Siriraj Medical Journal
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SMJ
Volume 74, Number 4, April 2022
By Voramon Teranasthiarphan, et al.
ORIGINAL ARTICLE
REVIEW ARTICLE
MONTHLY
Indexed by
THAILAND SECTION
1954
Siriraj Medical Journal
SMJ
Volume 74, Number 4, April 2022
ORIGINAL ARTICLE
211 Long Term Outcomes and Durability of Bioprosthetic Valve for Valve Replacement at
Siriraj Hospital
Wanchai Wongkornrat, et al.
217 The Reliability of the Thai Version of the Toddlers’ Temperament Questionnaire
Pat Rojmahamongkol, et al.
225 Predictive Value of Right Ventricular Pressure Measurement for Residual Pulmonary
Stenosis in Tetralogy Repair
Prompak Nitayavardhanam, et al.
233 The Efficacy of Inside-Out Transversus Abdominis Plane Block vs Local Infiltration before
Wound Closure in Pain Management after Kidney Transplantation: A Double-blind,
Randomized Trial
Chatporn Boonyapalanant, et al.
239 The Analgesic Effect of Transcutaneous Electrical Nerve Stimulation (TENS) on the
Opposite Side for Phantom Limb Pain
Janravee Vathakul, et al.
245 Propensity Score Matched Study of Triweekly vs. Weekly Platinum-Based Chemotherapy
Concurrent with Radiotherapy in the Treatment of Locally Advanced Cervical Cancer
Kullathorn Thephamongkhol, et al.
256 Validation of Several Formulas to Differentiate Thalassemia from Iron Deficiency Anemia
and Proposal of a Thalassemia–Iron Deficiency Discrimination (TID) Predictive Score
Nisachon Khorwanichakij, et al.
REVIEW ARTICLE
266 The Evolution of Associating Liver Partition with Portal Vein Ligation for Staged
Hepatectomy
Voramon Teranasthiarphan, et al.
ORIGINAL ARTICLE
142 Factors Influencing the Quality of Life and Nutritional Status of 0-2 Years Old Children
Somsiri Rungamornrat, et al.
152 Increasing Dialysate Flow Rate Over 500 ml/min for Reused High-Flux Dialyzers
do not Increase Delivered Dialysis dose: A Prospective Randomized Cross Over Study
Wiparat Srisuwan, et al.
161 Survival of Non-Small Cell Lung Cancer Patients With Unexpected N2 After Complete
Resection: Should Aggressive Invasive Mediastinal Staging be Encouraged?
Suparauk Geanphun, et al.
169 Incidence and Risk Factors of Neonatal Sepsis in Preterm Premature Rupture of
Membranes Before 34 Weeks of Gestation
Thitiporn Sirivunnabood, et al.
178 Incidence of Adverse Perioperative Airway Complications in Obese Non-Pregnant
and Pregnant Patients Undergoing General Anesthesia
Natwara Asanathong, et al.
185 Burnout among Mental Health Professionals in a Tertiary University Hospital
Nichada Khanngern, et al.
193 Attitudes Toward Long-Acting Injectable Antipsychotics Among Schizophrenia Patients in
Southern Thailand: A Multihospital-Based Cross-Sectional Survey
Jarurin Pitanupong, et al.
REVIEW ARTICLE
202 Kidney Health for All: Bridging the gGap in Kidney Health Education and Literacy
Robyn G. Langham, et al.
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Mitsuhiro Kida (Kitasato University & Hospital, Japan)
Seigo Kitano (Oita University, Japan)
Ichizo Nishino (National Institute of Neuroscience NCNP, Japan)
Masakazu Yamamoto (Tokyo Women’s Medical University, Japan)
Dong-Wan Seo (University of Ulsan College of Medicine, Korea)
George S. Baillie (University of Glasgow, UK)
G. Allen Finley (Delhousie University, Canada)
Sara Schwanke Khilji (Oregon Health & Science University, USA)
Matthew S. Dunne (Institute of Food, Nutrition, and Health, Switzerland)
Marianne Hokland (University of Aarhus, Denmark)
Marcela Hermoso Ramello (University of Chile, Chile)
Ciro Isidoro (University of Novara, Italy)
Moses Rodriguez (Mayo Clinic, USA)
Robert W. Mann (University of Hawaii, USA)
Wikrom Karnsakul (Johns Hopkins Children’s Center, USA)
Frans Laurens Moll (University Medical Center Ultrecht, Netherlands)
James P. Dolan (Oregon Health & Science University, USA)
John Hunter (Oregon Health & Science University, USA)
Nima Rezaei (Tehran University of Medical Sciences, Iran)
Dennis J. Janisse (Subsidiary of DJO Global, USA)
Folker Meyer (Argonne National Laboratory, USA)
David Wayne Ussery (University of Arkansas for Medical Sciences, USA)
Intawat Nookaew (University of Arkansas for Medical Sciences, USA)
Victor Manuel Charoenrook de la Fuente
(Centro de Oalmologia Barraquer, Spain)
Karl omas Moritz
(Swedish University of Agricultural Sciences, Sweden)
Nam H. CHO (University School of Medicine and Hospital, Korea)
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SMJ
Volume 74, No.4: 2022 Siriraj Medical Journal
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211
Original Article
SMJ
Wanchai Wongkornrat, M.D., Kornkan Mahasawas, M.D., Punnarerk Thongcharoen, M.D., Thaworn
Subtaweesin, M.D.
Department of Cardiothoracic Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, ailand.
Long Term Outcomes and Durability of Bioprosthetic
Valve for Valve Replacement at Siriraj Hospital
ABSTRACT
Objective: Bioprosthesis has been used in cardiac valve replacement for a long time. However, structural valve
deterioration is still a major cause of failure. ere are several risk factors for valve deterioration. is study evaluates
the risk factors of valve deterioration in the long term (10 years) at Siriraj Hospital.
Materials and Methods: We retrospectively reviewed the medical records of 249 patients who underwent mitral
or aortic valve replacement between January 2006 and December 2012 using various tissue valves, comprising
Carpentier–Edwards porcine, Carpentier–Edwards Perimount bovine pericardial, Carpentier–Edwards Perimount
Magna bovine pericardial, and St Jude Trifecta bovine pericardial types. e information from each patient was
entered into a database at the time of the operation and followed up regularly, with a mean follow-up of 10 years.
Results: Aer 10 years follow-up time, the incidence of valve deterioration events were 1.2% and 8.43% in the rst
ve and ten years, respectively. e overall death rate during follow-up was 2.41%. ere were three statistically
signicant risk factors (p < 0.05) of valve deterioration: gender (female) (p = 0.042), age ≤ 60 years old (p = 0.010)
and St Jude Trifecta bovine pericardial valve (p = 0.004).
Conclusion: In the surgical populations who underwent valve replacement at Siriraj Hospital with tissue valves,
we found an acceptable long-term durability of the tissue valve. e risk factors of valve deterioration were female
gender, age ≤ 60 years old, and St Jude Trifecta bovine pericardial valve.
Keywords: Tissue valve; bioprosthesis valve; structural valve deterioration (Siriraj Med J 2022; 74: 211-216)
Corresponding author: aworn Subtaweesin
E-mail: subtaweesin@gmail.com
Received 3 November 2021 Revised 30 December 2021 Accepted 8 January 2022
ORCID ID: https://orcid.org/0000-0003-4497-6171
http://dx.doi.org/10.33192/Smj.2022.26
All material is licensed under terms of
the Creative Commons Attribution 4.0
International (CC-BY-NC-ND 4.0)
license unless otherwise stated.
INTRODUCTION
ere are two types of prosthetic heart valves: the
mechanical heart valve and the bioprosthetic tissue
valve. The mechanical valve is recommended for
young patients because of its durability, but the patient
is required to take anticoagulants for life to prevent
thromboembolism events; whereas the tissue valve is less
durable than the mechanical valve, but the patient is not
required to take anticoagulants for life; thus leading to a
lower risk of bleeding events associated with the use of
anticoagulants.
In 1966, Dr. Alain Carpentier invented the stented
porcine valve and used glutaraldehyde solution as the
chemical preservative for porcine valves by creating collagen
cross-links. is preservation protected the denaturation
of tissue leaets and made the tissue immunologically
inactive.
1
Since 1980s, tissue valves have been improved
through the use of low-pressure xation to maintain a
normal leaet morphology. Anti-calcication and anti-
mineralization treatment methodologies were developed
to obtain longer durable leaets.
2
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212
Porcine and pericardial tissue valves have been
used for cardiac valve replacement surgery for 20 years
at Siriraj Hospital. However, it is known that these may
suer structural valve deterioration over time, which is
the major cause of tissue valve failure worldwide. Data
collected from 1970 to 2000 revealed that 30% - 40%
of tissue valves at the mitral or aortic position require
replacement within 15 years following implantation
because of structural valve deterioration.
3
ere are several
risk factors for structural valve deterioration, such as a
younger patient, renal insuciency, hyperparathyroidism,
hypertension, tissue valve at the mitral position, and an
older generation of tissue valve.
Calcication is accelerated in younger patients,
renal insuciency, or hyperparathyroidism patients.
Systemic hypertension damages tissue valves at the mitral
and aortic positions due to the increased systolic and
diastolic closing pressure. Older generations of tissue
valves are less durable than the newer generation of
tissue valves. Pericardial valves are more durable than
porcine valves.
4,5
e primary objective of this study was durability of
tissue valve and secondary objective was the risk factors
of long-term (10-year) structural valve deterioration in
patients at Siriraj Hospital, which are essential to have
a better understanding of in order to support selection
of the proper tissue valve types for patients in terms of
the position and timing of tissue valve replacement.
MATERIALS AND METHODS
is research was approved by the Ethical Committee
on Research Involving Human Subjects, Faculty of Medicine
Siriraj Hospital, Mahidol University on March 24, 2021.
We retrospectively reviewed the medical records
of 249 patients who underwent mitral or aortic valve
replacement since January 2006 to December 2012 using
the Carpentier–Edwards porcine (porcine) (24 cases),
Carpentier–Edwards Perimount bovine pericardial (PM)
(165 cases), Carpentier–Edwards Perimount Magna
bovine pericardial (PM magna) (57 cases), and St Jude
Trifecta bovine pericardial (trifecta) (3 cases) tissue
valves types and who survived the operation. e types
of tissue valve were selected by the individual surgeon’s
preference and the valves available at that time. e case
of structural valve deterioration was dened by clinical
presentation, echocardiographic nding results and
reoperation event.
Statistical analysis
e baseline demographic continuous data were
presented as number or percentage, mean and standard
deviation were carried out as normal distribution.
Categorical data was presented as percentage or ratio/
In inferential statistic, 95%CI was used. In case of time
to deterioration in univariate analysis, deterioration was
obtained from Kaplan-Meier survival curves and log-rank
test for compared each group. For multivariate analysis
using Cox (Proportional Hazards) regression analysis
was performed aer adjusted controlling confounding
factors with p-value < 0.2 from univariate analysis using
backward elimination for variable selection. e statistical
signicance was accepted if the p-value was < 0.05.
Table 1 summarizes the preoperative clinical
characteristics of all the patients. The male gender
represented 48.2% of cases and the female gender 51.8%.
e mean age was 69.2 years old (range 15–98 years old),
with 203 patients (81.5%) being more than 60 years old.
Overall, 148 patients underwent aortic valve replacement
(AVR) (59.4%), 84 patients underwent mitral valve
replacement (MVR) (33.7%), and 17 patients underwent
double valve replacement (DVR) (6.8%).
Also, 79 patients (31.7%) with signicant coronary
artery disease who received preoperative angiography
underwent concomitant coronary artery bypass gra
surgery were included in this study. e data obtained
from all the patients were entered into a database at
the time of the operation and then those patients were
followed up regularly.
TABLE 1. Preoperative clinical characteristics.
Variables (n=249) Number (%) or Mean ± SD
Gender; Male 120 (48.2%)
Female 129 (51.8%)
Age (years) 69.2 ± 11.4
≤60years 46(18.5%)
>60years 203(81.5%)
Follow-up time (years) 10.0 (4.0-15.0)
Diagnosis
Regurgitation 153(61.4%)
Stenosis 79(31.7%)
Mixed 17(6.8%)
Operation
AVR 148 (59.4%)
MVR 84(33.7%)
DVR 17(6.8%)
Type of tissue valve
PM 165(66.3%)
PMmagna 57(22.9%)
Porcine 24(9.6%)
Trifecta 3(1.2%)
Concomitant CABG 79(31.7%)
Wongkornrat et al.
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Original Article
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RESULTS
Aer 10 years (range 4-15 years) follow-up time,
the incident of structural valve deterioration events was
1.2% (95%CI: 0.25-3.47) and 8.43% (95%CI: 5.27-12.56)
in the rst ve and ten years, respectively (Fig 1). e
overall death rate during follow-up was 2.41% (95%CI:
0.97-5.66). A summary of the incidence of structural
valve deterioration is shown in Table 2.
According to Table 3, there were three statistically
signicant risk factors (p < 0.05) of structural valve
deterioration, i.e., female gender, age ≤ 60 years old,
and St Jude Trifecta bovine pericardial valve. e risk
of structural valve deterioration was 2.75 times (95%Cl:
1.04 to 7.28 times) higher signicant (p = 0.042) in
females compared to males, and the risk of structural
valve deterioration is 3.33 times (95%Cl: 1.34 to 8.29
times) more signicant (p = 0.010) in the adult group
(age ≤ 60 years old) compared with the elderly group
(age > 60 years old). e St Jude Trifecta valve was also
found to be a signicant risk factor of structural valve
deterioration (p = 0.004)
DISCUSSION
The expanding use of tissue valves for valve
replacement has been supported by evidence of their
long term durability and freedom from structural valve
deterioration. In this present study at Siriraj Hospital,
we followed 249 cases of tissue valve replacement in
the aortic and mitral valve positions. During the early
years of our experience, the main reasons for using a
tissue valve were patients having a contraindication
to taking anticoagulants, elderly patients, and women
of reproductive age. Nowadays, patient preference has
become one of the most important factors for choosing the
proper valve. In our series, the freedom from structural
valve deterioration at 10 years was 91.57% (Fig 1). ere
were three statistically signicant risk factors (p < 0.05)
of structural valve deterioration identied in our study:
female gender, age ≤ 60 years old and St Jude Trifecta
bovine pericardial valve (Table 3, Fig 2, Fig 3).
