 14% of

these individuals, however, actually received palliative

care.

1,3,4,5

Most of the developing countries are facing

challenges of resourcing, availability of morphine, number

of hospice-palliative care services.

Many countries are aware of the increasing need

for palliative care and thus have begun concentrating

on the development of palliative care services. e rst

step to this end is understanding public awareness of

the end of life and palliative care. International studies

on public awareness of palliative care have been used

as evidence in support of the development of palliative

care systems suitable to a given context. ese studies

revealed that the main barriers to use of palliative care

were attitudes based in the culture and traditions of the

country, along with knowledge of palliative care, especially

among the developing countries.

6,7,8,9

Furthermore, most

people were found to experience an end of life that t

with their way of life and culture and preferred home as

the place of death.

10,11,12

Overall, palliative care services

are facing many challenges, especially in developing

countries, where there is need to change the traditionally

negative attitudes toward the end of life and palliative

care, as well as increase knowledge and health care system

resources for the same.

13,14

Table 1 shows a summary of

the literature review public awareness of palliative care

and the end of life.

TABLE 1. Summary of literature review on public awareness of palliative care.

Author Country Sample Methodology Findings

Australian Department Australia • 750 members of the • Focus group • 75% heard about PC

of Health and Ageing general population • 41% able to explain PC

2003

• 100 patients and • 37% had experience with PC

family members • 51% were informed of PC by

doctors

McIlfatrick et al. Northern Ireland • 600 members of the • Postal and online • 56% unaware of PC

2011

Patient and Client survey • Culture and traditions

Council for Northern were the main barriers

Ireland, all aged • Lack of resources

18 years or older for promoting PC

MacLeod et al New Zealand • 1,011 adults aged • Online survey • 65% aware of PC

2012

18 years or older • 82% agree that PC is an

important service

• Aged was related to awareness

of PC

Harris/Decima Inc. Canada • 2,976 adults aged • Online survey • > 50% aware of PC

2013

18 years or older • Home was the preferred place

of death of the majority

• Culture and traditions were the

main barrier

Hospis Malaysia Malaysia • 600 adults aged • Three levels of • National study: 56,384 patients

2016

over 20 years study (national level, needed palliative care (96.1%

provider level, and were adults and 3.9% were youth)

community level) in 2012

• Interview survey • Provider study: lack of health

professionals on PC

• Community study: >50% unaware

of PC and 72.4% reported that

PC services should be covered

by public health

Abbreviation: PC = palliative care

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Kunakornvong et al.

According to a 2011 WPCA report on the level of

palliative care development, ailand is designated as

level 3a, which means “isolated palliative care provision”.

More specically, it means “development of palliative care

activism that is patchy in scope and not well-supported;

source of funding that is oen heavily donor dependent;

limited availability of morphine; and a small number of

hospice-palliative care services that are oen home-based in

nature and limited in relation to the size of the population”.

Like other countries, ailand is experiencing changing

demographics due to an ageing society, which has led to

an increasing demand for palliative care services. In 2015,

more than 23% of deaths were due to cancer, of which

61% were elderly deaths which related to the number

of palliative care needs.

However, health care costs

are comparatively higher at the end of life than during

other periods of life, and can lead to catastrophic health

expenditure especially among poor households.

e ai government adopted the National Health

Act, B.E. 2550 in 2007, Section 12 of the National Health

Act endorsed the right of terminally ill patients to refuse

futile medical interventions to prolong natural death or

to end the severe suering from that illness by writing a

living will as a part of advance care planning of palliative

care. e National Health Act provides a legal tool for

society to respect patient’s right to self-determination,

and it is not to hasten death or active euthanasia or

mercy killing.

e research aims to explore public awareness,

attitudes, and knowledge regarding palliative care in

ailand.

MATERIALS AND METHODS

We conducted a questionnaire survey using the

ailand NSO’s sampling frame and a four-stage stratied

sampling method. In the rst stage, nine provinces were

randomly selected to represent each part of the country.

ese provinces included Chiang-Rai and Sukhothai

from the north, Khon-Kean and Buri-Rum from the

northeast, Ayutthaya and Rayong from the center, Trang

and Surat-ani from the south, and Bangkok. In the

second stage, 24 enumeration areas in each province were

randomly selected. In the third stage, 20 households in

each enumeration area were randomly selected. Finally,

people aged 20–80 years who had lived in each of the

households for a minimum of 3 months were randomly

selected.

In total, 2,394 adults were interviewed face to face

using a structured questionnaire during February and

April 2018. is questionnaire was adopted from similar

studies in other countries, translating into ai language

and develop some questions to be more suitable with

ai context.

6,7,18

e questionnaire was divided into four

parts: 1) respondent demographic characteristics consisted

of 12 questions; 2) information on the respondent’s

attitude toward end of life consisted of 6 questions; 3)

information on the respondent’s knowledge, attitudes and

expectations toward palliative care and related legislation

consisted of 9 questions; and 4) information on advance

care planning consisted of 4 questions.

e interview took approximately 20 minutes. At the

beginning of interview, each respondent was informed

the objective and the steps of interview in the research,

then was asked to sign on consent form to participate

in the research. At the end of the interview, respondents

received an umbrella costing about 100 THB as a gi of

appreciation.

is research is approved by Khon-Kaen University

Ethics Committee in Human Research (HE 603032). e

institutional review board number was IRB00008614.

e project is approved by ethics committee and

the preserve respondent’ anonymity was concern by the

researchers, the personal information of the respondents

was recoded, and the results were shown as overall

population. e data were analyzed by using Microso

Excel 2016, Tableau Soware version 10.5 and IBM SPSS

Statistics 24.

RESULTS

Of the 2,394 respondents, 60% were female, 47%

were aged 40–59 years, 74% were married or in a couple,

74% were covered under the universal health insurance

scheme, 73% were employed, and half had education

level at secondary school and below. e average family

size was 4.2 persons and the average household annual

income was 9,692.52 USD.

Nearly all respondents

(95%) had a good health status and thought that their

health would worsen as they aged.

Public Awareness of End of Life

Less than half (43%) of respondents were concerned

about the end of life, and this proportion was higher

among respondents older than 60 years of age (60%)

and respondents with poor health (66%) as well as had

education at secondary and below (53%).

Furthermore, only 37% of respondents had ever

had a discussion about the end of life, with 33% holding

discussions with family members and 2% with doctors.

e main barriers to holding discussions about the end

of life were culture and tradition, the perceived diculty

of beginning such a discussion, and the knowledge that

talking about the end of life cause family members to

become upset.

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TABLE 2. Characteristics of respondents.

Number %

Gender Male 954 39.85

Female 1,440 60.15

Age (years) 20–29 228 9.52

30–39 349 14.58

40–49 550 22.97

50–59 578 24.14

60–69 483 20.18

70–80 206 8.60

Marital status Single 356 14.87

Marriage 1,774 74.10

Widow 205 8.56

Divorce 59 2.46

Education Secondary school and below 1,215 50.75

High school 737 30.79

University 442 18.46

Current health status Good health 2,260 94.40

Poor health 134 5.60

Employment Civil servant 46 1.92

Public employee 59 2.46

Private employee 371 15.50

Employer/owner 920 38.43

Unemployed 658 27.49

Other 340 14.20

Public health insurance Civil Servant Medical Benets 108 4.51

Universal Health Coverage 1,770 73.93

Social Security Scheme 472 19.72

Other 44 1.84

Household annual income Average (USD)

Total 9,692.52

Bangkok 11,552.66

Central 13,275.37

Northeast 4,159.94

Southern 1,4301.45

Northern 5,142.61

Remark: 1 USD = 32.669 THB (Bank of ailand 18.09.2018)

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Kunakornvong et al.

e majority of respondents preferred receiving

palliative care at home (59%), with a minority opting

to receive care at the hospital (40%). e preference was

related to the age of respondents, with older respondents

being more likely to prefer care at home. e chi-square

test showed that the age of respondents who prefer care

at home signicantly dier from those prefer care at

hospital. (Chi-square = 73.493, df = 4, P-value = 0.000).

Knowledge, Attitudes, and Expectations towards

Palliative Care

Only about one fourth of the respondents knew of

palliative care. However, 88% of respondents reported

that palliative care is provided to all patients at the

end of life, regardless of their illness; only about 5% of

respondents reported that palliative care services were

for only patients dying of life-threatening disease such

as cancer or HIV/AIDS. Furthermore, most respondents

(87%) believed that palliative care was mainly provided in

public hospitals, while 33% believed that it was provided

at home and 24% believed that it was provided at private

hospital.

Most respondents expected that palliative care involved

medical services, medical equipment, and psychological

support (with 97%, 97% and 95% respectively), while

fewer expected it to involve spiritual and social care or

homemaking (41% and 37%, respectively). Nevertheless,

98% of respondents strongly agreed that palliative care

should be integrated into care for anyone with chronic

or life-limiting conditions that palliative care should be

provided in a setting chosen by patients, that palliative

care improves quality of life of patients, and that palliative

care greatly reduces stress and burden placed on a patient’s

family.

Eighty percent of respondents indicated that palliative

care should be a service provided by a public institution

aliated with a central or local government, and importantly

palliative care services should be provided as one of benet

package under the public health insurance scheme. About

17% of respondents mentioned that family members

had the responsibility of looking aer patients receiving

palliative care. Only a few respondents (4%) suggested

including palliative care into private insurance schemes.

e doctor was the main source of information for people

seeking for information on palliative or end-of-life care

(56%), followed by health center or community health

volunteers (14%), and web pages or other media (8%).

Advance Care Planning

Advance care planning refers to the process of reecting

and communicating a written desire to let other know

the needs of patients as well as pre-treatment planning.