Fig 1. Freedom from structural valve deterioration for all tissue valves.
TABLE 2. Incidence of structural valve deterioration.
Variables (n=249) Number of Deterioration Incident of Deterioration (95%CI)
Deterioration
at5years 3 1.20%(0.25-3.47)
at10years 21 8.43%(5.27-12.56)
Died during follow-up 6 2.41%(0.97-5.66)
e risk of structural valve deterioration in the
mitral position has been considered to be higher than in
the aortic position because the systolic closing pressure
at the mitral position is higher than the diastolic closing
pressure at the aortic position. In an Edinburgh study
6
,
aer 15 year tissue valve follow-up, a reoperation rate of
29% due to structural valve deterioration was observed
in the AVR group and 44% in the MVR group. In our
series, aer 10 year tissue valve follow-up, we found
a rate of structural valve deterioration of 6.8% in the
AVR group and 10.7% in the MVR group. However,
the statistical dierence was insignicant (p = 0.183).
Regarding gender, as far as we know there has been no
report about the eects of gender associated with structural
valve deterioration aer tissue valve replacement, but we
found a structural valve deterioration rate of 11.6% in
females and 5.0% in males. e risk of structural valve
deterioration was 2.75 times (95%Cl: 1.04-7.28) more
signicant (p = 0.042) in female compared to male. e
suggested reason behind this result might be the use of a
smaller valve in female patients, which carries a higher
risk of structural valve deterioration.
4
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214
TABLE 3. Risk factors of structural valve deterioration.
Variable Number (%) or Mean ± SD Log-rank Multivariate Cox
Non- Deterioration test Adjusted HR regression
deterioration (n=21) (p-value) (95%Cl) (p-value)
(n=228)
Gender
Male(n=120) 114(95.0) 6(5.0) 0.069 1
Female(n=129) 114(88.4) 15(11.6) 2.75(1.04-7.28) 0.042*
Age (year) 69.8±10.7 63.05±15.7
Adultgroup;age≤60year(n=46) 38(82.6) 8(17.4) 0.021 3.33(1.34-8.29) 0.010*
Elderlygroup;age>60year(n=203) 190(93.6) 13(6.4) 1
Diagnosis
Regurgitation(n=153) 137(89.5) 16(10.5) 0.930
Stenosis(n=79) 75(94.9) 4(5.1)
Mixed(n=17) 16(94.1) 1(5.9)
Operation
AVR(n=148) 138(93.2) 10(6.8) 0.183
MVR(n=84) 75(89.3) 9(10.7)
DVR(n=17) 15(88.2) 2(11.8)
Type
PM(n=165) 153(92.7) 12(7.3) 0.052 1
PMmagna(n=57) 53(93.0) 4(7.0) 1.53(0.47-5.00) 0.479
Porcine(n=24) 20(83.3) 4(16.7) 2.22(0.70-7.01) 0.173
Trifecta(n=3) 2(66.7) 1(33.3) 23.71(2.69-209.09) 0.004*
CABG
yes(n=79) 75(94.9) 4(5.1) 0.176
no(n=170) 153(90.0) 17(10.0)
Fig 2. Freedom from structural valve deterioration for male and female patients.
Wongkornrat et al.
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Original Article
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Fig 3. Freedom from structural valve deterioration for adult and elderly patients.
Elderly patients have been shown to be the most
powerful determinants of tissue valve longevity.
7
Rizzoli
et al.
3
reported the actual freedom from structural valve
deterioration in patients younger than 65 years old was
less than that seen in older patients (84.5% vs. 95%).
Similarly, we found the rate of structural valve deterioration
was 17.4% in the adult group (age ≤ 60 years old) and
6.4% in the elderly group (age > 60 years old). e risk
of structural valve deterioration was 3.33 times (95%Cl:
1.34-8.29) more signicant (p = 0.010) in the adult group
(age ≤ 60 years old) compared to the elderly group (age
> 60 years old).
e newer generations of tissue valves are more
durable than older generations of tissue valves. Likewise,
pericardial valves are more durable than porcine valves.
5
Bourguignon et al.
8,9
reported the long-term outcomes
of patients tted with a Carpentier–Edwards Perimount
valve in the aortic or mitral position. ey found that
the expected valve durability was 19.7 years in the aortic
position and 14.2 years in the mitral position.
In our series, aer 10 year tissue valve follow-up,
we found structural valve deterioration in 7.3% of cases
in the Perimount group, 7.0% in the Perimount Magna
group, 16.7% in the porcine group, and 33.3% in the
Trifecta group. However, the statistical dierence was
insignicant for the Carpentier–Edwards porcine compared
to the Carpentier-Edwards Perimount bovine pericardial
type (p = 0.173, 95%Cl: 0.70-7.01). Conversely, the St
Jude Trifecta bovine pericardial type was found to be a
signicant risk factor of structural valve deterioration
(p = 0.004, 95%Cl: 2.69-209.09), but it should be noted
that the total number of cases in the Trifecta group was
very small (n = 3) compared to in the other groups. So,
we cloud not conclude that they were more likely to
deteriorate than other types.
When reoperation is required, reoperative AVR or
MVR can be done safely. e recent mortality outcomes
were 5%-7% in reoperative AVR or reoperative MVR.
10,11
Besides, in the future, valve in valve transcatheter aortic
valve replacement (TAVR) and transcatheter mitral
valve replacement (TMVR) may be the second optional
treatments for patients who develop structural tissue
valve deterioration. In our series, there were 7 cases who
underwent reoperative AVR or reoperative MVR without
mortality and 2 cases who underwent TAVR without
mortality, while 12 structural valve deterioration cases
were still waiting for their denitive treatment soon.
CONCLUSION
In surgical populations that underwent valve
replacement at Siriraj Hospital with tissue valves, we
found an acceptable long-term durability of the new tissue
valve. e risk factors of structural valve deterioration
were the female gender and age ≤ 60 years. e freedom
from reoperation was not signicantly dierent in terms
of the valve position. However, we need to further re-
evaluate the data in the next 5-10 years to obtain longer
term results.
ACKNOWLEDGMENTS
The authors thank Miss Nachasa Khongchu of
Research Department, Faculty of Medicine Siriraj
Hospital, Mahidol University, Bangkok, ailand for
her professional statistical analysis.
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216
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8. Bourguignon T, Bouquiaux-Stablo AL, Candol P, Mirza A,
Loardi C, May MA, et al. Very long-term outcomes of the
Carpentier-Edwards Perimount valve in aortic position. Ann
orac Surg. 2015;99(3):831-7.
9. Bourguignon T, Espitalier F, Pantaleon C, Vermes E, El-Arid
JM, Loardi C, et al. Bioprosthetic mitral valve replacement
in patients aged 65 years or younger: long-term outcomes
with the Carpentier-Edwards PERIMOUNT pericardial valve.
Eur J Cardiothorac Surg. 2018;54(2):302-9.
10. Chan V, Lam BK, Rubens FD, Hendry P, Masters R, Mesana
TG, et al. Long-term evaluation of biological versus mechanical
prosthesis use at reoperative aortic valve replacement. J orac
Cardiovasc Surg. 2012;144(1):146-51.
11. Potter DD, Sundt TM, 3rd, Zehr KJ, Dearani JA, Daly RC,
Mullany CJ, et al. Risk of repeat mitral valve replacement for
failed mitral valve prostheses. Ann orac Surg. 2004;78(1):
67-72; discussion 67-72.
Wongkornrat et al.
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Original Article
SMJ
Pat Rojmahamongkol, M.D., Supaluk Tangvalelerd, M.D.
Department of Pediatrics, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok 10700, ailand.
The Reliability of the Thai Version of the Toddlers’
Temperament Questionnaire
ABSTRACT
Objective: To evaluate the reliability of the Early Childhood Behavior Questionnaire (ECBQ)-very short form, ai
version; and to investigate ai toddlers’ temperaments
Materials and Methods: e English version of the very short form ECBQ was translated into ai language. e
primary caregivers of 360 healthy, 18-36 months old children, were asked to ll the questionnaire from the period
of April, 2018 to June, 2019. e scores were calculated to determine the child’s temperament. e reliability of
the very short form ECBQ- ai version was assessed by Cronbach’s alpha coecient for internal consistency and
Intraclass correlation coecient (ICC) for inter-rater reliability, two-week and six-month test-retest reliability.
Results: e Cronbach’s alpha coecients were 0.627-0.692, which indicated questionable internal consistency,
but almost reach those of the original ECBQ. e inter-rater ICCs were 0.463-0.670, which were comparable to
those in the original English version. e two-week ICCs were 0.602-0.750, which indicated moderate reliability,
whereas the six-month ICCs decreased to 0.459-0.602. However, these values almost reached those of the original
English version. Most toddlers were reported to have a surgency temperament. Boys signicantly had more surgency
temperament and had higher mean surgency scores, whereas girls exhibited a more eortful-control temperament.
Conclusion: e very short-form ECBQ, ai version can be implemented in assessing ai toddlers’ temperament.
e majority of ai toddlers in this study demonstrated surgency temperament. Boys tended to be more surgency,
while girls tended to be more eortful control.
Keywords: temperament, ECBQ questionnaire, ai toddlers (Siriraj Med J 2022; 74: 217-224)
Corresponding author: Pat Rojmahamongkol
E-mail: patojung@yahoo.com
Received 14 January 2022 Revised 24 January 2022 Accepted 25 January 2022
ORCID ID: https://orcid.org/0000-0003-3853-0026
http://dx.doi.org/10.33192/Smj.2022.27
INTRODUCTION
Temperament is dened as an inborn dierence
in reactivity and self-regulation when a child interacts
with his or her environment. Reactivity is the child’s
reaction to changes in the environment. Self-regulation
is a process to modulate one’s reactivity. Although one’s
temperament persists throughout life, heredity, maturation,
and experiences inuence it over time
1
, for example,
parental discipline and responses to a child’s behavior
can aect the child’s expressions and habits. e most
popular temperament concept among pediatricians
has been omas and Chess’s approach, which was
introduced in 1977.
2
is concept has included nine
dimensions of temperament, which were activity level,
rhythmicity or regularity of physical functions, approach
to or withdrawal from a new situation, adaptability, one’s
sensory threshold to external stimuli, intensity of reactions,
quality of mood, distractibility, and attention span or
persistent focus on tasks. Children are categorized from
the nine dimensions into three groups, which are easy,
dicult, and slow-to-warm up ones. e “easy child” is
easy to raise and care for, exhibits regular sleep, waking
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and feeding times, good moods, and high adaptability.
e “dicult child” has characteristics that are opposite
to those in the rst category. e “slow-to-warm-up
child” demonstrates initial withdrawal from new stimuli
and needs more time to adapt to those new situations,
though eventually he or she can adjust to such stimuli.
Some behavioral problems have been claimed to be
associated with temperament. e child who has a very
high activity level and is very distractible might mimic
the one with attention decit/ hyperactivity disorder
(ADHD). Toddlers with autism exhibited more sensitivity
to stimuli and have more negative moods, compared to
their typically developing peers.
3
Moreover, the child’s
temperament may have bidirectional interactions with
the parents’ responses and psychopathology. Parents
of negative-mood and low-impulse-control children
tended to report a history of anxiety.
4
One study found
that the authoritative parenting style - when parents were
always sensitive to the child’s needs and give him or her
freedom to make decisions in general situations while
limiting the child’s decision-making in more serious
ones, especially potentially dangerous activities - was
correlated with more patience and less irritability among
their children.
5
is highlights the fact that a successful
management strategy for behavioral problems based on
temperamental origin should harmonize with the child’s
temperament. us, a correct interpretation of the child’s
temperament helps pediatricians and other medical
personnel to assist parents in better understanding their
children’s characteristics and to guide parents in dealing
with his or her problems.
Although omas and Chess’s temperament concept
is clinically practical for the evaluation of children’s
behavior and in terms of offering recommendation
to parents, however, the Toddler Temperament Scale
questionnaire developed by Fullard et al, in 1984
6
to
measure the nine dimensions of temperament contains
97 question items which is not clinically practical for ai
context. Most of ai-version questionnaires developed
for time-constraint clinical use consists of 15-40 question
items.
7-9
ere is also the concept of temperament developed
by Rothbart in 1981. Rothbart’s temperament is dened
as biologically-rooted individual dierences in reactivity
and self-regulation in one’s emotional, activational,
and attentional processes.
1
In their eort to measure
children’s temperaments, Putnam et al.
10
formulated 18
scales of temperamental components based on Rothbart’s
temperamental concept, which are shown in the appendix.
e children were classied into three groups: “surgency,”
which refers to the ones with a high activity level and
positive anticipation regarding new activities; “negative
aectivity,” referring to children who display fear and
frustration; and “eortful control,” which applies to those
with high impulse control and attentiveness to tasks. is
approach led to the development of the Early Childhood
Behavior Questionnaire (ECBQ),
10
which was designed
to assess temperament in children from 18-36 months
old. e psychometric properties have demonstrated
good internal consistency and reliability.
7
ere are three
versions of the ECBQ - the standard ECBQ (consisting
of 201 items), the short-form ECBQ (107 items), and
the very short-form ECBQ (36 items).
11
e ECBQ has been widely used in English and in
more than 18 languages, such as Chinese, Japanese, and
French. e very short-form version has been widely
implemented in English and ten non-English-speaking
countries.
11
To the best of our knowledge, there is no temperament
questionnaire for ai toddlers. As a result, research on
temperament in the ai population has been very limited.
e aim of this study was to translate the original English
very short form of ECBQ into ai and to evaluate the
reliability of the ai version. We also aimed to study ai
toddlers’ temperament by using this form. e English
version of the very short-form ECBQ was selected for
this research study because the number of the question
items is feasible for implementation in busy clinical
settings in ailand.
MATERIALS AND METHODS
e details of the original questionnaire
The very short version of the Early Childhood
Behavior Questionnaire (ECBQ) is used to evaluate
the temperament of 18-36-month-old children. e
questionnaire includes 36 items regarding children’s
behaviors, which are specic to each temperament type.
ere are 12 items for surgency, 12 for eortful control, and
another 12 for negative aectivity. Parents or caregivers
give a Likert scale score regarding the frequency of their
child’s behaviors. e scores range from 1 (never) to 7
(always), and “Does not apply” (if the question is not
relevant to the child). e mean score of each temperament
type is calculated, and the highest mean scores dene
the child’s temperament type. If there is more than one
equally highest mean score, the child is classied as
more than one - i.e. a mixed-temperament type. Internal
consistency was evaluated by using Cronbach’s alpha
coecient. e internal consistency of negative aectivity,
surgency, and eortful-control temperament were 0.70,
0.72, 0.72, respectively. e longitudinal stability over
six months was 0.65.
12
Rojmahamongkol et al.
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Original Article
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e translation process
e ai version of the very short-form ECBQ
was translated with the permission of the pioneer of
the original English version. e content validity was
measured by three ai developmental and behavioral
pediatricians. e acceptable content validity index was
0.67. Each item’s content validity was initially ranged
from 0.33 to 0.67. e items which had low content
validity were retranslated. Aer substantial agreement
from those three specialists, reected by a content validity
index of 1, the translation back into English was done to
conrm that the ai version adhered with the original
English version.
Population and procedure
is cross-sectional, questionnaire-based research
included caregivers of 18-to-36-month-old children
who attended the well child clinic and daycare at Siriraj
Hospital, or who were in pre-kindergarten and daycare
in Bangkok and the surrounding metropolitan area. e
recruitment period was from April, 2018 to June, 2019.
e exclusion criteria were those whose children had a
diagnosis of developmental delay or chronic diseases.
Caregivers who could not read ai were also excluded.
is study was approved by the Human Research Protection
Unit, Faculty of Medicine Siriraj Hospital, Mahidol
University.
Aer signing an informed consent, 360 caregivers
were asked to ll out the 20-minute ai very short-form
ECBQ. Of these, 20 were randomized for two-week (short-
term) test-retest reliability; another 20 were allocated for
six-month (long term) test-retest reliability. Eighty-three
pairs of primary and secondary caregivers were recruited
for inter-rater reliability testing. e number of the
participants in each group randomized for test-retest and
inter-rater reliabilities were based on the reliabilities from
the original English version (0.6 and 0.31, respectively),
estimated type I error of 0.05, and the power of 80%. e
scores obtained from the questionnaire were calculated
so as to interpret the children’s temperament. At the end
of the study, all caregivers received the information about
their child’s temperament, as well as the developmental
and behavioral pediatrician’s guidance in child-rearing
practices specic to each child’s temperament.
Statistical analysis
e data were prepared and analyzed using PASW
Statistics 18.0 (SPSS Inc., Chicago, IL, USA). Descriptive
statistics were used to describe the participants’ characteristics.
Number and percentage were used to describe qualitative
data, while mean and standard deviation (SD) were used
to describe normally distributed quantitative data. A
median (25
th
, 75
th
percentile) was used to report non-
normally distributed data. e Chi-Square test was used
to evaluate statistical signicance.
Cronbach’s alpha coecient was used to evaluate the
internal consistency of the questionnaire. e coecient,
which was < 0.5, 0.5-0.6, 0.6-0.7, and > 0.7, was dened
as unacceptable, poor, questionable, and good internal
consistency, respectively.
13,14
Test-retest reliability was
interpreted by using the intraclass correlation coecient
(ICC). Inter-rater reliability was evaluated using the two-
way random-eects model, while intra-rater reliability
was evaluated by using the two-way mixed-eects model.
In this study, an ICC which was < 0.5, 0.5-0.75, and
0.75-0.9 was classied as of poor, moderate, and good
reliability, consecutively.
15
RESULTS
e demographic data are shown in Table 1. Of the
360 caregivers, 323 (89.7%) answered the questionnaire
regarding the child’s gender. e majority of these caregivers
were mothers. e short-term (two weeks) test-retest
reliability was performed involving 20 fathers or mothers
of the children, which included nine (45%) boys and 11
(55%) girls. Long-term (six months) test-retest reliability
was performed involving 20 participants whose children
were 11 (55%) boys and nine (45%) girls. Sixteen out
of 20 caregivers, who were randomized for long- term
test-retest reliability, were fathers or mothers. Another 4
out of 20 were other family members. Of the 83 pairs of
primary and secondary caregivers recruited for inter-rater
reliability, 46 (55.4%) were the caregivers of boys, and
37 (45.6%) were the caregivers of girls. All the children
were ai and lived in Bangkok and the surrounding
metropolitan area. e mean age (SD) was 27.9 (6.2)
months old.
Table 2 demonstrates Cronbach’s alpha coecient
for each temperament and the range of Cronbach’s
alpha coecient when one item was deleted. e overall
Cronbach’s alpha coecients were 0.682, 0.627, and
0.692 for surgency, negative aectivity, and eortful-
control temperament, respectively. e maximum of
the coecient when one item was deleted was 0.707.
Regarding the inter-rater reliability, the ICCs were
0.638, 0.670, and 0.463 for surgency, negative aectivity,
and eortful-control temperament, respectively. e
ICCs for short-term intra-rater reliability were 0.614,
0.750, and 0.602 for surgency, negative aectivity, and
eortful-control temperament, respectively. For long-
term one, the ICCs decreased to 0.602, 0.459, and 0.476,
respectively. (Table 3)
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TABLE 1. Demographic data of the children and the caregivers
TABLE 2. Cronbach’s alpha coecient for each temperament.
Characteristics Number (%)
Child’sgender
Boy 174(53.9)
Girl 149(46.1)
Missingdata 37
Child’sAge(N=357)
18-23months 98(27.5)
24-30months 110(30.8)
31-36months 149(41.7)
Missingdata 3
Caregivers
Parents 346(96.1)
Grandparents 12(3.3)
Others 2(0.5)
Caregivers’maritalStatus
Single 32(8.9)
Married 317(88.1)
Divorced 11(3.1)
Caregivers’education
UnderBachelordegree 42(11.7)
Bachelordegree 194(53.9)
AboveBachelordegree 124(34.4)
Family’smonthlyincome
≤30,000Bahts 111(31.7)
30,001-50,000Bahts 107(30.6)
50,001-100,000Bahts 82(23.4)
≥100,001Bahts 50(14.3)
Missing 10
Temperament Cronbach’salphacoefcient Cronbach’salphacoefcient
when item is deleted
Surgency 0.682 0.645to0.692
NegativeAffectivity 0.627 0.576to0.636
EffortfulControl 0.692 0.649to0.707
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TABLE 3. Inter-rater reliability, short-term and long-term intra-rater reliabilities.
Temperament ICC
a
(95% CI) ICC
b
(95% CI) ICC
c
(95% CI)
Surgency 0.638(0.495-0.747) 0.614(0.228-0.832) 0.602(0.244-0.819)
NegativeAffectivity 0.670(0.536-0.772) 0.750(0.461-0.896) 0.459(0.021-0.746)
EffortfulControl 0.463(0.280-0.614) 0.602(0.231-0.824) 0.476(0.040-0.756)
ICC: Intraclass correlation coecient
a
Intraclass correlation coecient between primary and secondary caregivers
b
Intraclass correlation coecient, two weeks apart (short-term)
c
Intraclass correlation coecient, six months apart (long-term)
e temperament classications of 360 ai children
in this study were 205 (56.9%) for surgency, 135 (37.5%)
for eortful control, and 3 (0.8%) for negative aectivity.
ere were 16 (4.4%) children whose caregivers rated
their temperaments as surgency and eortful control
equally; one (0.3%) child was classied as manifesting
surgency and negative aectivity. Boys signicantly had
more surgency temperament and a higher mean surgency
scores than girls. Girls exhibited more eortful-control
than boys. ere was no statistical signicance of gender
dierence in terms of negative aectivity and mixed
temperament. (Table 4)
TABLE 4. Descriptive statistics for the scale scores of each temperament in boys and girls.
Temperament Boys Girls p-value
Surgency
N(%) 107(61.5) 72(48.3) 0.019*
Meanscores±SD 5.36±0.62 5.16±0.69 0.008*
NegativeAffectivity
N(%) 0 3(2) 0.097
Meanscores±SD 2.86±0.67 3.00±0.73 0.056
EffortfulControl
N(%) 57(32.8) 68(45.6) 0.022*
Meanscores±SD 5.11±0.65 5.09±0.68 0.740
Surgency-EffortfulControlequally
N(%) 10(5.7) 5(3.4) 0.428
Meanscores±SD N/A N/A N/A
Surgency-NegativeAffectivityequally
N(%) 0 1(0.3) 0.461
Meanscores±SD N/A N/A N/A
p-value < 0.05 is considered statistically signicant
* p-value < 0.05
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DISCUSSION
is is the rst study in ailand that has used the
translated very short form of Early Childhood Behavior
Questionnaire (ECBQ), which is the clinically practical
evaluative tool for assessing ai toddlers’ temperament.
is study is also the rst preliminary report on ai
toddlers’ temperament. e majority of ai toddlers in
this study demonstrated surgency temperament. Boys
exhibited more surgency, while girls manifested more
eortful control.
The very short form of ECBQ, Thai version demonstrated
an internal consistency coecient at 0.682 for surgency
temperament, 0.627 for negative-aectivity temperament,
and 0.692 for eortful-control temperament. Although these
coecients suggested questionable internal consistency,
they were slightly lower than those of the original English
version (0.72 for surgency, 0.7 for negative aectivity,
and 0.72 for eortful control).
12
e maximum of the
Cronbach’s alpha coecient of the ai version of the
questionnaire, when any item was deleted, was 0.707,
which was slightly higher than the overall Cronbach’s alpha
coecient. is suggests that no item disproportionately
aected the overall internal consistency (i.e. No specic
item should be removed from the ai version of the
very short-form ECBQ). A recent study translating the
very short-form ECBQ into Czech, which recruited 709
children ages 18-36 months, also revealed an internal
consistency by Cronbach’s alpha coecients of 0.65, 0.70,
and 0.71 for surgency, negative aectivity, and eortful
control, consecutively. However, there was no report
regarding the inter-rater and test-retest reliabilities.
16
e intraclass correlation coecients exhibited
moderate to good short-term intra-rater reliability
(0.614, 0.602, and 0.750 for surgency, eortful control,
and negative aectivity, respectively). In contrast, the
long-term one had poor to moderate reliability (0.602
for surgency, 0.476 for eortful control, and 0.459 for
negative-aectivity temperament). We postulated that the
decline in the reliability might be due to chronological
fading. However, the long-term ICCs almost reached
those of the original English version, which was ranged
from 0.55-0.83.
12
e inter-rater reliability was classied
as being of poor to moderate reliability - i.e. 0.463,
0.638, and 0.670 for eortful control, surgency, and
negative aectivity, respectively, which were slightly
more favorable than in the original English version,
which reported an overall inter-rater reliability of 0.31
(0.32, 0.24, and 0.36 for eortful control, surgency, and
negative aectivity, respectively).
12
All of the properties
demonstrated that very short-form ECBQ, ai version can
be fruitfully used in research on temperament among ai
children.
Our study found that the majority of our participants
were reported as having a surgency temperament. Although
no previous studies reported the most common temperament
type in their populations, there has been plentiful evidence
that culture aects temperament. American children
get higher scores for surgency and lower scores for
negative aectivity than Japanese children.
17
One possible
explanation is that self-reliance, autonomy, and creativity
are highly valued and promoted in the Western cultures,
whereas such characteristics tend not to be in the Asian
ones. However, the American children got higher scores
for negative aectivity,
18
and tended to demonstrate
more eortful control than Chilean and Italian toddlers,
respectively.
19
erefore, how ai children’s temperament
diers from that of children’s from other regions should
be the subject of future research. Our ndings regarding
gender dierences are comparable to those of previous
international studies.
16,20
Possible explanations involve
how boys and girls are raised to behave dierently.
ere were some limitations to this study. e data
collection about parental temperament scoring did not
be specied that the parent was a father or a mother.
This lack of information hindered the comparisons
between fathers’ and mothers’ perspectives that may
lead to low inter-rater reliability, especially regarding
eortful-control temperament. Although our sample
size was adequate for evaluating the reliability of the
questionnaire, it was obviously too low to represent all
ai toddlers. Future research should be done using a
considerably larger sample size and should include the
participants from every region of ailand.
CONCLUSION
e very short form Early Childhood Behavior
Questionnaire, ai version demonstrated acceptable
internal consistency and reliability. e majority of the
ai toddlers revealed a surgency temperament. Boys
exhibited more surgency, while girls manifested more
eortful control.
ACKNOWLEDGEMENTS
e authors gratefully acknowledge Professor Samuel
P. Putnam for giving us permission to translate the
Early Childhood Behavior Questionnaire, very short
form into ai, and to Dr. Sasima Tongsai and Ms.
Kanokwan Sommai from the Division of Research,
Faculty of Medicine Siriraj Hospital, Mahidol University
for help with the statistical analysis.
Conict of interest declaration
e authors declare no conicts of interest relating
to any aspect of this study.
Rojmahamongkol et al.
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Original Article
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Funding disclosure
ere was no funding for this study.
APPENDIX
The ECBQ assesses the following 18 scales of
temperament:
Activity Level/Energy: Level (rate and intensity) of gross
motoractivity, including rate and extent of locomotion
Attentional Focusing: Sustained duration of orienting
on an object ofattention; resisting distraction
Attentional Shiing: e ability to transfer attentional
focus fromone activity/task to another
Cuddliness: A child’s expression of enjoyment in and
moldingof the body to being held by a caregiver
Discomfort: Amount of negative aect related to sensory
qualitiesof stimulation, including intensity, rate, or
complexity oflight, sound, texture.