Advance care planning can include communication

of patient preferences, advance decisions, and proxy

nominations.

ailand enacted National Health Act, B.E. 2550

on March 3, 2007. As noted earlier, section 12 of this act

concerns end of life and advance care planning. About

92% of respondents seem to understand legally context

as situations related to section 12. Despite this, only 21%

of respondents had heard of advance care planning, with

a greater proportion of female respondents than male

respondents being aware of such care planning (23%

and 17% respectively). e proportions of respondents

who knew of advance care planning were higher among

those aged 40–59 years (24%) and those living in Bangkok

(44%).

ere are three main public health insurance schemes in ailand: the Civil Servant Medical Benet scheme (CSMBS), Social Security Scheme (SSS) and

Universal Healthcare Coverage Scheme (UCS). e UCS covers the majority of ais.

1 USD = 32.669 THB (Bank of ailand 18.09.2018)

Fig 1: End of life concerns and preferred place of death by age group (shown as %).

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Original Article

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Only 14% of respondents had experience of advance

care planning or a living will. Aer respondents received

information about advance care planning, 72% of respondents

planned to perform advance care planning and living

will. However, 13% insisted that they did not want such

planning ahead of death.

Many patients desired to receive end-of-life care at

home, but were admitted to the hospital anyways. e

main reasons for the admissions were the recommendation

of a physician or health care provider, agreement among

family members, and the decision of a caregiver based

on the belief that healthcare providers could manage

the patient’s pain and symptoms.

DISCUSSION

e main barrier was culturally determined negative

attitudes and poor knowledge toward end-of-life care.

e end of life remains an avoided topic of discussion

among ais, just as among citizens of developed countries

such as Canada and Northern Ireland.

6,7,8

e second

barrier was a lack of knowledge of palliative care. Most

respondents reported that they were unaware of dying and

palliative care. A higher proportion of older respondents

had an awareness, likely because of their higher risk of

health problems (especially chronic illness) and the fact

that they are the population group with greatest need for

palliative care.

However, the promoting and educating

for all population is necessary to improve awareness and

attitude toward palliative care such as adding palliative

care in teaching program.

For the majority of ais, the home was the preferred

place of care and death, much the same the populations

of other countries.

10,11,12

Some countries showed large

variations in preferred place of death according to healthcare

resources, availability of a hospital, availability of long-

term care beds, and the number of health personals.

10,11

Obtaining sucient healthcare resources is a challenge

in the development of palliative care systems.

While

home is the preferred place of care and death for the

majority of individuals, the limited coverage of a health

system can be a barrier to the provision of home-based

palliative care. As a result, patients and families bear the

brunt of home care costs. e cost of care has been found

to dier according to place of care-at home, palliative

care costs in the last month of life were 826.47 USD,

while at the hospital, the costs were 1,377.45 USD.

us, home-based palliative care costs less than does

hospital-based care for patients. Promoting home-based

palliative care would be more cost-eective for patients,

meaning that home care services should be improved to

better serve patients’ need for palliative care. Moreover,

an eective referral system should be created to improve

the linkage between institutional and home care.

Palliative care has been promoted as an approach to

improve the quality of life of patients and families, and

covers prevention, treatment, and management of other

problems, whether physical, mental, or spiritual.

found that only one out of every ve respondents knew of

palliative care; however, most ais knew that palliative

care was meant for all end-stage patients, regardless of

their illness, and perceived that it was primarily focused

on medical care rather than social or spiritual care.

However, the concepts of advance care planning

and euthanasia are much more widely debated. ai

law has granted people the right to choose to die in a

passive manner.

Active euthanasia or mercy killing is

not considered legally or ethically acceptable in ailand,

unlike in countries such as Switzerland, Belgium, the

Netherlands, and the United States.

21,22

In addition, some

developed countries have a longstanding practice of

publicly discussing and empowering society to directly

deliberate on euthanasia issues.

As noted above, the World Health Assembly indicated

that palliative care service has limited availability across the

world, especially in low and middle income countries.

1,3,4,5

Palliative care can be further developed in these countries by

managing its barriers and thereby raising public awareness,

particularly by changing culture-bound attitudes and

increasing available resources. Enhancing the knowledge

and skills of health care providers involved in institutional

and community-based palliative care is also necessary.

Increasing communication among health professionals

or health care providers and the population may also be

important, given that health care providers are the key

information source of palliative care.

CONCLUSION

e ageing population is leading to an increasing

need for palliative care. Despite this, the development of

palliative care services continues to face challenges. In

ailand, end of life remains a topic of discussion to be

avoided, and the main barriers to discussing the end of

life are culture-bound attitudes and limited knowledge of

palliative care. Promoting and educating palliative care

for general population is necessary as well as improve

availability of palliative care both institutional and home-

based care as home was preferred place of death.

ACKNOWLEDGMENTS

e researchers wish to express their deepest thanks to

all those who helped in completing the study: the National

Statistical Oce, ai Health Promotion Foundation,

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430

and the ailand Development Research Institute. e

researchers want to specially thank Associate Professor

Dr. Worawan Chandoevwit, who provided suggestions

and encouragement.

Competing interest: No competing nancial or non-

nancial conicts of interest exist.

Funding: is research was supported by the ai Health

Promotion Foundation and Thailand Development

Research Institute.

List of abbreviations

WHO = World Health Organization, NCD = non-

communicable disease, WPCA = Worldwide Palliative

Care Alliance

REFERENCES

1. World Health Organization. Global atlas of palliative care at

the end of life. [Online]; 2014 [cited 2016 July 28]. Available

from: www.who.int/nmh/Global_Atlas_of_Palliative_Care.

pdf.

2. Davies E, Higginson I. e solid fact: Palliative care. [Online];

2004 [cited 2016 July 28]. Available from: www.euro.who.

int/_data/assets/pdf_le/0003/98418/E82931.pdf?ua=1.

3. World Health Organization. Palliative care for non-communicable

diseases: a global snapshot in 2015. [Online]; 2018 [cited 2018

October 19]. Available from: http://apps.who.int/iris/bitstream/

handle/10665/206513/WHO_NMH_NVI_16.4_eng.pdf?

sequence=1.

4. World Health Organization. Palliative care. [Online]; 2018

[cited 2018 October 19]. Available from: http://www.who.int/

en/news-room/fact-sheets/detail/palliative-care.

5. World Health Organization. 10 facts on palliative care. [Online];

2017 [cited 2018 October 19]. Available from: http://www.

who.int/features/factles/palliative-care/en/.

6. Anderson R, Grant L. What is the value of palliative care

provision in low-resource settings? BMJ Global Health 2017;2:

1-3.

7. Groeneveld EI, Cassel JB, Bausewein C, Csikós A,Krajnik M,

Ryan K, et al. Funding models in palliative care: lessons from

international experience. Palliat Med 2017; 31:296‐305.

8. Canadian Hospice Palliative Care Association, What Canadians

say: The way forward survey report, for the way forward

initiative. [Online]; 2013 [cited 2018 October 19]. Available

from: http://www.hpcintegration.ca/resources/what-canadians-

say.aspx

9. Malaysia H. Palliative care need assessment report. [Online];

2016 [cited 2018 October 19]. Available from: https://www.

hospismalaysia.org/wp-content/uploads/2016/10/Palliative-

Care-Needs-Assessment-Malaysia-2016.pdf

10. McIlfatrick S, Hasson F, McLaughlin D, Johnston G, Roulston

A, Rutherford L, et al. Public awareness and attitudes toward

palliative care in Northern Ireland. BMC Palliative Care

2013;12:1-7.

11. MacLeod RD, ompson R, Fisher JW, Mayo K, Newman

NW, Wilson DM. New Zealanders’ knowledge of palliative

care and hospice services. N Z Med J 2012; 125:51‐60.

12. Cohen J, Pivodic L, Miccinesi G, Onwuteaka-Philipsen

BD,Naylor WA,Wilson DM, et al. International study of the

place of death of people with cancer: a population-level comparison

of 14 countries across 4 continents using death certicate data.

Br J Cancer 2015;113:1397‐404.

13. Neergaard MA, Jensen AB, Sondergaard J, Sokolowski I, Olesen

F, Vedsted P. Preference for place-of-death among terminally

ill cancer patients in Denmark. Scand J Caring Sci 2011;25:627‐36.

14. Gauthier G, Bernard E, Darrieux JC. End of life at home

and preference for a place of death: a literature review. Exercer

2015;118:52-60.

15. Lynch T, Connor S, Clark D. Mapping levels of palliative care

development: a global update. J Pain Symptom Manage 2013;

45:1094‐106.

16. Ministry of Public Health. Public Health Statistics 2015

Nonthaburi: Strategies and Planning Division; 2015.

17. e National Health Commission Oce. National Health

Act, B.E. 2550 (A.D. 2007). [Online]; 2017 [cited 2018 October

19]. Available from: https://en.nationalhealth.or.th/wp-content/

uploads/2017/11/HealthAct07.pdf.

18. e Australian Institute of Health and Welfare. Palliative care

services in Australia. Canberra: e Australian Institute of

Health and Welfare; 2013.

19. Chandoevwit W, Vajragupta Y. Long term care insurance

system: Long term care system for ailand (in ai). Bangkok:

ailand Development Research Institute (TDRI); 2017. Report

No.978-616-92250-5-8.

20. World Health Organization. WHO denition of palliative care.

[Online]; 2018 [cited 2018 October 17]. Available from: http://

www.who.int/cancer/palliative/denition/en/.

21. e National Health Commission Oce. ai living will (in

ai). [Online]. [cited 2018 October 19]. Available from: http://

www.thailivingwill.in.th/.

22. Bosshard G, Fischer S, Bar W. Open regulation and practice

in assisted dying: How Switzerland compares with the Netherlands

and Oregon. Swiss Medical Weekly 2002; 132:527-34.

23. Nunes R, Rego G. Euthanasia: A challenge to medical ethics.

J Clin Res Bioeth 2016;7: 1000282.

24. Millintangkul U. National policy on palliative care in

ailand. [Online]; 2015 [cited 2019 June 2]. Available from:

https://en.nationalhealth.or.th/wp-content/uploads/2017/11/

NationalPolicyonPCare2015_09_17-1.pdf.

Kunakornvong et al.

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Review Article

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Paisit Siriwittayakorn, M.D.

On behalf of the Royal College of Surgeons of ailand and Division of Gastrointestinal Surgery and Endoscopy, Department of Surgery, Faculty of

Medicine, Chiang Mai University, Chiang Mai, ailand.

Announcement of the Royal College of Surgeons

of Thailand on Guidance for Surgery in COVID-19

Patients

ABSTRACT

COVID-19 has demonstrated signicantly impact on healthcare professionals practice including surgeons. e

Royal College of Surgeons of ailand (RCST) has developed the “Guidance for Surgery in COVID-19 Patients”

for surgeons and related medical personnel to handle surgical care during COVID-19 pandemic.

COVID-19 is the newly emerged outbreak, the understanding of its nature, also the prevention and control of

this disease is limited. Since there are very few studies on this new coronavirus, some knowledge and assumption

were drawn from the lesson learnt from the outbreak of SARs and MERs (both are also RNA coronavirus) in the

past. erefore, the recommendation, as stated in this manuscript, needs to be updated accordingly to the current

situation. e medical practitioners need to cling on the new status of COVID-19 constantly. In case that anyone

who has any relevant information and want to bring to our attention, please email to siriwittayakorn@gmail.com.

With no legal eect, this guidance should contemporarily conform to the occurrence (current situation or

incident), character (internal factors of the patient), and circumstances (external factors of the patient, e.g. hospital

resources, equipment, and capacity).

Keywords: COVID-19; Guidance for Surgery; RCST (Siriraj Med J 2020; 72: 431-435)

Corresponding author: Paisit Siriwittayakorn

E-mail: siriwattayakorn@gmail.com

Received 29 April 2020 Revised 11 May 2020 Accepted 12 May 2020

ORCID ID: http://orcid.org/0000-0003-2588-5469

http://dx.doi.org/10.33192/Smj.2020.58

INTRODUCTION

COVID-19 is an RNA virus. Until now (April

2020), it is believed that the disease can be spread out

via two modes of transmission, which are respiratory

droplets (thus, a person should stay at least 2 meters

away from a carrier, and a medical-grade mask/respirator

is required for protection), and contact transmission,

caused by contact with infectious secretions and then

manipulate T-zone mucous membrane of face with

contaminated hand. It is not clear confirmed that

COVID-19 can be transmitted via respiratory aerosol

or not, even though, WHO has warned about respiratory

aerosol transmission. Also, there is no shown evidence

to prove that the disease can be transmitted via blood

transfusion, even the coronavirus has been reported

found in lymphocyte. In RNA coronavirus family, SARS

and MERs, both of them are not infected through blood

transfusion. However, the patients infected by COVID-19

are not recommended to donate their blood for at least

28 days aer being completely cured. As the evidence

on the infection via blood infusion remains unclear,

the surgeons should comply with the measurement

for surgery in AIDS patients in those cases infected by

COVID-19.

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Overall Disease Management in Hospital

Recommendations

1) Limit numbers of regular patients. Separate patients

with acute respiratory illness from other patients.

2) Implement technology such as telemedicine to

screen and to manage patients.

3) Limit numbers of medical personnel to contact

patients.

4) Avoid face-to-face communication. Alternatively,

communicate through divider screen or via telephone/

VDO conference system.

5) Limit numbers of accompany person of the patient.

6) Group patients with similar disease in the same

zone.

7) All relevant stas, including patient transfer stas and

cleaners, must be well-trained for putting on,

removing, leakage testing, and disposing of PPE.

8) In case that there are limited N-95 respirator, give

priority to the person/sta in need.

9) ere should be divider curtains in the waiting area

to separate patient individually. If the waiting area

has enough space, each patient shall stay at least 2

meters away from others.

10) Zone the patients with infectious respiratory

diseases separately. Infected cases must be isolated

in AIIR that reserved only for COVID-19 cases.

11) Conduct the intensive training for emergency

physicians to handle COVID-19 cases.

12) Set up a joint operation team to handle the COVID-19

cases. A team consists of a surgeon, an anesthesiologist,

a pulmonologist, and an infectious disease specialist.

13) Avoid using a central air-conditioner.

Surgeons and Resource Management during the pandemic

During pandemics, the preserving of limited resources

and workforce is mandatory. Surgeons need to manage

available resources (including workforce, equipment,

drug, and consumable) with eciency to deal with the

unpredictable situation.

Recommendations

1) Postpone all non-urgent operations indenitely

or until the situation returns to normal. All patients

are ocially informed with written notication.

2) Minimize the numbers of patients and the frequency

of OPD visit. Use alternative channels such as phone

call or social media for the patient follow-up. Advise

the patients to receive medication from the hospital

in the closed-by location instead.

3) Ban signicant events and social gatherings, especially

events of the same surgical specialty. Use teleconference

as an alternative.

4) Allow only one accompanying person per patient.

5) Measure the hospital capacity (including the numbers of

ORs, ICUs, ventilators, wards, beds, facilities,

consumables, and workforce) to assess the readiness

of each hospital and the country in overall.

6) The hospital should arrange laboratory testing

with a high rate of speed, accuracy and eciency. e

delayed result leads to wastage of resource uses during

the quarantine. Precise and expedited testing result

help to downsize the preparation to handle potential

COVID-19 cases. It keeps down the expense and

workforce.

7) Start fundraising to cover the increasing expenses

of necessary supplies, due to the lack of government

funding.

Patient Transport

Recommendations

1) Patient transfer staffs must be well-trained for

putting on and removing PPE.

2) Secure the route from ward/ICU to the OR (including

elevator) and vice versa route with stas in-charge.

Use only a designated route that prevents contamination

of other people. Not allow other people to access

the designated route on the same day.

3) All non-intubated patients should wear their medical-

grade mask.

4) Transport respiratory used for COVID-19 patients

must be separated from those for other patients.

At Operating Room

Recommendations

1) e OR for COVID-19 patients should be with a

negative pressure environment, located at a corner

of the operating complex, and separated from the

setting for non COVID-19 cases.

2) Crucially understand the airow within the OR. It

needs to ow from non-contaminated to contaminated

area, to minimize the risk of infection.

3) Use the same OR and the same anesthesia machine

only for COVID-19 cases. Place an additional HME

with HEPA lter on the expiratory limb of the

circuit. Both HME with HEPA lter and soda lime

are changed aer each case.

4) Before starting the case, the anesthesiologist prepares

all required drugs and equipment onto a trolley,

each trolley for each operating room. Try not to

move the trolley between the rooms. In case that

the additional drugs or equipment are needed during

the case, glove changing and hand hygiene with 70%

alcohol are required before handing the drugs

trolley in the other room.

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Review Article

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5) Provide enough amount of airway equipment. Use

disposable airway equipment.

6) Handle a video-laryngoscope, if needed, concisely.

Decontaminate the video-laryngoscope with an

eective disinfectant agent aer use. Avoid repeated

instrumentation before decontaminate the instrument.

7) All machines/equipment in limited supply in OR

setting such as monitors and infusion pumps need

to be thoroughly wiped down aer uses.

At Induction Room

Recommendations

1) Follow the “Practical Recommendations for Caring

of COVID-19 or Suspected COVID-19 Patients”,

issued by e Royal College of Anesthesiologists of

ailand. Use this guidance as an additional guideline.

2) Minimize number of personnel in the induction

room.

3) Designated stas keep N-95 respirator or PAPR

on during the procedure. In case of a patient with

a tracheostomy, all stas at induction room must

wear N-95 respirator throughout.

4) Regional anesthesia is preferable.

5) If general anesthesia is required, aerosol-generating

procedure (e.g. manual ventilation before intubation,

tracheal intubation, non-invasive ventilation,

tracheostomy, bronchoscopy, CPR, etc.) shall be

conducted concisely. All aerosol-generating procedure

shall be done in an adequate ventilation room (at

least 160 L/sec/patient) or in a negative pressure

room with at least 12 air changes/hr.

6) In order to reduce aerosol generation, intubation

shall be conducted by a well-practiced anesthesiologist.

7) For induction, pre-oxygenation with 100% oxygen

and the rapid sequence induction (RSI) are required.

e manual ventilation is not recommended due to

the spread of disease. In the signicant cases, such as

the patient with very high alveolar-arterial oxygen

gradient, patients who cannot tolerate an about

30 second apnea, or those who cannot be administered

succinylcholine, must comply with low tidal volume

manual ventilation before intubation.

8) Avoid using awake ber-optic intubation.

9) If need, tracheal intubation should be done. Do not

perform ventilation support using laryngeal mask.

10) In the signicant respiratory failure case outside OR,

intubation is recommended instead of a non- invasive

ventilator.

11) For CPR, do not perform chest compressions while

conducting intubation. Administration of neuro-

muscular blockade is required before intubation.

During the Operation

Recommendations

1) Follow transmission-based precautions, including

- at least, standard respirator, such as: N-95

(US Standard) or FFP2 (European Standard).

Updated respirator t testing is required.

- goggles, or face shield

- uid-resistant gown

- gloves

- cases which are required aerosol-generating

procedure (AGPs) should be operated in AIIR.

- orthopedic surgical cases need to proceed

with extra caution to minimize the risk of

aerosolized contaminants.

2) Get all necessary instruments/consumables prepared

before the operation

3) Avoid some surgeries which have to be done under

high pressure, such as Laparoscopic Surgery, Robotic

Surgery, ese may increase the risk of aerosolized

contaminants.

4) Avoid taking unnecessary items into the OR (e.g.

radiograph, medical record, mobile phone, etc.)

5) e circulating nurse shall be stationed outside the

OR. If additional items are needed during the

procedure, these items shall be placed onto a trolley

that le in the ante room for the OR team to retrieve.

is same process in reverse is used to send anything,

such as specimen for frozen section, out of OR.