Fear: Negative aect,including unease, worry, or nervousness
related to anticipated pain or distress and/or potentially
threatening situations;being startled by sudden events
Frustration: Negative aect related to interruption of
ongoingtasks or goal blocking
High-intensity Pleasure: Pleasure or enjoyment related
to situations involving high stimulus intensity, rate,
complexity, novelty and incongruity
Impulsivity: Speed of response initiation
Inhibitory Control: e capacity to stop, moderate,or
refrain from a behavior under instruction
Low-intensity Pleasure: Pleasure or enjoyment related
to situations involving low stimulus intensity, rate,
complexity,novelty and incongruity
Motor Activation: Repetitive small-motor movements;
dgeting
Perceptual Sensitivity: Detection of slight, low-intensity
stimuli from the external environment
Positive Anticipation: Excitement about expected
pleasurableactivities
Sadness: Tearfulness or lowered mood related to exposure
to personal suering, disappointment, object loss, loss
of approval,or response to other’s suering
Shyness: Slow or inhibited approach and/or discomfort
in social situations involving novelty or uncertainty
Sociability: Seeking and taking pleasure in interactions
with others
Soothability: Rate of recovery from peak distress,
excitement, or general arousal
Children’s temperament divided into three factors:
Surgency/Extraversion is characterized by high
positive loadings for Activity Level, High-Intensity
Pleasure, and the Impulsivity scale and strong negative
loadings on the Shyness scales.
Negative Affectivity is characterized by high
positive loadings for Anger/Frustration, Sadness, Fear,
and Discomfort and negative loading for the Soothability
scales.
Eortful Control is characterized by high positive
loadings for Inhibitory Control, Attention Control, and
the Perceptual Sensitivity scales.
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Original Article
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Prompak Nitayavardhanam M.D., Teerapong Tocharoenchok M.D.
Division of Cardiothoracic Surgery, Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, ailand.
Predictive Value of Right Ventricular Pressure
Measurement for Residual Pulmonary Stenosis in
Tetralogy Repair
ABSTRACT
Objective: e long-term outcome of tetralogy of Fallot repair depends on an adequate relief of right ventricular
outow tract obstruction and preservation of the pulmonary valve function. Since intraoperative transesophageal
echocardiography is not routinely performed in small patients, we postulated that the post-bypass right ventricular
pressure measured intraoperatively could predict residual pulmonary stenosis when evaluated by transthoracic
echocardiography.
Materials and Methods: Of the 187 patients who underwent tetralogy repair between 2012 and 2019 at Siriraj
Hospital, ailand, 95 with right ventricular pressure measurements and pre-discharge echocardiography were
included in the study. eir intraoperative parameters, and postoperative outcomes were analyzed. e tolerable
pressure cuto was determined.
Results: e median patient age was 3.9 years old (interquartile range 2.75–6). Fiy-three patients (54.6%) required
the use of the transannular patch. Ten patients (10.3%) had signicant residual pulmonary stenosis with a mean
right ventricular systolic pressure of 64.0±10.6 mmHg compared with 48.7±14.4 mmHg for the other patients.
ere was an association between the pressure gure and the degree of residual pulmonary stenosis (rho=0.391,
p=0.01). A systolic pressure above 49 mmHg predicted pulmonary stenosis with a likelihood ratio of 2.18 (1.94-
2.80, 95%CI). e likelihood rose to 2.93 (2.44-4.01, 95%CI) if the pressure resulted in a right to le ventricular
pressure ratio above 0.62. e patients whose gures did not exceed 49 mmHg experienced no signicant residual
obstruction, regardless of the pressure ratio.
Conclusion: Intraoperative measurement of the right ventricular pressure can predict residual pulmonary stenosis
aer tetralogy repair with a reassuring cuto of 49 mmHg.
Keywords: Tetralogy of Fallot repair; right ventricular pressure; residual pulmonary stenosis; intraoperative
assessment (Siriraj Med J 2022; 74: 225-232)
Corresponding author: Teerapong Tocharoenchok
E-mail: Teerapong.toc@mahidol.ac.th
Received 26 November 2021 Revised 21 December 2021 Accepted 22 December 2021
ORCID ID: https://orcid.org/0000-0001-9983-3915
http://dx.doi.org/10.33192/Smj.2022.28
INTRODUCTION
Tetralogy of Fallot is the most common cyanotic
congenital heart disease worldwide. e rst corrective
surgery was performed in the 1950s and the treatment
has been evolving ever since.
1
e current strategies
involve adequate relief of right ventricular outow tract
obstruction and optimal preservation of the right ventricular
and pulmonary valve function, guided predominantly
by intraoperative transesophageal echocardiography.
2,3
Residual pulmonary stenosis or regurgitation aer
the repair is not infrequent and, to some extent, it can
lead to progressive right ventricular dysfunction requiring
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226
subsequent reoperation to prevent sudden cardiac death.
4-6
In the light of a paradigm shi from complete relief of the
right ventricular outow tract obstruction to preserving
the pulmonary valve and infundibulum during tetralogy
repair, the adequacy of resection has gained elevated
importance as some reports have revealed a high incidence
of residual right ventricular outow tract obstruction
following valve-sparing surgery. even during short-term
follow-up.
7
Intraoperative echocardiography is not routinely
performed in small children at many institutes, including
at our institute, and instead, many surgeons measure the
right ventricular pressure intraoperatively to predict the
degree of residual pulmonary stenosis and to identify
whether the problematic outow justies immediate
revision.
8
Unfortunately, the maximum tolerable pressure
is arbitrary and depends on the individual threshold of
acceptance. Besides, the le to the right systolic ventricular
pressure ratio alone is subject to errors as it depends on
the systemic vascular resistance, which may vary across
patients in response to the cardiopulmonary bypass.
We postulate that, in the absence of intraoperative
echocardiography, the right ventricular systolic pressure can
predict residual right ventricular outow tract obstruction.
Further, in this study, we tried to identify the pressure
criteria for outow tract revision.
MATERIALS AND METHODS
Patients
Between 2012 to 2019, 187 consecutive tetralogy
of Fallot patients underwent total correction at Siriraj
Hospital, ailand. Aer exclusion of the patients without
documented post-bypass right ventricular systolic
pressure measurements and pre-discharge transthoracic
echocardiography, 95 patients were included in the study
analysis. e decision to measure the ventricular pressure
primarily depended on the surgeon’s routine. Table 1
shows the baseline characteristic and operative variables
of the study population. e preoperative pulmonary
valve z-value and McGoon ratio were obtained from
the cardiac catheterization measurements. e clinical
outcomes between the 95 included patients were similar
to those of the rest patients (who were excluded because of
no documented intraoperative right ventricular pressure
measurement) concerning signicant residual pulmonary
stenosis and in-hospital care duration (the results not
shown).
e study was approved by Siriraj Institutional
Review Board (COA no. Si 003/2020). e patient consent
is waived as it contained minimal risk to the subject.
TABLE 1. Patient characteristics.
Variables Study patients
(n=95)
Age,y mean±SD 6.0±6.7
median[IQR] 3.9[2.75–6]
Weight,kg mean±SD 15.7±8.7
median[IQR] 13[10.5–17.8]
PreoperativePVz-score -2.14±1.52
McGoonratio 2.21±0.47
Bypasstime,min 165.5±58.7
Cross-clampingtime,min 121.2±39.2
Transannularpatch,n(%) 52(54.7)
DirectRVSP,mmHg 50.3±14.8
DirectPrv/Plvratio 0.60±0.18
PostOpTTERVOTPPG,mmHg 25.2±14.3
missing,n(%) 15(15.8)
PostOpTTEPSgrade,n(%)
none 16(16.8)
mild 69(72.6)
moderate 10(10.5)
severe 0
SignicantresidualPS,n(%) 10(10.5)
ICUstay,d mean±SD 3.2±6.6
median[IQR] 2[1,3]
Hospitalstay,d mean±SD 9.8±7.4
median[IQR] 8[7–11]
Abbreviations: ICU; intensive care unit, Plv; le ventricular pressure,
Prv; right ventricular pressure, PostOp; postoperative, PPG; peak
pressure gradient, PS; pulmonary stenosis, PV; pulmonary valve,
RVOT; right ventricular outow tract, RVSP; right ventricular systolic
pressure, TTE; transthoracic echocardiography.
Surgical technique and right ventricular pressure
measurement
All repairs were conducted through median
sternotomy with cardiopulmonary bypass under mild
systemic hypothermia. Intermittent, antegrade cold blood
cardioplegia was given for myocardial protection. e
surgical approach was transatrial and transpulmonary
and/or transventricular in all the patients depending
on the degree of infundibular hypoplasia and on the
anatomy of the ventricular septal defect. The right
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ventricular outow was managed with either annular-
preserving repair or standard transannular patch repair
with monocusp creation using a 0.1 mm-thick expanded
polytetrauoroethylene membrane according to the
intraoperative annular measurement. e patch size was
tailored for a normal pulmonary valve size for the age
and height of the patient. Aer the patients had come
o the bypass, all the transducers were calibrated, and
the right ventricular pressure was obtained by direct
puncture to the right ventricular free wall using a 25
mm-long, 22-gauge needle connected to the pressure
transducer system. e le ventricular pressure was
simultaneously estimated by the peripheral arterial line
and an arterial outlet pressure monitoring device.
Postoperative course and transthoracic echocardiography
In the intensive care unit, the hemodynamic support
and ventilator management were adjusted according
to the clinical progress by the attending physicians.
Postoperative echocardiography was performed by pediatric
cardiologists before hospital discharge or otherwise as
clinically indicated. e pressure gradient across the
right ventricular outow tract, degree of pulmonary
stenosis, and regurgitation were noted.
Denitions
e degree of residual pulmonary stenosis was
estimated using transthoracic echocardiography by a
combination of the morphologic appearance, and the
measured peak velocity and peak pressure gradient across
the pulmonary valve.
• Mild: peak velocity < 3 m/s, peak gradient < 36
mmHg
• Moderate: peak velocity = 3–4 m/s, peak gradient
= 36–64 mmHg
• Severe: peak velocity > 4 m/s, peak gradient >
64 mmHg
Signicant residual pulmonary stenosis is dened
as a moderate or greater degree of pulmonary stenosis.
Statistical analysis
Based on the expected correlation coecient of 0.3,
a minimum sample size of 85 was required to estimate
Spearman’s rank correlation with a power of 0.8 and a
signicance level of 0.05. Descriptive statistics were used
to present the baseline characteristics of the patients.
Continuous variables were presented as the mean with the
standard deviation or the median with the interquartile
range. e dierences were evaluated using the Student’s
t-test or Mann–Whitney U test, as appropriate. Categorical
variables were presented as number and percentage, and
dierences were evaluated using the chi-square test or
Fischer’s exact test, as appropriate. A p-value < 0.05 was
set as the threshold for statistical signicance. Receiver
operating characteristic (ROC) curves were generated
to determine the optimal cuto values for the variables
in the prediction of signicant residual outow tract
obstruction. All the data were analyzed using the SPSS™
soware version 20.0 (SPSS Inc., IBM Company, Chicago,
Illinois, USA).
RESULTS
No operative mortality was observed. e pre-
discharge transthoracic echocardiography was performed
at the median post-operative day 5 (interquartile range
1-6). e mean intraoperative right ventricular systolic
pressure aer the repair was 50.3±14.8 mmHg (range
17–83 mmHg). e mean intraoperative right to le
systolic ventricular pressure ratio was 0.60±0.18 (range
0.21–1.08). Concerning the degrees of postoperative
tricuspid regurgitation, only 5 patients experienced
moderate tricuspid regurgitation while the rest had
no or mild regurgitation. Table 2 shows comparisons
between the two surgical approaches: the transannular
and non-transannular techniques. e transannular
patch repair group was associated with less residual
outow obstruction, more pulmonary regurgitation,
and a longer ICU stay and hospital stay.
Ten patients (10.5%) were documented to have
significant residual right ventricular outflow tract
obstruction with a higher systolic right ventricular
pressure and pressure ratio. None of them underwent
surgical revision at the index admission. Comparisons
between the patients with and without signicant residual
pulmonary stenosis are shown in Table 3. e patients
with residual subpulmonary obstruction required less
transannular patching and subsequently a shorter in-
hospital care duration. e characteristics of the patients
with signicant residual pulmonary stenosis are shown
in Table 4.
rough Spearman’s rank correlation analysis, we
found a correlation between the systolic right ventricular
pressure and the degree of postoperative residual pulmonary
stenosis (rho = 0.391; p = 0.01). e right to le systolic
ventricular pressure ratio was also correlated with the
degree of postoperative residual pulmonary stenosis
(rho = 0.369; p = 0.01). rough ROC curve analysis,
we analyzed each intraoperative pressure parameter and
the combination of both to identify the diagnostic cuto
for signicant residual pulmonary stenosis identied
by pre-discharge transthoracic echocardiography. e
results are depicted in Fig 1. A systolic right ventricular
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TABLE 2. Comparison of two outow reconstruction techniques among the study patients.
Variables Transannular approach Transatrial/Pulmonary P-value
(n=52) (n=43)
Age,y mean±SD 5.1±4.9 7.1±8.3 0.15
median[IQR] 3.4[2.8–6.2] 4.8[2.8–6.0] 0.43
Weight,kg mean±SD 14.5±6.9 17.1±10.5 0.16
median[IQR] 12.2[10.4–16.3] 14[10.5–18.5] 0.27
PreoperativePVz-score -2.82±1.47 -1.30±1.14 <0.001
McGoonratio 2.21±0.47 2.27±0.59 0.58
Bypasstime,min 176.1±68.5 148.7±40.1 0.022
Cross-clamping,min 129.5±42.3 108.4±32 0.007
DirectRVSP,mmHg 52±15 48.5±14.7 0.26
DirectPrv/Plvratio 0.62±0.19 0.58±0.18 0.26
PostOpTTEPSgrade,n(%) 0.46
none 8(15.4) 7(16.3)
mild 41(76.9) 27(62.8)
moderate 2(3.8) 8(18.6)
severe 0 0
SignicantresidualPS,n(%) 2(3.8) 8(18.6) 0.039
PostOpTTEPRgrade,n(%) <0.001
none 0 7(16.3)
mild 4(7.7) 10(23.3)
moderate 20(38.5) 21(48.8)
severe 27(51.9) 4(9.3)
PostOpTTERVOTPPG,mmHg 24.4±13.9 25.6±13.5 0.72
missing,n(%) 9(17.3) 7(16.3)
ISatICUarrival mean±SD 11.3±12.7 8.2±6.2 0.15
median[IQR] 7.5[5–15] 7[4–13] 0.38
ICUstay,d mean±SD 4.3±8.8 2±1.5 0.09
median[IQR] 2.5[1–4] 1[1–2] 0.006
Hospitalstay,d mean±SD 11.5±10 8.1±2.7 0.032
median[IQR] 10[7–11.8] 8[6–10] 0.007
Abbreviations: ICU; intensive care unit, IS; inotropic score, Plv; le ventricular pressure, Prv; right ventricular pressure, PostOp; postoperative,
PPG; peak pressure gradient, PR; pulmonary regurgitation, PS; pulmonary stenosis, PV; pulmonary valve, RVOT; right ventricular outow
tract, RVSP; right ventricular systolic pressure, TTE; transthoracic echocardiography.
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TABLE 3. Comparison of two outow reconstruction techniques among the study patients.
Variables Patients with Patients without P-value
signicantresidualPS signicantresidualPS
(n=10) (n=85)
Age,y mean±SD 3.8±2.0 6.3±7.0 0.019
median[IQR] 3.3[2.3–5.3] 4.3[2.8–6.3] 0.31
Weight,kg mean±SD 14.2±5.0 15.9±9.1 0.39
median[IQR] 13.3[10–17.6] 13[10.6–17.8] 0.85
PreoperativePVz-score -1.59±0.74 -2.21±1.58 0.22
McGoonratio 2.58±0.57 2.17±0.44 0.05
Bypasstime,min 144±24.9 168±61 0.028
Cross-clampingtime,min 109.6±29.5 122.6±40.1 0.23
Transannularpatch,n(%) 2(20) 49(57.6) 0.039
DirectRVSP,mmHg 64±10.6 48.7±14.5 0.001
DirectPrv/Plvratio 0.76±0.13 0.58±0.18 0.002
PostOpTTERVOTPPG,mmHg 46.7±10.2 21.8±10.9 <0.001
missing,n(%) 0 14(16.5)
ISatICUarrival mean±SD 8.6±6.9 9.9±10.7 0.60
median[IQR] 7[4–11.3] 6.8[4.4–15] 0.89
ICUstay,d mean±SD 1.7±1.9 3.5±6.9 0.07
median[IQR] 1[1–1.3] 2[1–3] 0.018
Hospitalstay,d mean±SD 7.7±1.8 9.3±3.6 0.042
median[IQR] 7[6.8–8.5] 8[7–11] 0.27
Abbreviations: ICU; intensive care unit, IS; inotropic score, Plv; le ventricular pressure, Prv; right ventricular pressure, PostOp; postoperative,
PPG; peak pressure gradient, PS; pulmonary stenosis, PV; pulmonary valve, RVOT; right ventricular outow tract, RVSP; right ventricular
systolic pressure, TTE; transthoracic echocardiography.
pressure above 49 mmHg predicted postoperative
residual pulmonary stenosis with a likelihood ratio of
2.18 (95%CI 1.94–2.80). A systolic right to le ventricular
pressure ratio above 0.62 predicted postoperative residual
pulmonary stenosis with a likelihood ratio of 2.57 (95%CI
2.21–3.42). e combination of both pressure criteria
raised the likelihood of residual outow obstruction to
2.93 (95%CI 2.44–4.01). Fig 2 shows the outow tract
decision owchart according to our results. None of the
study patients whose ventricular pressure did not meet
both criteria experienced signicant residual outow
obstruction.
DISCUSSION
We found an association between right ventricular
systolic pressure and the degree of pulmonary stenosis.
As a predictor for residual right ventricular outow tract
obstruction, the absolute gure of the intraoperative
pressure performed comparably to the pressure ratio
(an almost identical area under the ROC curve). When
we combined both parameters, the predictive value from
the likelihood ratio increased considerably. Apart from
the pressure ratio, this information implies how high the
right ventricular pressure is also matters, especially when
the right to le systolic pressure ratio approaches the
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TABLE 4. Characteristics of the patients with signicant residual pulmonary stenosis.
Patient Gender Preoperative McGoon Technique RVSP, Prv/lv PostOp TTE IS at ICU ICU stay, Hospital
PV z-score ratio mmHg ratio RVOT PPG, arrival day stay, day
mmHg
1 M -2.06 2.73 Subannular, valvulotomy 52 0.66 39 4 1 6
2 F -1.5 2.3 Subannular, valvulotomy 50 0.63 49 15 2 6
3 M -1.18 3.5 Supravalve, valvulotomy 69 0.69 47 11.7 8 12
4 F -2.6 3 Transannular, monocusp 67 0.76 55 20 4 10
5 M -1.9 2.5 Supravalve, valvulotomy 64 0.75 42 7 1 8
6 M -1.63 1.5 Sub/supravalve patch, 50 0.70 38 5 1 8
valvulotomy
7 M -2.4 2 Supravalve, valvulotomy 81 0.70 55 10 1 7
8 F -1.79 3.12 Transannular, monocusp 75 0.90 66 7.5 1 7
9 M -0.4 2.53 Supravalve, valvulotomy 70 1.08 41 5 1 8
10 M -0.4 2.6 Transatrial 62 0.73 44 10 1 7
Abbreviations: ICU; intensive care unit, IS; inotropic score, Plv; le ventricular pressure, Prv; right ventricular pressure, PostOp; postoperative, PPG; peak pressure gradient, PV; pulmonary valve, RVOT;
right ventricular outow tract, RVSP; right ventricular systolic pressure, TTE; transthoracic
Echocardiography.
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Fig 2. Outow tract assessment decision owchart
Abbreviations: Prv/lv; right ventricular to le ventricular systolic pressure ratio, PS; pulmonary stenosis, RV; right ventricle, RVSP; right
ventricular systolic pressure.
Fig 1. Receiver operating characteristic (ROC) curves of the predictors of right ventricular outow tract obstruction. (A) Right ventricular
systolic pressure (RVSP). (B) Right to le ventricular pressure ratio (Prv/Plv ratio).
Abbreviations: AUC; area under the curve, Sn; sensitivity, Sp; specicity.
published revision criteria. Although in the majority of
the cases both the pressure and pressure ratio went in the
same direction and magnitude, in some patients with a
relatively low systolic blood pressure initially o the pump,
use of the pressure ratio alone tended to overestimate
the residual outow obstruction. Only one of the sixteen
patients (specically, patient #9) with an initial systolic
blood pressure below 70 mmHg experienced signicant
residual pulmonary stenosis despite a mean pressure ratio
of 0.75±0.29 in the group with hypotension. Adding the
absolute right ventricular pressure to the consideration
could prevent unnecessary intervention in this context.
To the best of our knowledge, this piece of information
has not been reported before in the literature.
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Regarding the pressure ratio cuto value of 0.62,
which is quite low compared with other reports
2,9
, this
gure was selected as a reassuring cuto, not the revision
one. As the specicity of the test suggested, some patients
whose measurement exceeded these criteria eventually
fell into the insignicant residual outow stenosis at the
sonographic follow-up. is implies that even if both
proposed criteria are met, the surgeon should logically
identify the culprit location and consider the possibility of
further resection without scarifying the pulmonary valve
integrity before commencing the second pump run. e
reason behind this is possibly due to the heterogeneous
nature of postoperative Fallot’s outow tract restriction
(i.e., xed or dynamic)
10
, which, unfortunately, might
need intraoperative echocardiography to dierentiate.
3
Unsurprisingly, the patients who needed the pulmonary
valve ring enlarged performed worse than those with an
intact pulmonary valve ring in terms of the pulmonary
valve integrity and in-hospital care duration (Table 2).
In contrast to a previous report
8
, our study demonstrated
better in-hospital outcomes among the patients with
signicant residual outow tract obstruction (shorter
ICU and hospital stay). is result could probably be
attributed to the eect of the transannular approach and
the resultant pulmonary insuciency rather than the
gradient itself (the transannular patching requirement
of the patients with insignificant residual stenosis
was almost triple that of the signicant counterpart,
Table 3).
It is to be noted that our study had limitations due
to its retrospective nature and short period of follow-up.
Also, changes in the outow tract gradient over time
were monitored only in selected patients. Furthermore,
as we did not have a patient with critical residual outow
tract obstruction in our series, the diagnostic cuto of
such a condition was, therefore, unattainable. Longer-
term follow-up of such a ‘signicant’ patient is needed
to elucidate the clinical signicance of such ndings.
CONCLUSION
In the setting without intraoperative transesophageal
echocardiography, the direct measurement of right
ventricular pressure can predict the adequacy of outow
tract reconstruction during the repair of tetralogy patients.
Adding an absolute pressure criterion of 49 mmHg to
the pressure ratio could prevent unnecessary surgical
revision and protect pulmonary valve integrity.
ACKNOWLEDGEMENTS
We acknowledge the contribution of Dr. Sasima
Tongsai from the Clinical Epidemiology Unit, who
performed the statistical analysis for this study.
Funding statement: is research received no specic
grant from any funding agency.
Conict of interest statement: None declared.
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Chatporn Boonyapalanant, M.D.**, Varat Woranisarakul, M.D.*, Siros Jitpraphai, M.D.*, Ekkarin Chotikawanich,
M.D.*, Tawatchai Taweemonkongsap, M.D.*, Hari Bahadur KC, M.D.***, itipat Hansomwong, M.D.*
*Division of Urology, Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, ailand, **Division of Urology,
Department of Surgery, Faculty of Medicine, Panyananthaphikkhu Chonprathan Medical Center, Srinakharinwirot University, Nonthaburi, ailand,
***Department of Surgery, Pokhara Academy of Health Sciences, Nepal.
The Efcacy of Inside-Out Transversus Abdominis
Plane Block vs Local Inltration before Wound
Closure in Pain Management after Kidney
Transplantation: A Double-blind, Randomized Trial
ABSTRACT
Objective: Transversus abdominis plane (TAP) block is a form of multimodal pain management in open abdominal
surgery. Among patients who undergo kidney transplantation, their choice of painkillers is limited. is study
aims to determine the ecacy of TAP block vs local inltration in pain management aer kidney transplantation.
Materials and Methods: In this prospective, randomized, double-blinded clinical trial, 46 patients with end-stage
kidney disease who had undergone kidney transplantation were randomly divided into two groups: a local anesthetic
inltration (LA) group receiving 0.25% Bupivacaine 20 ml around the surgical wound before wound closure and a
TAP block group receiving 0.25% Bupivacaine 20 ml by the inside-out technique. eir postoperative pain scores
and morphine consumption were recorded at 2, 6, 12, 18, 24, and 48 hours.
Results: ere was no statistically signicant dierence in the baseline characteristics between the groups. e
postoperative pain score at two hours in the TAP block group was signicantly lower than in the LA group
(P value = 0.037), but without other dierences in their pain scores aer two hours. ere was no statistical dierence
in the morphine consumption between the two groups. e total morphine consumption in the TAP block group
was less than in the LA group, but this was not statistically signicant. No patients suered from complications of
the TAP block.
Conclusion: Transversus abdominis plane block can reduce postoperative pain at two hours aer kidney transplantation,
without signicant complications.
Keywords: Transversus abdominis plane block; kidney transplantation; pain management; postoperative pain
(Siriraj Med J 2022; 74: 233-238)
Corresponding author: itipat Hansomwong
E-mail: thitipat.han@mahidol.ac.th
Received 7 September 2021 Revised 1 February 2022 Accepted 17 February 2022
ORCID ID: https://orcid.org/ 0000-0002-8243-7876
http://dx.doi.org/10.33192/Smj.2022.29
Abbreviations
TAP Transversus abdominis plane
NRS Numerical rating scale
BMI Body mass index
LA Local anesthesia
QL Quadratus lumborum
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INTRODUCTION
Kidney transplantation is the treatment of choice
in patients with end-stage kidney disease. A kidney
transplant is a major operation requiring a classical
incision at the lower abdomen, extending from laterally
to the pubic symphysis to the anterior superior iliac crest
called Gibson incision. Many patients require a painkiller
aer the operation, and postoperative pain control is
crucial to improving one’s surgical outcome. Multimodal
analgesia aims to decrease opioid consumption and its side
eects. Especially among patients who undergo kidney
transplantation, their choice of painkiller is limited, due
to any such drugs’ interaction with immunosuppressive
drugs and nephrotoxicity.
1
Local anesthesia inltration
around the incision is one of the traditional methods of
local pain control. Two decades ago, transversus abdominis
plane (TAP) block was introduced as a new technique to
reduce postoperative pain. is was originally reported by
Ra in 2001.
2
TAP block is a regional anesthesia, targeting
sensory nerves running between the internal oblique
muscle and the transversus abdominis muscle layer, these
nerves receiving signal from anterior abdominal wall
between level of T9 and T12 via a blinded technique or
ultrasound guidance.
3,4
A TAP block can be performed
by a surgeon or anesthesiologist using the outside-in
technique aer the induction of anesthesia or through
the inside-out technique before the wound is closed. A
TAP block has been used to control postoperative pain
involving many kinds of abdominal surgery. e results
from many trials have produced variable outcomes, some
showing no signicant dierence in post-operative pain
management, while others have resulted in signicant pain
scores and/or opioid consumption.
5-11
According to meta-
analyses, the TAP block seems to benet postoperative
pain control in kidney transplantation patients.
12
Until
now, there has been no report comparing traditional,
local anesthetic inltration with the TAP block by the
inside-out technique in kidney transplantation patients.
is study aims to determine the ecacy of the TAP
block vs local inltration in pain management aer
kidney transplantation.
MATERIALS AND METHODS
This prospective, randomized, double-blinded
clinical trial was approved by the Ethics Committee
of the Faculty of Medicine Siriraj Hospital, Mahidol
University, ailand, protocol number 826/2019(IRB4).