6) A minimum of ONE hour is planned between cases

to allow OR sta to send the patient back to the

ward, conduct thorough decontamination of all

surfaces, screens, keyboard, cables, monitors, and

anesthesia machine.

7) All unused drugs and consumables placed in the

OR should be assumed to be contaminated and

need to be decontaminated or discarded.

Post-Operation

Recommendations

1) Remove used gown and gloves in ante room. Touch-

free disposal bin is needed for discarding PPE.

2) Perform hand hygiene before leaving ante room.

3) Remove respirator or PAPR outside ante room.

4) The patient who does not require ICU care

postoperatively is fully recovered in the OR itself.

Once ready for sending back, the patient is transferred

via a designated route back to the isolation ward.

5) Take a shower, including washing your hair,

immediately aer case.

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Disinfectant Agents

Recommendation

1) Conduct thorough decontamination of all surfaces

in OR with Hydrogen peroxide vaporizer.

2) Clean and disinfect the contaminated area with

soapy water or detergent, and re-clean with alcohol-

based hand rub (70% ethyl or Isopropyl alcohol),

Quaternary Ammonium Disinfectant, or Potent

Oxidizer. e disinfection can be eective if the

exposure time is within the range of 30 seconds to

10 minutes, depends on the type of disinfectant

agent.

3) Faculty of Pharmacy, Ubon Ratchathani University

(UBU) introduces the cleaning and disinfection

guideline for non-hospital settings (Table 1). is

guideline can be adapted for a hospital setting as

well. (Announced in March 2020)

- Block o the contaminated area for clean-up

- Put on well-fitting personal protective equipment (PPE)

- Use cleaning equipment/tool that has a handle.

- Open doors and windows to increase airow.

- Wash clothes on 70°C degrees for at least 25 minutes.

- Disinfect reusable cleaning equipment.

- Clean oor and other surfaces with disinfecting

wipes. Do not use the pressure-washers to avoid

aerosolization. (is recommendation is reinforced

by Infectious Disease Association of ailand on

10 April, 2020)

- Discard any infectious wastes properly.

TABLE 1. e cleaning and disinfection guideline for non-hospital settings by Faculty of Pharmacy, Ubon ratchathani

Univesity (UBU).

Disinfectant Agents Unit of Concentration Recommended for Caution

Bleach 0.05% general surfaces strong odors, corrosive,

(Sodium hypochlorite) (1 part : 99 parts water) causes irritation to skin

Bleach 0.5% surface contaminated strong odors, corrosive,

(Sodium hypochlorite) (1 part : 9 parts water) with bodily uids spills, causes irritation to skin

toilet bowl (leave on

surface for at least 15 min )

Alcohol 70% metal surfaces causes irritation to skin,

cause rust stains

4.8% Chloroxylenol 2.5% cloth washing, causes irritation to skin

(Dettol) (1 part : 39 parts water) cleaning surfaces

(soak in or leave on

surface for at least 5 min)

4.8% Chloroxylenol 5% household utensils causes irritation to skin

(Dettol) (1 part : 19 parts (soak in for at least 5 min)

70% alcohol)

Laundry detergent mixed with 70°C degrees cloth washing causes irritation to skin

water

Siriwittayakorn et al.

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Review Article

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REFERENCES

1. Guidance of National Health Service (NHS) 2020, UK.

2. Ti LK,Ang LS,Foong TW,Ng BSW. What we do when a

COVID-19 patient needs an operation: operating room reparation

and guidance. Can J Anaesth2020 Mar 6. doi: 10.1007/s12630-

020-01617-4. [Epub ahead of print]

3. Peng PWH,Ho PL,Hota SS. Outbreak of a new coronavirus :

what anesthetists should know? Br J Anaesth.2020 May;124(5):

497-501. doi: 10.1016/j.bja.2020.02.008. Epub 2020 Feb 27.

4. Seminar on Prevention & Treatment of COVID-19: Experience

from China. Co-hosted by Medical Association of ailand,

teleconference on 07 April, 2020.

Abbreviation

AIIR = Air borne Infection Isolation Room

HME = Heat + Moisture Exchange

PAPR = Powered Air-Purifying Respirator

PPE = Personal Protective Equipment i.e. well-tted

respirator/mask, safety goggles or face shield, splash-

resistant gown, latex gloves, and boot covers

HEPA = High Eciency Particle Air

Volume 72, No.5: 2020 Siriraj Medical Journal

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436

Santosh Kumar Swain, MS, DNB, MNAMS*, Somadatta Das, MA**, Rabindra Nath Padhy, Ph.D. **

*Department of Otorhinolaryngology, **Central Research Laboratory, IMS and SUM hospital, Siksha “O” Anusandhan University, K8, Kalinganaga

r,Bhubaneswar-751003, Odisha, India.

Performing Tracheostomy in Intensive Care Unit-

A Challenge duringCOVID-19 Pandemic

ABSTRACT

COVID-19 is a rapidly spreading infection caused by novel corona virus. It is a challenging to the medical

community in an unprecedented degree. Clinicians and health care workers are at added risk for infection during

the procedure performing at the intensive critical care unit (ICU). Tracheostomy is a common surgical procedure

performed at ICU for prolonged ventilation of the patient. Performing tracheostomy is currently a challenging for

otolaryngologist at the ICU because of high chance of spread of the virus to the surrounding health care workers

and also to the other patients. e location for this procedure in ICU should be well ventilated and the pressure in

the room must be maintained negative or neutral. e health care personnel particularly Otolaryngologists have

a central role for managing this situations where they are assessing the patients, preventing the contamination

to other assisting sta and other patients. As there is progressive rise of the COVID-19 patients worldwide, it is

surely expected that several patients may need intubation and mechanical ventilation. So, in this condition, patient

my require tracheostomy for prolonged ventilation. Because of the very minimum literature available regarding

tracheostomy in the COVID-19 pandemic, so this review article will surely increase awareness among health care

workers and surgical team for prevention of the transmission of the infection from tracheostomy to medical stas

and other patients.

Keywords: COVID-19 pandemic; tracheostomy; intensive care unit; aerosolization (Siriraj Med J 2020; 72: 436-442)

Corresponding author: Santosh Kumar Swain

E-mail:santoshvoltaire@yahoo.co.in

Received 29 April 2020 Revised 29 May 2020 Accepted 5 June 2020

ORCID ID: http://orcid.org/0000-0001-7457-4443

http://dx.doi.org/10.33192/Smj.2020.59

INTRODUCTION

Currently we are facing a devastating pandemic

with a great impact on the whole world because of the

rapid spread of a novel corona virus (COVID-19). e

medical fraternity is on the process to know the behavior

of the virus. is knowledge of the medical community

is extremely dynamic as the behavior of this virus is still

not established. COVID-19 is a contagious infection of

the respiratory tract caused by a novel virus called acute

respiratory syndrome corona virus 2(SARS-CoV-2).

is patient oen presents with cough, sore that and

fever. Indications for tracheostomy include emergent

airway and prolonged mechanical ventilation. COVID-19

patients sometime require tracheostomy for prolonged

ventilation in the ICU. Otolaryngologists, intensivist and

nursing stas in the ICU play an indispensable role for

performing this procedure. Performing tracheostomy

and post-tracheostomy care are usually considered as

high chance for contamination of health care personnel

during COVID-19 pandemic due to corona virus (SARS-

CoV-2).

Anticipating the rapid spread of the infection in

case of the tracheostomy, all patients should be considered

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as potential candidates for virus infection. Appropriate

protective measures can be taken for preventing the

transmission of this viral infection to the health care

workers.

Method of literature search

We performed a literature review of tracheostomy

during the SARS pandemic consisting data base of PubMed,

Medline, SCOPUS and Google scholar search with the

terms COVID-19, SARS and tracheostomy. We reviewed

the different current articles and recommendations

from national and international medical societies and

decisions from several government medical councils.

is manuscript reviews the details of tracheostomy

along with preventive measures for transmission of

infection. is review article presents a baseline from

where further prospective trials for safe technique of

tracheostomy could be designed and helps as a spur

for further research in the COVID-19 pandemic and so

prevent transmission of the infections to the health care

professions and other patients during this procedure.

Epidemiology

COVID-19 is a highly infectious disease of the

respiratory system due to novel virus SARS-CoV-2.

e rst patient of COVID-19 was reported in Wuhan,

China in late December 2019 by novel corona virus

now called as SARS-CoV-2 (severe acute respiratory

syndrome corona virus 2) and now spreaded worldwide.

By 27

February, 2020, more than 82,000 COVID-19

positive cases and more than 2800 deaths have been

documented of which around 95% of the cases and

97% of deaths were in China.

By the march 26

, 2020,

there were 462684 cases of the COVID-19 reported in

199 countries.

At the time of draing the manuscript

i.e. 25

April, more than 50000 persons were died due

to COVID-19 in United States. In the hospital setting,

critically patients with respiratory failure oen require

endotracheal intubation and changed to tracheostomy

in case of prolonged ventilation. In one study, 6.30%

patients need tracheostomy during the COVID-19

outbreak.

Study showing 7.3-32% of the patients with

COVID-19 progress to severe respiratory failure or

critical ill condition, where patient may subsequently

need tracheostomy for dierent reasons.

6,7

Transmission of the COVID-19 infection

Open or surgical tracheostomy is usually an aerosol

producing procedure with a high risk for contamination by

exposing the secretions from the airway to the health care

personnels.

e novel SARS-CoV-2 virus is transmitted

from one person to another by respiratory droplets or

contact with infected person. e procedures which

deals with nose, nasopharynx, oral cavity, pharynx,

larynx and trachea which generate respiratory droplets

lead to high risk for infections. e common clinical

symptoms of the COVID-19 patients are cough, fever,

fatigue and dyspnea. ere are some patients those are

asymptomatic and considered as silent carriers in this

pandemic. Symptoms like an osmia and taste alterations

are two important clinical features oen associated with

these patients. So health care workers should be aware

about these symptoms and so can prevent them from

transmission to other patients.