Aer informed consent, 46 patients with end-stage kidney
disease who had undergone kidney transplantation from
both living-donor and cadaveric kidney transplant at
Siriraj Hospital were recruited. Patients were excluded
if they had a history of painkiller allergy, if they could
not dene a pain score in the numerical rating scale
(NRS), were suspected of having a painkiller addiction
or an abnormal coagulopathy, or had incomplete data.
Patients’ demographic data (sex, age, BMI, and
previous abdominal surgery); intraoperative data (operative
time and length of wound); and postoperative data
covering 48 hours (pain score and opioid usage) were
collected. Patients were randomly divided into two groups:
a local anesthetic inltration (LA) group and a TAP
block group. e group allocations were concealed in
opaque envelops which were randomly picked up and
opened just before each wound was closed. Aer standard
monitoring, all patients received general anesthesia. e
kidney transplantation was then done routinely. In the
LA group, patients received 0.25% Bupivacaine 20 ml
around the surgical wound before the wound was closed.
In the TAP block group, the TAP block was performed
by a surgeon with the ultrasound- guided inside-out
technique. A curvilinear ultrasound probe was placed
just lateral to the quadratus lumborum muscle above
the iliac crest as high as possible via a standard Gibson
incision. Aer the layer between the internal oblique
muscle and the transversus abdominis muscle was found,
0.25% Bupivacaine 20 ml was injected into the space
via needle 25-gauge 1.5 inch with the appearance of a
Goose egg sign before the wound was closed (Fig 1). All
patients were received postoperative care and pain control
at postanesthesia care unit following Siriraj protocol
13
including Acetaminophen 500 mg 1 tab per oral every
6 hours for 3 days. Aer the operation, patients were
assessed on a pain score with a numerical rating scale
Fig 1. TAP block procedure
0.25% Bupivacaine 20 ml was injected
into the space between the internal oblique
muscle and the transversus abdominis
muscle via needle 25-gauge 1.5 inch
with ultrasound guided.
Boonyapalanant et al.
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235
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SMJ
(NRS) (0=no pain, 10=worst possible pain) at 2, 6, 12,
18, 24, and 48 hours. If the pain score was more than
3 or analgesics were required, 1 mg of morphine was
intravenously administered, and then the pain score was
rechecked aer ve minutes. e amount of morphine
consumption was recorded. All pain scores and morphine
consumption were recorded by investigators who were
blinded to the group allocations.
e goal was to compare the pain score and morphine
consumption aer the TAP block and LA technique.
e sample size was calculated from previous study on
TAP-block ecacy.
9-11
Statistical analysis was conducted
using SPSS version 21 soware. Demographic data and
intraoperative data were present as mean ± SD. In a
normal distribution of data, the Student’s t-test and
Pearson’s chi-square were used to compare the results
between the two groups. e postoperative pain scores
and morphine consumption were present as a median
with IQR, and compared between the groups by using
the Mann-Whitney U test. A P value less than 0.05 was
determined as having statistical signicance.
RESULTS
From January, 2020 to November, 2020, 46 patients
were enrolled in this study and were randomized into
two groups, with 23 people in each group. One patient
in the TAP block group was excluded due to the need for
reoperation within 24 hours because of bleeding from
tissue around the kidney gra (Fig 2). 62.2% of the study
population was male, and the mean age was 46.7 years
old (range: 26 – 62). e mean body mass index was
21.39 kg/m
2
(range: 15.6 – 27.9). 28.9% of the patients
had previous abdominal surgery. e mean operative
time was 177 minutes (range: 110 – 360) and the mean
length of the wound was 16.6 centimeters (range: 12 –
23). ere was no statistically signicant dierence in
the baseline characteristics between the groups, as is
indicated in Table 1.
The pain scores (NRS) were compared in two
groups, (as seen in Fig 3), at 2, 6, 12, 18, 24, and 48 hours
postoperatively. e median and IQR of pain scores at
2, 6, 12, 18, 24, and 48 hours in LA group are 3 (3-4),
2 (1-3), 2 (0-3), 1 (0-2), 0 (0-1) and 0 (0) respectively.
Fig 2. Patients ow chart.
TABLE 1. Comparison of two outow reconstruction techniques among the study patients.
LA group TAP block group P value
Sex 0.848
Male 60.9% 63.6%
Female 39.1% 36.4%
Age(years) 48.4±9.7 44.9±10.2 0.247
Bodymassindex 21.8±3.1 20.9±2.8 0.339
Previousabdominalsurgery 30.4% 27.3% 0.815
Operativetime(minute) 181.8±50.1 172.5±36.9 0.484
Lengthofwound(cm) 16.5±2.2 16.7±2.3 0.771
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236
e median and IQR of pain scores at 2, 6, 12, 18, 24,
and 48 hours in TAP block group are 2 (2-3), 2 (1-2),
2 (1-2), 0 (0-1), 0 (0-0.25) and 0 (0). e postoperative
pain score at two hours in the LA group was higher than
in the TAP block group (P value = 0.037), though there
were no other dierences in the pain scores aer two
hours and throughout a 48-hour period.
ere was no statistical dierence in morphine
consumption between the groups, in terms of total usage,
and any recorded time point, as shown in Fig 4. e
median total morphine consumption in the LA group
was 2 mg (IQR 1-4); in the TAP block group, it was 1 mg
(IQR 1-3), with a p value of 0.105. No patients suered
from complications of the TAP block.
DISCUSSION
e most eective options for postoperative pain
control aer kidney transplantation are not always easily
determined, due to the many limitations arising from
patients’ status. In post-kidney transplant patients, many
kinds of painkillers have a risk of causing nephrotoxicity
and can alter renal clearance. An epidural block is an option
for postoperative pain control in abdominal surgery, but
there is risk of epidural hematoma formation in kidney
transplantation patients because of platelet dysfunction.
14
Regional nerve block has become a promising choice for
postoperative pain control in kidney transplant patients.
Regional nerve block or TAP block is target on specic
sensory nerve but local anesthesia can be variable due to
Fig 3. Postoperative pain score (NRS) at 2, 6, 12, 18, 24, and 48 hours postoperatively (median with IQR).
Fig 4. Morphine consumption at 2, 6, 12, 18, 24, and 48 hours postoperatively (median with IQR).
Boonyapalanant et al.
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Original Article
SMJ
operator dependent and variations of anatomy.
3
From
a meta-analysis
15
, we see that a TAP block can reduce
total opioid consumption (morphine consumption to
6 mg per day) as well as a patient’s pain score within 24
hours aer the operation. Our study shows that the pain
scores two hours aer the operation in the TAP block
group were lower than in the LA group, but, again, there
was no signicant dierence between the groups aer
that. Our LA group were given 0.25% Bupivacaine 20 ml
around the surgical wound, which can also reduce the
postoperative pain scores and morphine consumption.
Even though our study had local pain control in the LA
group, the results still reveal that the TAP block was better
than the LA, as regards post-operative pain control aer
kidney transplantation. TAP block is recommended
if ultrasound is available and patients do not have an
abnormal coagulopathy.
Concerning the duration of pain control aer the
TAP block, our meta-analysis
15
showed that 0.375%,
0.5% and 0.75% Ropivacaine TAP block reduced the
pain score at two hours aer surgery, but only 0.75%
Ropivacaine was eective 12 to 24 hours aer surgery.
We used 0.25% Bupivacaine 20 ml for the TAP block.
Onset of action of 0.25% Bupivacaine is about 19 ± 41
seconds and duration of action is about 7.02 ± 1.46 hours
aer injection.
16
is may be one of the reasons why there
were signicantly reduced pain scores only at two hours
aer the operation. In some studies, specialists added
drug regimens to the TAP block in order to prolong
the pain-control eect. Yang et al.
17
have shown that
the addition of dexmedetomidine can provide a more
eective analgesic eect for the TAP block. Systematic
review and meta-analysis from Choi et al.
18
have indicated
that adding dexamethasone to the local nerve block can
prolong the eect of nerve block more than by just doing
a local nerve block alone.
In a meta-analysis
14
, some of researchers used the
blinded technique of the TAP block, but many used the
ultrasound-guided approach. e ecacy of the latter has
been shown to be superior. Today, the ultrasound-guided
technique is considered the gold standard for the TAP
block.
4
Regarding the other technique of TAP block in our
study, we used the ultrasound-guided method with the
inside-out technique. e typical outside-in TAP block
technique may cause visceral organ damage, even if the
procedure is ultrasound-guided.
19,20
e inside-out technique
can reduce the possibility of visceral organ damage due
to performers’ visualization while performing the TAP
block. Additionally, the TAP block, which is performed
by a surgeon intra-operatively, requires less time than
the conventional TAP block by an anesthesiologist, and
there is with no dierence in the postoperative pain-
control outcomes.
21
ere is an important question involving the timing
of the administration of the TAP block. In our study, the
TAP block was applied before the wound was closed,
though some performers do this before starting to operate.
Dahl et al.
22
have demonstrated that postoperative pain
scores were not signicantly dierent between the pre- and
post-incisional nerve block. Another technique that may
help in pain management for kidney transplant patients
is the quadratus lumborum (QL) block 2. According to
Kolacz et al.
23
, this kind of block can reduce fentanyl
consumption within 24 hours aer kidney transplantation,
without a dierence in the pain score, compared to the
TAP block. Given the inside-out technique used in our
study, we may also perform a QL block via a kidney-
transplantation incision.
ere were a number of limitations in this study.
First, we could not assess the patients’ sensory-distribution
level because the TAP block was performed before the
wound was closed and while patients were still under
general anesthesia. Secondly, our inside-out technique is
dierent from original TAP technique. e double pop
sensation described in original technique cannot be felt
during needle passage, so ultrasound guided is necessary
to determine the depth of the needle. e third limitation
is no use of intravenous patient control analgesia to
access accurate dose of morphine requirement. Lastly,
our sample size was too small to broadly assess the safety
of the TAP block technique. Further studies are required
to compare the safety of the inside-out method with the
outside-in technique of the TAP block, and to determine
the optimum dose or volume to use for the TAP block.
CONCLUSION
e transversus abdominis plane block can reduce
postoperative pain aer kidney transplantation, without
signicant complications. We conclude that the TAP block
can be used as a part of multimodal pain management
for post-kidney transplantation patients.
Conicts of interest statement: e authors declare
that there are no nancial or other conicts of interest
involved in this project.
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9. Srivastava U, Verma S, Singh TK, Gupta A, Saxsena A, Jagar KD,
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12. Singh PM, Borle A, Makkar JK, Trisha A, Sinha A. Evaluation of
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Saudi J Anaesth. 2018;12(2):261-71.
13. Sanansilp V. Pain Control System in Siriraj Hospital Postanesthesia
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14. Basta M, Sloan P. Epidural hematoma following epidural
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15. Sun N, Wang S, Ma P, Liu S, Shao A, Xiong L.Postoperative
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Dierent Concentrations of Ropivacaine for Abdominal Surgery:
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Janravee Vathakul, BNS*, Nanticha Kessava, M.D.*, Julaporn Pooliam, M.Sc.**, Madonna Damayanthie Datu,
M.D.***, anawut Jitsinthunun, M.D.*, Nantthasorn Zinboonyahgoon, M.D.*
*Department of Anesthesiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, ailand, **Clinical Epidemiology Unit, Oce
for Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, ailand, ***Department of Anesthesiolgy, Dr.
Wahidin Sudirohusodo-Hasanuddin University General Hospital, Makassar-Indonesia.
The Analgesic Effect of Transcutaneous Electrical
Nerve Stimulation (TENS) on the Opposite Side for
Phantom Limb Pain
ABSTRACT
Objective: To observe the eects of TENS on the contralateral limb and PLP reduction.
Materials and Methods: is was a single center retrospective study of 20 amputee participants with phantom limb
pain. e inclusion criteria were participants aged above 18, average pain of at least 4/10 on the numerical rating
scale (NRS), duration of pain longer than one week and treatment with TENS on the opposite side. We recorded
pain intensity before and aer TENS application, response time to treatment, satisfaction, and adverse eects.
Results: Of the 20 amputee participants, all patients suered from PLP and three also suered from residual limb
pain. e average pain score before use of TENS was 4.85/10 and aer was 1.15/10. e mean pain intensity score
was reduced by 3.7/10 (95% CI 2.95-4.45/10) or 76.28% (95% condence interval 63.61-89.47%). e average overall
satisfaction was 81.65%, and no adverse eects from application of TENS was reported.
Conclusion: e study shows that the application of TENS on the opposite side is a safe and eective treatment
method for intractable pain from PLP.
Keywords: Transcutaneous electrical nerve stimulation; amputee; phantom limb pain; contralateral; neuromodulation;
neuropathic pain (Siriraj Med J 2022; 74: 239-244)
Corresponding author: Nantthasorn Zinboonyahgoon
E-mail: nantthasorn@gmail.com
Received 8 October 2021 Revised 20 February 2022 Accepted 21 February 2022
ORCID ID: https://orcid.org/0000-0002-5946-7962
http://dx.doi.org/10.33192/Smj.2022.30
INTRODUCTION
Up to 80% of amputees experience pain sensation
to a limb aer amputation (phantom limb pain: PLP)
and/or pain at the stump (residual limb pain; RLP) that
negatively impacts their quality of life.
1-5
Although chronic
PLP is common, evidence evaluating the ecacy of
treatments remains scarce, and there is still no consensus
for a standard treatment in standard guidelines.
5,6
e
most common treatments are pharmacological. However,
strong evidence supporting the short and long-term
ecacy of pharmacological treatments for PLP is still
lacking.
6,7
In an eort to identify additional eective treatment
options for PLP, clinicians and investigators have examined
a variety of non-pharmacological treatments such as
application of mirror visual feedback
8,9
and transcutaneous
electrical nerve stimulation (TENS)
10-13
, especially for the
patients who had limited success from pharmacological
treatment. TENS delivers pulsed electrical currents across
the intact surface of the skin to stimulate the peripheral
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240
nerves and spinal cord, resulting in segmental and extra-
segmental analgesia.