Suspecting the COVID-19 patients

e most commonly found symptoms in patient of

the hospitalized patients are fever (77-98%), dry cough

(46-82%), fatigue, myalgia (11-52%) and dyspnea (3-

315) at the onset of the COVID-19 infections.

Another

study shows fever in 44% at the time of hospitalized

COVID-19 patients whereas it goes to 89% during the

period of hospitalization.

Other less commonly found

symptoms in COVID-19 infections are sore throat,

headache, cough with sputum production with or without

hemoptysis. Few cases present with gastrointestinal upsets

like diarrhea and nausea before development of the fever

and lower respiratory airway symptoms and signs. ere

is established symptom such as anosmia/hyposmia in

COVID-19 infection. In German, it was documented that

more than two thirds of positive patients of COVID-19

infections presented with an osmia whereas in South

Korea, 30% patients with COVID-19 infections showed

symptom of the anosmia.

Indications of tracheostomy

e progressive rise of the COVID-19 patients will

expect more requirements of the orotracheal intubation

and prolonged ventilation. In this clinical scenario of

ICU, tracheostomy can be considered by health care

professionals. Performing tracheostomy on COVID-19

patients or suspected patients for COVID-19 impose

challenges not only to Otorhinolaryngologists but also to

the entire health care team. If the trachesotomy is not an

emergency, this can be reviewed by a multidisciplinary

team and risk versus benets of this surgery and also the

associated health care team should be assessed. Unlike the

bacteriogenic pneumonia, cases of COVID-19 present

with dry cough and produce little mucus secretions, so it

makes tracheostomy for pulmonary toilet less critical.

Bedside tracheostomy at the ICU with negative pressure

is ideal for performing this procedure for needy patients.

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Bed side tracheostomy avoids unnecessary transport of

the patients and frequent connections and disconnections

of the ventilator circuits during transfer.

e bedside

tracheostomy should be well planned at the ICU because

of the limited space, below optimal positioning of the

patient and limited transfer of the surgical instruments.

In case of planning tracheostomy at the operating room

(OR), it should be undertaken in negative pressure at

well demarcated area inside the OR complex with proper

route for transferring the patients. During tracheostomy,

provide adequate sedation including paralysis which

eliminates the chance of coughing during the time of

the procedure. Ventilation should be paused (apnea)

at the end-expiration when making the opening on the

trachea where the ventilation circuit is disconnected. A

non-fenestrated cued trachesotomy tube is better and

it keeps the cu inated to stop the spread of the virus

through the upper airway. Tracheostomy suctioning

should be done by a closed suction system with a viral

lter. Heat moisture exchanger device can be used instead

of tracheostomy collar at the time of the weaning for

preventing virus spread or re-infection of the patient.

Tracheostomy tube changing should be avoided until

the viral load is as low as possible.

Surgical steps

The COVID-19 pandemic is highly infectious

and performing the tracheostomy in such pandemic

is highly contagious to other patients and health care

workers. e classical tracheostomy should not be done

and it must be modied to minimize the chance of the

viral transmission.

For successful tracheostomy, the

whole procedure is divided into 5 steps (5Ts) such as

theater set up/area in ICU, team brieng, transferring the

patient, tracheostomy and team dong and De-brief.

Tracheostomy should be done in dedicated COVID theatre

or designated area in ICU. e OR should under negative

pressure with reverse laminar ow around the operating

table. In team brieng, all the team members should be

explained about their role during the procedure. All the

equipments including suction probe should be ready

before performing the tracheostomy. e tracheostomy

tube can be sprayed with 5% lidocaine then aspiration

for a few minute later is helpful. If the ventilation is done

with tracheostomy tube, then anesthesiologist should

sedate the patient and perform the neuromuscular block

for decreasing chance of the cough at the time of the

tube change. e patient must be completely paralyzed

for the period of the procedure and the closed suction

is connected to the endotracheal tube before beginning

of the procedure. Before starting the tracheostomy,

anesthetist/intensivist should perform suctioning the

endotracheal tube including the subglottic area. Before

making a window over the trachea, anesthetist is to stop

the ventilator and deate the cu of the endotracheal

tube. en the surgeon creates a window on the second

or third ring of the trachea. Minimal suctioning can be

done at the window site and the endotracheal tube is

advanced further below the window and the cu is re-

inated/over-inated and so establish a closed circuit.

is is a very crucial step for preventing spread of the

infection. In this stage, patient is a t risk of alveolar

derecruitment and may need aggressive recruitment

aer ination of the cu. So two number of anesthetists

or intensivist are useful to deal with endotracheal tube

and one will manage the ventilator.

Tracheostomy tube

e tracheostomy tube should be non-fenstrated,

cued and the smaller side to make the tracheostomy

smaller opening on the trachea. Shiley size of 6 for male

and female is oen adequate. e cu of the tracheostomy

tube should be inated for preventing the spread of the

virus via the upper airway.

Operating place/ICU

e place for this high risk procedure should be

properly designated with negative pressure.

Unprotected

health care workers should not be allowed to the site of

the tracheostomy because of the high aerosol generating

procedure. Appropriate PPE should be worn by the

Otolaryngologist and the assisting personnel. e team

for tracheostomy includes a consultant surgeon and two

experienced assistant along with a scrub nurse and a

oor nurse. Dierent case series of Open tracheotomies

were done at the time of COVID-19 pandemic showing

techniques and preventing measures (Table1).

18,19,20

Benets versus risk of trachesotomy at the ICU

Study of non-COVID-19 infected patients of

critically ill reveal that early tracheostomy (within ten

days of intubation) is associated with longer ventilator

free days, lesser ICU stays, lesser duration of sedation

and lower long-term mortality rates, although other

studies document that timing of the trachesotomy does

not aect the clinical outcomes.

21,22

In another study,

66.7% of the patients those underwent tracheostomy did

not achieve the clinical benet aer the tracheostomy.

Another report from China is also against the positive

outcome for tracheostomy in COVID-19 patients.

ere

is also another report from SARS treatment suggests that

tracheostomy was not related to the signicant better

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TABLE 1. Dierent case series of Open tracheostomies done at the time of COVID-19 pandemic.

18,19,20

Parameters Wei et al

Chee et al

Tien et al

Hospital Queen Mary Hospital, Tan Tock Seng Hospital, Sunnybrook and

Hong Kong SAR, Singapore China Women’s College

Health Sciences Centre,

Toronto, Ontario, Canada

Number of 3 15 3

tracheostomies done

Barrier precautions Standard PPE, Standard PPE, Standard PPE, Stryker T4

at time of surgery shoecovers, faceshield, Shoecovers, powered protection system

goggles air-purifying respirator

system

Setting Negative pressure room Negative pressure room Negative pressure room

in ICU or OR in ICU in ICU

Intraoperative steps Complete paralysis of Complete paralysis of Complete paralysis of

to minimize patient, mechanical the patient, mechanical the patient,mechanical

aerosolization ventilation stopped before ventilation stopped before ventilation stopped before

tracheostomy, no suction tracheostomy,limited suction tracheostomy,no suction

used during procedure, used during procedure, used once trachea

diathermy avoided as no specic avoidance of opened,diathermy avoided

much possible diathermy other than as much as possible

during tracheostomy

Surgical team Single surgeon, one An experienced surgeon, Senior attending trauma

intensive care specialist, an experienced surgeon, most senior

one standby medical or anesthesiologist, one surgical staff member

nursing staff scrub nurse and one available, attending ICU

surgical assistant anesthesist and no

circulating nurse or

scrub nurse.

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outcome.

Sometimes the trachesotomy is associated

with potential complication such as tracheal bleeding.

Without doing specic treatment for this infection, the

mortality rate goes to severe or critical ARDS is very

high as around 70%, which goes against for performing

the tracheostomy on patients with COVID-19 related

ARDS.

ese clinical experiences from China suggest that

prolonged intubation should not be alone an indication

for doing tracheostomy in COVID-19 patients, as there

are risk for patients and health care providers likely

show any marginal benets in this pandemic. Rather

the procedure like tracheostomy should only be done

in specic condition such as airway obstruction where

the successful extubation is compromised or certain

situation where tracheostomy placement has positive

impact on patient’s potential for successful weaning of

the ventilatory support. So, it needs careful consideration

when the health resources like ventilators are in limited

supply in present COVID-10 pandemic. Agreement with

current recommendations by ENT UK, clinicians should

believe the situations and evaluations by multidisciplinary

fashion like consensus among the specialists for clinical

benets aer tracheostomy as weighed against the risk

of this procedure.

Post-tracheostomy care

Patient with tracheostomy tube should be covered

by trach collar for preventing aerosol from trachea.

e

tracheostomy patients at the ICU those are connected with

a closed ventilator circuit, standard precautions should

be used for an patient who endotracheally intubated with

ventilator. is type of closed strategy has been also used

in Hong Kong in this current outbreak.

e suctioning

of the tracheostomy should be done by a closed suction

system with presence of the viral lter. Tracheostomy

tube change should be avoided until the viral load is as

low as possible. A heat moisture exchanger (HME) device

is used instead of the trach collar during the weaning

for preventing the virus spread or re-infection of the

patients.

Pediatric tracheostomy

In the children, the tracheal intubation is oen

better tolerated. e ideal timing for performing the

tracheostomy is not established but some authors suggest

if there is no chance of weaning by two weeks, then

tracheostomy can be considered.

During prolonged

intubation, optimum care must be given for adequate

size of the endotracheal tube with low pressure cu and

avoid movement of the tube.

Percutaneous dilatational tracheostomy

Percutaneous tracheostomy aects extensive airway

manipulation like bronchoscopy and or serial dilations

at the time of the tracheal entry. Patient having high

ventilatory settings may need repeated disconnection

and connection from the ventilatory support. ere is

increased chance of aerosolization in comparison to

the open tracheostomy.