14
Research indicates that the application
of TENS at the site of residual limb pain or projected
site of phantom pain is associated with decreases in pain
intensity, both at rest and during movement.
10
However,
residual limb application of TENS can be challenging in
certain situations because it may aggravate discomfort
in patients with pre-existing pain or cause skin irritation
that reduces stump integrity in recent amputees.
Contralateral TENS, by inhibiting the contralateral
segmental in the dorsal horn from another side
14
, potentially
alleviates PLP and can address the problems associated
with the stump. A number of reports and small case
series have reported successful outcomes of contralateral
TENS for PLP
11-13
, and we already apply this treatment
in our daily practice. As there is no data collection of
large series for such treatment, we conducted this study
to examine the eects in the ai population.
We hypothesized that patients with PLP who received
TENS on the contralateral limb would report signicant
pain reduction aer treatment. e primary objective
of this study was to observe the eects of TENS on the
contralateral limb and PLP reduction. e secondary
objectives included observing for adverse eects, satisfaction,
and the duration of contralateral TENS treatment for
PLP.
MATERIALS AND METHODS
In this retrospective observational study, in order to
compare the analgesic eect before and aer treatment, we
performed sample size calculations with the aim to detect
a 30% reduction in pain scores aer treatment, which is
a meaningful change. Using data from a pilot study, the
mean pain score of patient suering from phantom limb
pain in our center was 5.2/10 (SD=2). By using PASW
Statistics version 18 (Chicago, IL, USA), a sample size
of 16 patients was enough to detect a dierence, with an
alpha error of 0.05 and power of 90%. As the estimate of
incomplete data was 20%, the nal number of patients
needed for this study was adjusted to 20 patients.
Aer approval by the Mahidol University-IRB, the
research team identied the medical records of patients
who suered from phantom limb pain at the Siriraj
Pain Clinic and received contralateral TENS treatment
for pain relief at Siriraj Hospital from January 1, 2018
to December 31, 2018. e research team collected the
following data points:
1. General demographic and medical history, including
age, sex, and cause of amputation
2. Pain history, including pain diagnosis, past
medications and previous treatment(s) for PLP, and
pain-related interference assessed by a validated ai
version of a brief pain inventory questionnaire
15
3. NRS before and aer treatment
4. Side eects and patient satisfaction of treatment
In routine practice, we oer the treatment to adult
patients who have moderate to severe pain (average pain
intensity from numeric rating scale more than 3 out of
10) despite appropriate pharmacological treatment (the
patients had taken at least two analgesics). TENS was not
oered in contraindicated conditions such as pregnancy,
epilepsy, active malignancy, deep vein thrombosis, frail
or damaged skin or to patients with cardiac pacemakers
or implantable cardioverter debrillators.
We used commercially available TENS units in our
daily practice (Fig 1) due to their low cost and ease of use.
First, we applied TENS’ electrodes on the contralateral
limb, mimicking the pain area on the opposite side.
As the commercial TENS units were obtained from a
variety of brands and did not have measurable parameter
settings (frequency, pulse width, amplitude), we used
clinical response as our end point. We turned on the
stimulation and increased the intensity until the patient
felt pain-free paresthesia.
We recorded an initial pain score, then applied the
stimulation for at least 30 minutes and recorded their
subsequent pain score. If the patient did not report
any change, the session was extended to 45 minutes or
60 minutes. At the end of the session, we assessed the
patient satisfaction scale (0-100) and the presence of
any adverse eects. ere was no long-term follow-up
aer the session.
Fig 1. Commercially available TENS unit.
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TABLE 1. Patient’s demographic data. PLP (phantom
limb pain), RLP (residual limb pain).
TABLE 2. Medication used for treatment of phantom limb pain.
Demographic data (n=20)
Sex
Male 10(50%)
Female 10(50%)
Age:mean(SD)years 57.1(15.63)
Pain
PLP 20(100%)
PLP+RLP 3(15%)
Levelofamputation
Transhumeral 5(25%)
Transfemoral 9(45%)
Transtibial 6(30%)
Cause
Vascular 8(40%)
Trauma 5(25%)
Tumor 7(35%)
Medication Number of patients (Percentage) Dose range (mg/day)
Gabapentin 20(100%) 600-3000
Tricyclicantidepressants(amitriptyline,nortriptyline) 15(75%) 10-25
Weakopioids(tramadol,codeine) 11(55%) Tramadol50-400mg/day
Strongopioids(morphine) 1(5%) 20mg/day
RESULTS
We collected data from a total of 21 patients who
received treatment. However, one patient was excluded
because of amputation on both legs. ere is no exclusion
due to unreliable reporting of pain score because of
psychological or physical morbidities. Finally, the data
of 20 patients were included in this analysis. All patients
had been suering from PLP, and three of them also
suered from residual limb pain (RLP). e demographic
data of all patients is shown in Table 1. e average pain
score was 4.85 out of 10 despite the use of at least two
analgesics such as gabapentin, tricyclic antidepressant,
or opioids (Table 2). e pain-related interferences were
evaluated by a brief pain inventory questionnaire.
15
e
average total score of pain-related interference (impact of
pain on general activity, mood, work, relationships, sleep,
and enjoyment of life) was 16.35 out of 60. e average
time elapsed since amputation before this treatment was
1.9 years.
Pain intensity
Pain intensity was rated by the average numeric rating
pain score (NRS). e average NRS before application of
TENS was 4.85/10 ±1.18, and it decreased to 1.15/10±1.38
aer the treatment. e dierence in average pain intensity
was 3.7±1.59 with a p-value of <0.001 for the paired
T-test (95% condence interval was 2.95-4.45). e NRS
ranged from 3-8 out of 10 before application of TENS
and decreased to 0-5 post-treatment.
Nineteen out of 20 patients reported clinically
signicant pain relief (pain score decreased by more than
30%). e mean percentage of pain reduction was 76.54
± 6.18% (95% condence interval was 63.61-89.47%).
e individual responses to treatment are shown in
Fig 2. Only one patient who had PLP aer a right elbow
amputation due to recurrent brosarcoma (number 12)
did not respond to treatment. is patient also did not
respond well to other treatments, including gabapentin
and tricyclic antidepressants.
Duration of treatment
In this study, we applied TENS on the contralateral
limb until the pain score decreased or for 60 minutes, if
pain did not improve. Sixteen participants responded
to treatment in the rst 30 minutes, and another three
responded aer it was extended to 45 minutes. Only one
participant (patient 12) reported no signicant change
in NRS aer 60 minutes. e median time required for
TENS to decrease pain was 30 minutes. e cumulative
number of responders over time is shown in Fig 3.
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242
Fig 2. Individual response to contralateral TENS stimulation.
Fig 3. Cumulative number of patient reporting pain relief over time.
Adverse eect and satisfaction
e application of transcutaneous electrical nerve
stimulation on the contralateral side was tolerated by
all participants without any adverse events during the
session. Participants reported no difficulty in using
TENS and titrating the amplitude. e average overall
satisfaction was 81.65% (0-100% and 0% for patient 12).
DISCUSSION
is study aimed to determine if the application of
TENS on the opposite limb could reduce pain intensity
in patients suering from PLP. Our ndings suggest a
signicant reduction of NRS immediately aer treatment.
Additionally, the treatment led to high satisfaction rates
and no report of adverse events.
Following amputation, up to 80% of patients reported
pain, either in the part that was amputated (phantom
pain) or at the site of amputation (residual limb pain), or
both.
1-4
is pain can aect their quality of life and prevent
proper rehabilitation and prosthetic usage. PLP is poorly
understood and one of the most dicult type of pain to
treat.
16
e underlying pathophysiology of PLP is unclear,
although it is generally accepted that nociceptive and
neuropathic processes are involved and that neuropathic
changes include reorganization and adaptation within the
peripheral and central nervous systems.
17
Additionally,
evidence evaluating the ecacy of treatments for chronic
PLP remains scarce.
6
Currently, multimodal treatment
strategies are used, including pharmacological treatments
(gabapentinoids, tricyclic antidepressants, and opioids),
pain intervention (sympathetic blocks, sympathectomies),
mirror box therapy, and TENS.
17
However, there is no
strong evidence that supports the long-term ecacy of
each treatment for PLP.
17,18
TENS delivers pulsed electric currents across the
intact surface of the skin to stimulate peripheral nerves
and the spinal cord, resulting in segmental and extra-
segmental analgesia.
14
Additionally, physiological and
clinical research suggest that TENS inhibits second-order
nociceptive neurons, may increase blood ow, reduces
muscle spasms, and selectively activates large diameter
aerent bers, which reduces nociceptor cell activity and
sensitization in the central nervous system,
17,19,20
all of
which are potential analgesic mechanisms for phantom
pain and/or residual limb pain. Mulvey et al, indicates that
TENS application at the site of residual limb pain or on
the site of phantom pain is associated with decreases in
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pain intensity, both at rest and with movement (frequency
100 hertz, pulse width 80 microseconds and the current
increased until the patient achieved strong non-painful
sensations).
10
However, residual limb application of
TENS can be challenging in certain situations because
this stimulation may aggravate pain in patients with
preexisting pain or allodynia. e application of TENS
on the residual limb can also cause skin irritation that
reduces stump integrity in recent amputees.
Contralateral TENS can address problems associated
with residual limb TENS. Moreover, a number of case
reports and small case series have reported successful
outcomes of contralateral TENS for PLP/ RLP and
phantom limb sensation.
11-13
Additionally, Carabelli
13
described a better response when TENS was applied
to the contralateral limb compared to residual limb
stimulation. e benecial eects may be the result of
stimulation on contralateral segmental inhibition in the
dorsal horn.
14
e case series of contralateral TENS were done
by Kawumara (10 cases), Katz (2 cases), and Carabelli
(3 cases).
11-13
e settings of TENS applications in these
studies varied from frequency 4-80 hertz, pulse width
90-225 microseconds and range of amplitude 50-80
MA depending on patients’ tolerance. Compared to
these previous studies, we use commercially available
machines without standard settings, but adjusted the
treatment by clinical response. Nevertheless, the results
from our larger series still conrmed that contralateral
TENS application successfully reduced pain signicantly
in 95% of patients. e NRS pain score decreased by an
average of 3.7/10 (from 4.85 to 1.15/10) or 76.28%. Since
almost all patients in this study experienced moderate
to severe pain despite the use of at least two analgesics
and suered a negative impact on their quality of life, the
population in this study were considered patients with
dicult to treat or intractable PLP. To the best of our
knowledge, this is the largest application of contralateral
TENS for intractable PLP. Moreover, the treatment is
associated with a high satisfaction rate as no adverse
events were reported and the method is inexpensive and
easy to use. is data demonstrates that TENS is one of
the logical options for treatment of phantom limb pain.
An additional interesting nding was the duration of
treatment in this study. Many studies of the application
of TENS for phantom limb pain treatment do not have an
exact duration to reduce pain.
17,18
Our study showed that
80% of patients responded aer 30 minutes of treatment
and 95% responded aer 45 minutes, with no additional
response aer 45 minutes. e data suggests that the
duration for application of TENS on the contralateral
limb for treating phantom limb pain should be at least
30 minutes, which can be extended to 45 minutes. For
treatments longer than 45 minutes, there is probably no
additional benet.
ere were several limitations to this study. First, the
design was an observational study and not a randomized
control trial, so it is possible that factors such as the placebo
eect or natural regression may have an eect. Second,
as we used commercially available TENS machines,
there was no standard treatment protocol. However,
commercially available machines were more practical
in clinical practice due to low cost and accessibility by
the patients. Although this research suggests short term
analgesic eect of the application of TENS in contralateral
limb for PLP, a randomized control trial is needed to
conrm this nding. Finally, as we only collected short
term data immediately aer treatment in this study,
long-term follow up regarding duration of the treatment
and its impact on quality of life and medication use aer
treatment is needed. Nevertheless, this study provides
useful information such as the eect of treatment on a
sample size and duration of application of treatment
for protocol design for a future prospective randomized
study.
CONCLUSION
is cohort study shows that the application of
TENS in the contralateral limb can lead to meaningful
reduction of pain in patients suering from dicult
to treat phantom limb pain. is treatment has a high
success rate and is associated with high satisfaction rates
and no reported adverse events. e suggested duration
of treatment is at least 30 minutes and may be extended
up to 45 minutes.
ACKNOWLEDGEMENTS
We would like to thank Ms. Nattaya Bunwatsana
for assistance with document preparation for the IRB
approval process. e authors have no conict of interest
to declare.
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electrical nerve stimulation (TENS) applied to the contralateral
leg: a case study. Pain. 1989;36(3):367-77.
13. Carabelli RA, Kellerman WC. Phantom limb pain: Relief
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Kullathorn ephamongkhol, M.D., M.Sc.*, Arb-aroon Lertkhachonsuk, M.D., MMEd.**, Chomporn Sitathanee,
M.D.***, Petch Alisanant, M.D.****, Napapat Amornwichet, M.D., Ph.D.****, Chonlakiet Khorprasert, M.D.****,
Jidapa Bridhikitti M.D.*****, Pornpim Korpraphong, M.D.******, Kobkun Muangsomboon, M.D.******,
Sith
Phongkitkarun, M.D.*******, Saowanee Srirattanapong, M.D.*******, Duangkamon Prapruttam, M.D.*******,
aworn Dendumrongsup, M.D.********, Kewalee Sasiwimonphan, M.D.*********,
Chamnan Tanprasertkul, M.D.,
Ph.D.**********,***********, Mantana Dhanachai, M.D., MS.c.***,
Jayanton Patumanond, M.D., Dr.Sc.************,
Jiraporn Setakornnukul, M.D.*
*Division of Radiation Oncology, Department of Radiology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok 10700, ailand, **Gynecological
Oncology Unit, Department of Obstetrics and Gynecology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok 10400, ailand,
***Division of Radiation and Oncology, Department of Diagnostic and erapeutic Radiology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University
10400, Bangkok, ailand, ****Division of erapeutic Radiology and Oncology, Department of Radiology, King Chulalongkorn Memorial Hospital, Faculty
of Medicine, Chulalongkorn University, Bangkok 10330, ailand, *****Division of Radiation Oncology, Department of Radiology, Faculty of Medicine,
Songklanagarind Hospital, Prince of Songkla University, Hat Yai, Songkhla 90110, ailand. ******Division of Diagnostic Radiology, Department of Radiology,
Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok 10700, ailand, *******Diagnostic Radiology Unit, Department of Diagnostic and
erapeutic Radiology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University 10400, Bangkok, ailand, ********Abdominal Imaging Section,
Department of Radiology, Faculty of Medicine, Songklanagarind Hospital, Prince of Songkla University, Hat Yai, Songkhla 90110, ailand, *********Division
of Diagnostic Radiology, Department of Radiology, King Chulalongkorn Memorial Hospital, Faculty of Medicine, Chulalongkorn University, Bangkok
10330, ailand, **********Minimally Invasive Gynecologic Unit, Department of Obstetrics and Gynecology, ammasat University, Pathum ani 12120,
ailand, ***********Center of Excellence in Applied Epidemiology, ammasat University, Pathum ani 12120, ailand, ************Center for Clinical
Epidemiology and Clinical Statistics, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, ailand.