In open tracheostomy, the

tracheostomy tube is entered quickly by making an

opening of the trachea so aerosolization has less chance

to spread. e open tracheostomy is more favorable

than percutaneous tracheostomy during COVID-19

pandemic.

However, as per recommendation of

French Anesthesiology and ENT Societies, percutaneous

tracheostomy is preferable to minimize the aerosolization

and chance of viral contamination of the surrounding

health care personnel.

e surgical tracheostomy is

performed in case of anatomical contraindication, failure

of the percutaneous tracheostomy or exhaustion of

the percutaneous kits. Two techniques are possible,

the Percutaneous technique and the open technique.

In accordance with the recommendations of French

Anesthesiology and ENT Societies (SFAR and SFORL),

in the COVID-19 context

, the percutaneous technique

is to be preferred to reduce aerosolization and the risk

of viral contamination for the nursing sta and to avoid

having to move the patient to an operating room.

Use of personal protection equipment during tracheostomy

e surgeon, assisting surgeon and nursing sta

should wear proper personal protection equipment (PPE)

(Fig 1). Head protection should be done by a hood cap

Fig 1. Surgeon with PPE before performing tracheostomy.

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rather than with a simple cap for better protection of

the exposed skin in head and neck area. e protective

eye glass should be used for preventing exposure of

the infection to the eye. Face mask must be FFP (N95)

or FFP3. e head light used for light source during

tracheostomy should be covered by a head cap. An

impermeable protective apron or an overcoat must be

worn under the surgical gown because it is sterile. Aer

removal tracheostomy, the appropriate time to do the

PPE is at least 20 minutes. is dong should be done

at a designated area with standard practice of current

guidelines.

Prognosis

Some patients with tracheostomy during COVID-19

pandemic may develop some complications such as ulcers in

the pharynx and bleeding from the stoma or tracheostomy

tube which need further care by Otorhinolaryngologists.

Tracheostomy should be avoided or delayed even beyond

two weeks because of the high chance of the infections

during the procedure and subsequent tracheostomy

care.

When the acute phase of infection is subsided

or the likelihood of the recovery of infection is high,

tracheostomy can be done for less likelihood of infection

transmission. Early tracheostomy should be avoided in

case of COVID-19 patients because of the higher viral

load. Early tracheostomy is not related to the improved

mortality or less ICU stay.

Preventing measures

e primary method of transmission of the infections

during tracheostomy is droplets from the tracheal airway

via the tracheostomy tube which carry the virus particles.

PPE is known to be very eective measures for reducing

the transmission of the infections from the trachesotomy.

Although the safety recommendations for health care

personnel have continued to change depending on the

resources. e center for disease control and prevention

(CDC) and WHO recommended the gown, gloves,

goggles, head shield and N95 mask for preventing the

transmission of the droplets from the tracheostomy.

Health care personnel should learn proper technique

for donning and dong of the PPE eectively to protect

them. If the post-tracheostomy care is done in a health

care facility or in home, there is no diagnostic facility and

the care givers do not know whether patient is infected

with SARS-CoV2 or not. So the precautions are justied

and must be with FFP2 (N95) mask, protective glasses,

head shield and gown. All the disposable materials that

have been in touch with tracheostomy tube or tracheal

lters and suction probes must be removed from this

infectious waste. The overall surgical procedure for

tracheostomy should thoroughly and appropriately

planned, explained to all concerned stas and executed

in order for ensuring the safety of the sta and patients.

CONCLUSION

COVID-19 is a real challenge for global medical

community. Acute respiratory distress syndrome and

respiratory failure need mechanical ventilation. As the

COVID-19 infection escalates, the staying of the patient

in ICU extended with ventilator. So, tracheostomy is

required in prolonged ventilation. It is thus crucial for

ICU teams and surgical personnel and they should be

well prepared for performing the tracheostomy when

required. As surgeon perform tracheostomy closely

with anesthetist/intensivist and nursing sta, so the

surgery should be done in safely manner for preventing

transmission of infections. is worldwide pandemic

reinforced the requirement of the adaptable and reective

surgical practice. e need of surgical tracheostomy will

increase in coming time so for this reason, we have to

manage this in a robust, repeatable and safe manner.

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Paweena Phaliwong, M.D.

Reproductive Medicine Unit, Department of Obstetrics and Gynecology, Bhumibol Adulyadej Hospital, Royal ai Air Force, Bangkok 10220, ailand.

The Effect of Myoma Uteri on Infertility

ABSTRACT

Myoma Uteri is the most commonly found tumors in women of reproductive age. eir eects on reproductive

function and fertility are unknown. Treatment is dependent on myoma’s location and size. While there is medical

consensus on the treatment of submucosal myoma, there exists controversy in treatment and management of intramural

myoma in infertile patients. Surgical treatments include hysteroscopic, laparoscopic and open myomectomies

(laparotomy). Results from endoscopic and open myomectomies are comparable. Endoscopic treatment is generally

favored due to lower morbidity, same day treatment, shorter hospitalizations and lower costs. Alternative methods,

including medical and radiological intervention, are discussed.

Keywords: Myoma uteri; infertility (Siriraj Med J 2020; 72: 443-450)

Corresponding author: Paweena Phaliwong

E-mail: paweenaphaliwong@gmail.com

Received 10 March 2020 Revised 13 May 2020 Accepted 20 May 2020

ORCID ID: http://orcid.org/0000-0002-2407-1714

http://dx.doi.org/10.33192/Smj.2020.60

INTRODUCTION

Myoma Uteri is the most commonly found tumors

in 50-60% of reproductive age women. One quarter of

patients seeking reproductive assistance present with

myoma. ey might be the sole cause of infertility in

1-3% of patients.

Mechanisms of Infertility

1-3

Myomas vary considerably in size, location and

number, and mechanisms by which they may cause

infertility. Several theories explain myoma’s role in

infertility.

Mechanisms involving alteration of local anatomy

Myomas are associated with anatomical distortion

of the endometrial cavity and the obstruction of tubal

ostia or cervix. ey may cause changes in the uterine

contour, and impair the movement of eggs, sperm and

embryos. Histological observations include elongation

and distortion of glands, cystic glandular hyperplasia,

polyposis and endometrial venule ectasia.

Mechanisms involving functional change

Increased uterine contractility, chronic endometrial

inammation, endometrial blood supply impairment are

all potential complications. Myomas can interfere with

sub endometrial arterial blood ow, which depresses

implantation rates and in vitro fertilization (IVF) outcomes.

Myomas can also lead to impaired physiologic decrease

of uterine peristalsis during embryonic implantation.

is disrupts typical reproductive processes, resulted

in decreased pregnancy rates, especially in submucous

or intramural myoma cases. e higher myometrial

contractility was postulated to come from too much

cytokines in myoma capsule. Neuropeptides, growth

factor, enkephalin and oxytocin modulators in myoma

capsule may also be involved. Glandular atrophy and

ulceration aecting the proximal and distal endometrium

are the most frequently observed histological changes.

Endocrine mechanisms

e theory of abnormal local hormonal milieu

supports the possibility of an endocrinal mechanism

for infertility.

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Paracrine molecular eects on adjacent endometrium

Myoma may induce paracrine molecular eects on adjacent

endometrium. e secretion of vasoactive amines and

local inammatory might cause impaired fertility function.

Cytokine factors

Many early pregnancy intrauterine cytokines are

instrumental in implantation and initial embryonic

development. Glycodelin, a progesterone-regulated

glycoprotein, promotes angiogenesis and suppress natural

killer (NK) cells. Ben-Nagi and his group reported that

interluekin 10 and glycodelin levels were signicantly

decreased in mid luteal uttering washings submucous

myoma’s patients.

Endo-myometrial Junctional (EMJ) zone alteration

EMJ, represented a 1/3 of the myometrium abutting

the endometrium, produces macrophages and uterine

natural killer cells (uNK). Macrophages and uNK cells

are instrumental in endometrial decidualization during

the window of implantation in mid luteal. Japanese

researchers documented a clear reduction of macrophages

and uNK cells concentration in EMJ of women with

uterine myoma. at corresponded to negative eects

on implantation.

e presence of intramural and/or

submucosal myoma possibly disrupts EMJ. It also aects

steroid receptors and cause implantation problem or

failure.

Endometrial receptivity

6-7

Examining myoma’s eect on endometrial receptivity

illuminates a potential mechanism of how myomas

can aect fertility without a mechanical component.

Embryonic implantation requires endometrial receptivity,

which is moderated by levels of cytokines, hormones,

growth factors and other signaling molecules. HOXA10

and HOXA11 genes, as well as leukemia inhibiting

factors, are theorized to be necessary components for

the implantation process. Reduced gene expression

was shown in women with myomas. Lower amount

or the absent of uterine endometrium HOXA10 can

prohibit implantation, later leading to infertility. Rackow

and coworkers reported endometrial HOXA10 and

HOXA11 mRNA levels reductions in follicular phase of

infertile patients who presented submucosal myoma’s

(FIGO L0 to L2). e drop of endometrial HOXA10 and

HOXA11 mRNA expression were noted for the entire

uterine cavity. The presence of intramural myomas

seemed to lower endometrial HOXA10 and HOXA11

mRNA levels, but not at a signicant levels.

By contrast,

Matsusaki et al. demonstrated a signicant decrease in

HOXA10 concentrations during luteal phase in infertile

patients with intramural myomas when compared to

control groups.

Myomectomy of intramural broid has

been demonstrated to increase HOXA10 and HOXA11

expression in the endometrium.

Eect on sexual function

Myomas are associated with higher incidences of

pelvic pain and dyspareunia. Decreased libido or sexual

dysfunction might be reported due to bulk eect on the

vagina. Orgasm might also be aected. Mass eect on

the urinary system may increase urination frequency or

incontinence leading to stress and embarrassment. While

not directly connected to fertility (Assisted Reproductive

Technology is unaected), these factors may contribute

to decreased frequency of sexual intercourse and thus

a corresponding reduction in opportunity for natural

conception.

Classication of myoma uteri

Myomas are classied by their relative uterine wall

placement. Subserosal myomas manifest on the outer

surface and grow outwards. Intramural myomas grow inside

the uterine wall. Submucosal myomas develop around

the endometrium and typically grow inwards towards

the cavity. Subserosal and submucosal pedunculated

myomas both grow on stalks.

FIGO provides additional guidance for users of the

myoma subclassication system. ey include tertiary

classication of myoma categories, with subcategorization

for intramural, subserosal and intramural lesions. Fig 1

shows FIGO myoma subclassication system 2018.

Fig 1. FIGO myoma subclassication system 2018

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Submucous type

Type 0: intracavitary lesions are attached to the endometrium

by a narrow stalk (< 10% or the mean of three diameter

of the myoma).

Type 1: requires a portion of the lesion to be intramural

and one diameter <50% of the mean diameter.

Type 2: requires a portion of the lesion to be intramural

and at least 50% of the mean diameter.

Type 3: lesions are completely intramural and around

the endometrium.

Intramural myoma: transmural lesions are categorized

by their relationship to both the endometrium and the

serosal surfaces. e endometrial relationship is noted

rst, followed by the serosal relationship.

Type 4: intramural myomas that are entirely within the

myometrium, with no extension to the endometrium

surface or the serosa.

Subserous myoma

Type 5: ≥50% intramural

Type 6: <50% intramural

Type 7: attached to the serosa by a stalk that is also <

10% or the mean of three diameters of the myomas.

Other types

Type 8: myomas that do not relate to the myometrium

at all, including cervical lesions (demonstrated), those

that exist in the round or broad ligament without direct

attachment to the uterus, and other ‘parasitic’ lesions.

Impact of myomas on reproductive function

e eect on fertility depends on the myoma’s location

Subserous myoma

e consensus based on clinical experience implies very

little causation linking subserosal myomas and infertility.

It is not evidence based to perform a myomectomy to

remove subserosal myomas to treat infertility.

Submucous myoma

Submucosal myomas that distort the uterine cavity

lower implantation rates and increase early pregnancy

losses when compared to myoma free patients. Pritts et al.

reported a meta-analysis showing submucosal myomas

patients with signicantly decreased live birth rates/

ongoing pregnancies (RR=0.318, 95% CI: 0.119–0.85,

P < 0.001), pregnancy rates (RR=0.363, 95% CI: 0.179-

0.737, P = 0.005) and implantation rates (RR=0.283, 95%

CI: 0.123-0.649, P= 0.003). is class of myomas is also

correlated with increased risk of spontaneous abortion

(RR=1.678, 95% CI: 1.373–2.051, P = 0.022).

Casini

and his group studied a RCT in myomas patients with

unexplainable infertility. Patients with clear subserous

myomas were excluded. Consented subjects were randomized

either to undergo myomectomy or not receiving the

procedure. Patients then reported if they could conceive

by themselves, and the conception rate was recorded for

the following 12 months or longer. Patients who received

hysteroscopic or open myomectomy showed increased

pregnancy rates. Baseline myoma staging showed no

statistical dierence. Statistically signicant pregnancy rate

increases were only observed in patients with submucosal

myoma (pregnancy rates between myomectomy/ no

myomectomy; submucosal group = 43.3/27.2 %, p <

0.05; intramural with submucosal component = 40/15 %,

p < 0.05; all submucosal = 40.4/21.4 %, p < 0.05).

summarize: submucosal myomas demonstrably lower

fertility rates, and studies have shown their removal

improve both conception and live birth rates.

Intramural myoma

Many hypotheses explain infertility from intramural

myomas without uterine cavity involvement. Alterations

of uterine peristalsis and vascular ow could disrupt sperm

and ovum transportation and embryo implantation.

Meta-analysis of Sunkara et al. work showed a signiﬁcant

decrease in clinical pregnancy rate (RR=0.85, 95% CI:

0.77–0.94, P < 0.002) and live birth (RR=0.79, 95% CI:

0.70–0.88, P < 0.0001) in women with non-cavity-distorting

intramural myomas compared with those without myomas,

following an IVF treatment.

Literature review produced

a single non-randomized controlled trial investigating

pre-IVF myomectomy eects. Patients had one to 5

myomas, with at least one of 5 cm, with no submucosal

component. e study revealed many benets of pre-

IVF myomectomy demonstrated by a 25/12 % birth rate

in treated/ control group.

A Cochrane’s review of the

RCTs concluded that there was insucient evidence to

recommend myomectomy to improve fertility in cases

of asymptomatic intramural myoma.

e evidence

for using myomectomy to treat infertility in intramural

myoma is weak.

Diagnosis

Uterine myomas, can be identied and characterized

by the use of transabdominal or transvaginal ultrasounds,

sonohysterogram, hysterosalpingogram, MRI and

hysteroscopy. Each modality has its own advantage used

to characterize the involvement of the uterine cavity.

Ultrasounds are adequate, rapid, safe, and cost-

eective in evaluating the size, number, and location

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of myomas. Transvaginal ultrasound might be used to

identify myomas of up to 5 mm in diameter. Transvaginal

ultrasound yielded accurate result in submucous myomas

evaluation. Older studies showed a sensitivity of 100%

and specicity of 94%.

Ultrasound, due to acoustic

shadowing, may be suboptimal for multiple myomas as

well as endometrial impingement. Additionally, inter-

observer variation has been found to be greater with this

method compared to MRIs.

Hysterosalpingogram is oen performed to assess

tubal patency in women with infertility and to exclude

intrauterine pathology. However, the sensitivity and

positive predictive value of this test for the identication

of intrauterine lesions can be as low as 50 and 28.6%

respectively. erefore hysterosalpingography cannot

reliably be used to exclude endometrial distortion secondary

to submucosal myomas.

Sonohysterography gives similar results to

hysteroscopy for submucous myomas diagnosis. Both

techniques are superior to transvaginal ultrasound. e 3D

sonohysterography is comparable to 2D sonohysterography

and hysteroscopy.

MRI has been well studied in the evaluation of

uterine myomas, especially for myoma mapping and

submucosal penetration. It was shown to be the most reliable

evaluation method (100% sensitivity and 91% specicity)

compared to transvaginal ultrasound, hysterosonography

and hysteroscopy. e gold standard is the pathological

examination. e disadvantages of MRI evaluation are

the low accessibility and prohibitive cost.

Hysteroscopy provides both diagnostic and therapeutic

value. Direct evidence of intrauterine pathology or

submucous myoma that distorted the uterine cavity

was demonstrated by hysteroscopy. e sensitivity and

specicity were 82 and 87 %, respectively.

Treatment

17-18

Medical management

ere is limited data with regards to the medical

management of myomas in patients attempting conception.

Surgery has associated risks. Not all patients are qualied

as candidate for surgery.

Gonadotropin-Releasing Hormone Agonists

(GnRH agonist)

ese medications work by decreasing estrogen-

dependent myoma growth through down regulation

of GnRH receptors in the pituitary gland. Follicle-

stimulating hormone, luteinizing hormone release and

estrogen availability are decreased. By inducing a state

of hypoestrogenism and temporary menopause with

amenorrhea, GnRH agonists have been used to shrink

myomas and restore hemoglobin levels in symptomatic

women. Preoperative use of GnRH agonist appears to

be relevant and beneﬁcial in patients with submucous

myomas. Beneﬁts include resolution of preoperative

anemia, decrease in myoma size, reduction of endometrial

thickness and vascularization with subsequently improved

visibility and reduced ﬂuid absorption.

However, GnRH

agonists have signiﬁcant side eects, including medically

induced menopause leading to possible hot ﬂashes, vaginal

dryness, and osteoporotic eects in bone. When used as

a pretreatment to myomectomy, GnRH agonists show no

apparent eect on pregnancy rates aer surgery, nor is

there a dierence in the recurrence rate of the myomas.

Selective Progesterone Receptor Modulators

(SPRMs)

Oral SPRMs, i.e., ulipristal acetate (UPA) can be

used in uterine myoma management. Studies suggested

the role of progesterone in the growth of myomas but

not in normal myometrial cells. SPRMs could inhibit

myoma growth and induce apoptosis selectively.

UPA

reduces the amount of vascular endothelial growth factor

(VEGF) and Bcl-2 expression while increases caspase-3

expression. All events led to impaired vascularization,

cell growth, and myoma proliferation.

UPA was found

to signiﬁcantly reduce myoma size. Its use could possibly

reduce the morbidity rate of the surgery. Or potential

patients would no longer require surgery. Adverse eects

include headaches, hot ﬂashes, and breast discomfort.

Adhesions, uterine rupture, and cesarean rates may be

decreased for those patients who could avoid myomectomy

or repeat myomectomies by the use of medication. UPA

is an alternative preoperative medical treatment prior

to myomectomy.

Type 1 myomas - If a myoma is type 1 but >3cm,

or if the patient presents with anemia, pre-hysteroscopic

medical therapy (SPRMs or GnRH agonist) is indicated.

UPA may be given in one or two courses of three

months. In a majority of cases, type 1 myomas respond

to preoperative therapy and decrease in size, facilitating

hysteroscopy conditions. It should be pointed out that

in some cases, myomas regress suciently that surgery

may be avoided.

19,21

Type 2 myomas - UPA can be proposed. Myomas

oen respond to this preoperative therapy and regress in

size. is reduction also allows a hysteroscopic approach

aer the ﬁrst menstrual bleed. In some cases, myomas

regress enough that they no longer distort the uterine

cavity. Surgery may not be further required.

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Type 2 or type 2-5 myomas (single or multiple)

distorting the uterine cavity – When multiple myomas

(≥2) or myomas of multiple types (type 2–5) are observed,

UPA can be administered over two to three month courses.

Myoma regression is expected to be very signiﬁcant (>50%

decrease), with no longer distorted uterine cavity. e

patient can then attempt natural conception or undergo

assisted reproductive techniques.

22-23

If myoma regression

is signiﬁcant (≥25% but <50%), but the uterine cavity

remains distorted or if the myoma remains large due

to great volume at baseline, a surgery will be indicated.

In young patients with symptomatic myomas desiring

future fertility, UPA can be administered long term, i.e.,

in four courses of three months.

SPRMs are beneﬁcial, because long-term intermittent

therapy (repeated in case of recurrence during the interval)

might help to avoid or postpone surgery until the patient

seeks to conceive.

Aromatase Inhibitors (AIs)

e use of AIs in reducing myoma volume has been

demonstrated. is medication class works by inhibiting

aromatase, a cytochrome p450 enzyme, which blocks

the conversion of androgens to estrogens. AIs appear to

be as or more eective than GnRH agonists at reducing

myoma volume but have signiﬁcantly fewer adverse

eects during short term use.

In one randomized control trial, an AI was shown

to decrease the total myoma volume comparatively

to GnRH agonists (45.6 versus 33.2%, respectively).

Aromatase appears to be prevalent within myoma tissue

but not in myometrium, allowing these medications

to specically target myoma. One retrospective study

revealed that myomas had triple aromatase amount than

in normal myometrium.

AIs might work to decrease

the complexity of myoma surgery, leading to improved

fertility outcomes.

Surgical treatments

When patients’ conception diculties or recurrent

miscarriages are attributed to myomas, surgical removal is

a recommended option. Removal of submucous myomas

was shown to increase clinical pregnancy rates compared

to controls where myomas were le in situ. However,

myomectomy in cases of intramural myomas is more

controversial.

Hysteroscopy

Hysteroscopic myomectomy is a popular surgical

method. It is a choice for up to 4-5 cm submucous

myomas. It can be performed on type 0, 1 or 2 myomas.

But type 2 myomas oen require multiple procedures for

a complete resection. Uterine perforation, uid overload,

bleeding, and intracavitary adhesion formation are common

hysteroscopic myomectomy complications. Several

techniques are available for hysteroscopic myomectomy,

including electrocautery resection, morcellation, laser

ablation and vaporization.

Laparoscopic versus laparotomy

It is known that all myomas FIGO L3 and large

L2 are best removed by laparoscopy or laparotomy.

Reproductive outcomes appears comparably improved

in both methods.

Laparotomy (Open myomectomy)

Laparotomy is a method of choice, especially with

multiple complicating intra-abdominal adhesions. All

large myomas (i.e., >20 cm in diameter) or any malignant

ones require a conventional open approach. e standard

risks of open abdominal surgery are increased blood loss

and longer recovery times compared to less invasive

choices.

Laparoscopy

Laparoscopic myomectomy yields improved

visualization, decreased blood loss, faster recovery and

reduced postoperative pain compared to laparotomy.

Pregnancy outcomes and the risk of myoma recurrence

are comparable.

Uterine rupture during pregnancy

following laparoscopic myomectomy is a great concern,

However, the real risk has never been documented.

e concern originates from the technical diculty

of performing a multilayer closure. e actual rate of

uterine rupture following laparoscopic myomectomy

is extremely low.

Robotic-assisted laparoscopy

e Food and Drug Administration (FDA) gave a

green light to the da Vinci system for laparoscopic surgery

in 2000, and for the use in gynecologic procedures in

2005. Since then, the use of robotic-assisted laparoscopic

procedures, including hysterectomy and myomectomy

has become increasingly common. e robotic system

improves visibility in 3D viewing and intuitive movement

of the operating arms. e short-term outcomes are

comparable to traditional laparoscopy in terms of blood

loss and recovery time. A recent retrospective cohort

study displayed pregnancy outcomes following robotic

myomectomy to be comparable to traditional laparoscopy.

e system incurs higher costs and longer operative

time.

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Other treatment methods

Uterine artery embolization (UAE) and magnetic

resonance focused ultrasound surgery (MRgFUS) are

minimally invasive alternative treatments for symptomatic

myoma. Pregnancy is possible aer these treatments.

However, increased obstetrical complications including

miscarriage, abnormal placentation and postpartum

hemorrhage are reported. e evidence supporting these

modalities for patients seeking fertility is limited.

Uterine Artery Embolization (UAE)

UAE was rst described in 1995 as an alternative

radiological treatment option for women with large

myomas no longer seeking to preserve fertility (Fig 2).

A transient ischemia is shown by MRI imaging in the

body of the uterus and the endometrium lasting for

up to 72 hours. is ischemic change is intended to be

irreversible only within myoma tissue

and temporary

within healthy uterine muscle and endometrium. e uterine

and ovarian artery has also been shown to anastomose

angiography in at least one side in approximately 46 %

of patients.

miscarriage, preterm delivery, abnormal placentation

and postpartum hemorrhage), UAE is not a preferred

choice for women with infertility or those desire future

fertility. It is to be reserved for poor surgical candidates.

Magnetic Resonance-Guided Focused Ultrasound

Surgery (MRgFUS)

MRI-directed beams of ultrasound capable of

heating an area of myoma tissue to up to 70 °C is used

in this method (Fig 3). MRgFUS will cause destruction

by coagulative necrosis.

Rabinovici et al. reported

pregnancies following MRgFUS. Fiy four pregnancies

were reported in 51 women. e mean age at MRgFUS was

37.2 years and mean time to conception was 8 months.

e miscarriage rate was 28%. e preliminary ndings

are successful with a high rate of delivered and ongoing

pregnancies. ere is limited evidence for the use of these

methods in patients who later want to get pregnant. It is

too early to recommend MRgFUS in the infertile patient

desiring conception until further study.

Current practice

When patients seek pregnancy (agnostic to IVF),

gynecologists should establish an integrated approach

based on the current knowledge by considering patients’s

age as well as myomas’ size, number, and location. e

following parameters should be considered before

deciding on a surgical treatment: (1) How would the

lesion impact patient fertility? (2) What is the ecacy of

surgical intervention? (3) What are additional clinical

indications associated with the presence of myoma? e

current practice for myoma treatment is presented in

Table 1.

e recurrent of myoma uteri aer treatment

Surgical treatments: Candiani and his group

found overall 10-year cumulative new appearance rate

at 27 percent. Diagnostic tool in their study was clinical

examination with ultrasound conrmation. e new

appearance of myomas from both laparoscopic and

abdominal approaches were not statistically signicant.

Malone reported the subsequent surgery rate among single

and multiple myomectomy at 11 and 26 percent during

an average of 7.6 years follow-up period, respectively.

Other treatment methods: ere were limited

recurrence rate data among women who initially underwent

non-surgical treatment, namely medical and radiological

intervention treatments.

GnRH agonist, SPRMs and

AIs were medical treatments which caused temporary

myomas’ size reduction. However myoma would return

Fig 2. Uterine Artery Embolization

Inadvertent embolization of ovarian tissue may

result in ovarian insuciency and failure, especially

in older patients or those with low baseline ovarian

reserve. e incidence of amenorrhea is <1% in patients

under 40. RCT was conducted for evaluating UAE versus

abdominal myomectomy in an infertile population with

pregnancy rates of 50 and 78 % respectively.

ey

recruited young patients below age 35 which may explain

the high overall conception rates. Time to conception was

longer for patients with UAE compared to myomectomy,

18 versus 13 months, respectively. Considering the poor

reproductive and obstetric outcomes (increased rate of

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to its original size when medication was stopped. e

use of these agents would be recommended only for

preoperative myomectomy but not for any denitive

treatment. Radiological intervention treatment was

appropriated for women who were not t for surgery.

Radiological hazard made the method not suitable for

the women who needed future fertility function. e

use of any non-surgical treatment should be under the

physician’s consideration on a case by case basis.

CONCLUSION

e evidence regarding the eect of myomas on

infertility and reproductive outcomes is weak and largely

inconclusive. In infertile patients, appropriate evaluation

and classication of myomas is important. Submucosal

myoma (FIGO L0-L2) should be treated hysteroscopically

(or laparoscopic for large L2) to improve conception rates.

e management of any intramural myomas should be

an individualized case. Subserosal myomas impact on

fertility are rather insignicant. Conservative treatment

measures (medical, UAE and MRgFUS) should not be

routinely oered to women who wish to maintain or

improve their fertility due to lack of safety and ecacy

data.

ACKNOWLEDGMENTS

I would like to express my sincere appreciation to

Dr. Kornkarn Bhamarapravatana and Associate Professor

Komsun Suwannarurk for their assistance with this

review article.

Potential conict of interests: None

Fig 3. Magnetic Resonance-Guided Focused Ultrasound Surgery (MRgFUS)

TABLE 1. Current recommended practice for the treatment of myomas.

Type Indication for surgical treatment Recommendations

Impact Effectiveness Additional

Submucosal A B AUB Hysteroscopy

Intramural

> 4 cm A C PPC, S Laparoscopy

< 4 cm D D D Expectant

Subserosal E E PC Expectant

Impact: Impact on reproductive potential, Eectiveness: eectiveness of surgical intervention, Additional: additional indications, Submucosal:

type 0-2, Subserosal: type 5-7, A: signicant impairment, B: signicant improvement, C: improvement that needed further evidence, D:

unclear, E: no signicant, AUB: abnormal uterine bleeding, PPC: potential pregnancy complications, S: symptomatic myoma, PC: potential

complications, Hysteroscopy: excision via hysteroscopy, Laparoscopy: excision via laparoscopy (preferable), Expectant: expectant management,

: Surgery indicated only in cases of multiple IVF failures or poor obstetrical outcome,

: Surgery indicated only in the presence of associated

symptoms or poor obstetrical outcome.

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