Propensity Score Matched Study of Tri-Weekly vs.
Weekly Platinum-Based Chemotherapy Concurrent
with Radiotherapy in the Treatment of Locally
Advanced Cervical Cancer
Corresponding author: Jiraporn Setakornnukul
E-mail: jiraporn.set@mahidol.ac.th
Received 23 December 2021 Revised 13 February 2022 Accepted 21 February 2022
ORCID ID: https://orcid.org/0000-0002-7201-0377
http://dx.doi.org/10.33192/Smj.2022.31
ABSTRACT
Objective: To compare tumor control and toxicity between tri-weekly chemotherapy and weekly platinum-based
chemotherapy in locally advanced cervical cancer using the propensity score matching method.
Materials and Methods: DESIGN: Retrospective cohort with propensity score matched population. SETTING: Four
university hospitals. PARTICIPANTS: 781 advanced local cervical cancer patients. INTERVENTION: tri-weekly
platinum-based chemoradiotherapy versus weekly chemoradiotherapy OUTCOMES: Overall survival (OS), local
recurrence-free survival (LRFS), regional recurrence-free survival (RRFS), distant metastasis-free survival (DMFS),
and toxicity, including hematological and renal toxicity.
Results: Overall median follow-up time was 59.5 months. Aer the propensity score matching process was completed,
326 patients were analyzed (163 in each group). e ve-year OS was 66% and 64% (p 0.630); ve-year LRFS was
85% and 81% (p 0.209); ve-year RRFS was 89% and 94% (p 0.307); and ve-year DMFS was 75% and 79% (p 0.420)
in the tri-weekly and weekly groups, respectively. e patients in the tri-weekly and the weekly group had grade 2
-3 neutropenia (10.5% vs 2.5%). e other toxicities appeared to be similar in both groups in terms of white blood
count, platelet and creatinine.
Conclusion: ere was a potential small benet of local control (4%) and overall survival (2%) with the tri-weekly
regimen but we could not demonstrate statistical signicance. However, this came at the price of an increase of
7% to 8% in grade 2-3 neutropenia.
Keywords: Cervical cancer; chemotherapy; radiotherapy; weekly regimen; tri-weekly regimen (Siriraj Med J 2022;
74: 245-255)
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INTRODUCTION
A 1999 US National Cancer Institute announcement
dened concurrent platinum-based chemotherapy with
radiotherapy as the standard of care for women with
locally advanced cervical cancer due to approximately
10% added survival benet aer ve years without a
signicant increase in late toxicities.
1
is was based on
the results of ve randomized controlled trials.
2-4,5,6
Despite this, the frequency of the platinum-based
regimen remains heterogeneous and routine chemotherapy
is dierent among hospitals. For example, some hospitals
administer weekly chemotherapy sessions whereas
others give tri-weekly chemotherapy. To compare these
treatment methods, many randomized controlled have
been carried out.
7-14
Interestingly, most of the evidence
remains conicting in terms of both tumor control and
toxicity. For example, a randomized controlled trial from
the University of Ulsan, Korea in 2008
13
showed that
the weekly regimen not only improved compliance but
was comparable with the tri-weekly regimen in response
and survival rate. On the other hand, a collaborative
randomized controlled trial by the Korea Institute of
Radiological and Medical Sciences, Dongnam Institute of
Radiological and Medical Sciences and National Cancer
Institute, Korea
12
showed that the tri-weekly regimen
was 20% more eective in terms of overall survival and
had less grade 3-4 neutropenia than the weekly regimen.
Moreover, evidence from meta-analyses looking at
the same question is also conicting. Zhu J et al,
15
carried
out a meta-analysis based on six randomized controlled
trials and two retrospective studies. It showed that the
tri-weekly regimen was superior to the weekly regimen
only in local recurrence but not overall survival. e
same results were reported in a recent meta-analysis
16
based on eight randomized controlled trials. Meanwhile,
a meta-analysis was also carried out by Petrelli et
al,
17
based on four randomized controlled trials and
four retrospective studies. Its results showed that the
platinum-based combined therapy should be the preferred
treatment over weekly regimen due to benets in overall
survival.
As a result, there are dierent policies for the weekly
and tri-weekly regimen. e routine regimen at the Radiation
Oncology Division at Siriraj Hospital is weekly cisplatin
(40 mg/m
2
) or carboplatin (AUC2), but some hospitals
have a routine tri-weekly regimen of cisplatin (75-100
mg/m
2
) (or carboplatin AUC5) with or without 5FU. We
are still waiting for high-quality evidence, notably results
of the Tri-weekly Cisplatin Based Chemoradiation in
Locally Advanced Cervical Cancer (TACO) trial (Clinical
Trials. gov Identier: NCT01561586). In the meantime,
we still require evidence for solving this issue. Hence,
we collected data from a multicenter in ailand where
locally advanced cervical cancer patients underwent
concurrent chemoradiotherapy. is could help provide
a suitable answer to a controversial issue with the help
of advanced statistical analysis, such as propensity score
matching that can simulate pseudo randomization by
matching pre-treatment variable factors.
MATERIALS AND METHODS
We used retrospective cohort data from a multicenter
in ailand (Siriraj Hospital (SI), Ramathibodi Hospital
(RA), King Chulalongkorn Memorial Hospital (CU) and
Songklanagarind Hospital (PSU). We recruited patients
with squamous cell carcinoma, adenocarcinoma, or
adenosquamous carcinoma of locally advanced cervical
cancer who were denitively treated with concurrent
chemoradiotherapy between Jan 2007 to Dec 2015. For
staging purposes, all patients underwent a CT scan with
contrast media of the whole abdomen, chest X-ray and
cystoscopy. Diagnostic radiologists in each hospital
newly reviewed the lymphadenopathy status according
to the pelvic lymphatic pathway.
18,19
Depending on the
policy of each hospital, a weekly or tri-weekly regimen of
cisplatin or carboplatin concurrently with radiotherapy
was given to the patient. Generally, 46-50 Gy of external
beam radiotherapy and 4 fractions of each 6.5 to 7.0 Gy
high dose rate brachytherapy were routinely prescribed.
For chemotherapy, usually, the clinical policy of SI, CU
and PSU is to give cisplatin weekly whereas RA gives
cisplatin tri-weekly. Additionally, Siriraj Hospital may
also adhere to the weekly carboplatin regimen as it is the
preference of some radiation oncologists regardless of
the patient’s performance status. e main outcome of
this study was overall survival. e secondary outcomes
were local-recurrence free survival, regional-recurrence
free survival and distant metastasis-free survival, which
were dened as rst day of radiotherapy to the date of
rst failure at cervical area, regional pelvic or paraaortic
lymph node and visceral distant metastases or lymph
node metastases above the diaphragm respectively.
Hematological toxicity (hemoglobin, white blood cell
count, neutrophil count and platelet) and renal toxicity in
the maximum grade of each patient were also reported.
Sample size
A randomized controlled trial from Korea
12
showed
that the tri-weekly regimen was more eective in overall
survival. is study reported a hazard ratio of 0.375.
When using this hazard ratio, 0.05 type I error and
80% statistical power, the sample size contained only 38
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Original Article
SMJ
patients in each arm. However, we planned to include
more patients as per our data availability.
Statistical analysis
In order to eliminate the selection bias of weekly
or tri-weekly chemotherapy regimen, we performed a
propensity score-matching analysis. is method is based
on balancing baseline characteristics of patients to simulate
randomization. eoretically, the best propensity score
came from factors that clinicians unfairly selected in the
weekly or tri-weekly regimen, such as patient or tumor
characteristics before treatment, especially pelvic or
para-aortic lymph nodes. In this study, we used the new
2018 FIGO stage, which included pelvic and para-aortic
lymphadenopathy status, histology, tumor grade, tumor
size, age, initial hemoglobin and hydronephrosis status.
For this purpose, we used MatchIt package version 3.02
in R soware version 4.05. Logistic regression with the
factors above was used to predict the linearized propensity
score. We then used this score in the MatchIt function
with the nearest method with varying caliper distances.
We further proved whether this procedure worked by
comparing baseline characteristics before and aer the
propensity score-matched procedure.
Aer we got the matched population, we also explored
whether the factors aer the start of the treatment were
well-balanced, especially the chemotherapy regimen
(cisplatin or carboplatin). We aimed to control this
additional confounder in non-parametric analysis. For
time-to-event analysis, we used the Kaplan Meier method
and log-rank test to determine the hypothesis. Non-
parametric analysis was performed to show a dierence
with 95% condence interval. For toxicity comparison,
we used the Fisher exact test to test the hypothesis.
Institutional Review Board Statement: e study was
conducted according to the guidelines of the Declaration
of Helsinki, and approved by the Institutional Review
Board of Faculty of Medicine Siriraj Hospital, Mahidol
University (Si 312/2016).
RESULTS
e patient characteristics before and aer the
propensity score matching process is shown in Table 1.
Missing data were in only histopathological grade,
which was available 80%. Before the matching process,
a total of 781 patients (618 in the weekly group and 163
patients in the tri-weekly group) were compared. e
patients in the tri-weekly group seemed to have a better
prognosis in terms of 2018 FIGO stage. For example, less
pelvic lymph node metastases (stage IIIc1, 20.2%) were
observed in the tri-weekly group, compared with the
weekly group (stage IIIc1, 34.3%). Aer the propensity
score matching process was completed (163 patients
in the weekly group and 163 patients in the tri-weekly
group), there was a similar prognosis, especially in terms
of FIGO staging. e pelvic lymph node metastases were
only 20.2% in both the weekly and tri-weekly groups.
Also, the proportion of histology was very similar in
terms of adenocarcinoma (22.1% in the weekly group
and 22.7% in the tri-weekly group). Furthermore, age,
tumor type, tumor size, tumor grade, initial hemoglobin
and also any side eects of hydronephrosis were better
balanced in both groups (Table 1). Despite the balance
in these prognostic factors, the chemotherapy regimens
(cisplatin or carboplatin) were dierent in both groups.
Cisplatin was given to half of the patients (56%) in the
weekly group, but almost all the (96%) patients in the tri-
weekly group. is dierence was then further adjusted
in a statistical analysis.
e overall median follow-up time was 59.5 months.
e follow-up rate for disease recurrence status and
for death status was 87% and 100% respectively. For
tumor control outcome, the tri-weekly group showed
an unadjusted non-statistically small benet in overall
survival (Fig 1A). is small benet was only 2%-3% as
per the follow-up time (Supplementary Fig S1). Aer
chemotherapy regimen (cisplatin or carboplatin) adjustment,
this small dierence disappeared and the survival curve
seemed to cross each other (Fig 1B). Interestingly, the
tri-weekly group showed better local recurrence-free
survival (Fig 2A). is dierence was about 6%-7% in
the rst two years of follow-up and about 3%-4% in the
third to h year (Supplementary Fig S2). Unfortunately,
with our limited sample size, a statistical dierence could
not be detected. Again, aer chemotherapy regimen
adjustment, this dierence disappeared (Fig 2B). For
regional recurrence-free survival (Fig 3A) and distant
metastasis-free survival (Fig 4A), the dierence between
the weekly group and tri-weekly group was small and
not consistent with the follow-up time (Fig 3B and Fig
4B). Also, the adjustment of chemotherapy regimen
(Supplementary Fig S3 and Fig S4) showed no signicant
change from unadjusted analysis.
Toxicity outcome was available for 96% of study
population. For grade 2 or greater toxicity (Table 2),
the patients in the tri-weekly group had more absolute
neutrophil count toxicity (10.5%), when compared
to patients in the weekly group (2.5%). On the other
hand, patients in the tri-weekly group seemed to have
less hemoglobin toxicity (29.4%) when compared to
patients in the weekly group (33.8%). ese results are
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TABLE 1. Patient characteristics before and aer propensity score matching.
Before Propensity score Matching After Propensity score Matching
Patient Characteristics Weekly Tri-weekly
p-value
Weekly Tri-weekly
p-value
n=618 n=163 n=163 n=163
Age 53.8(11.7) 54.1(10.6) 0.80 54.7(11.7) 54.1(10.6) 0.59
Stage:I-II 132(21.4%) 51(31.3%) 0.004 51(31.3%) 51(31.3%) 0.92
IIIa-b 180(29.1%) 55(33.7%) 53(32.5%) 55(33.7%)
IIIc1 212(34.3%) 33(20.2%) 33(20.2%) 33(20.2%)
IIIc2 82(13.3%) 20(12.3%) 24(14.7%) 20(12.3%)
IVa 12(1.9%) 4(2.5%) 2(1.2%) 4(2.5%)
Type:Exophytictype 428(69.3%) 129(79.1%) 0.015 120(73.6%) 129(79.1%) 0.30
Ulcerativetype 190(30.7%) 34(20.9%) 43(26.4%) 34(20.9%)
Tumorsize 4.43(1.54) 4.15(1.37) 0.036 4.21(1.41) 4.15(1.37) 0.72
Histology:SCC 475(76.9%) 121(74.2%) 0.50 122(74.8%) 121(74.2%) 1.00
Adenocarcinoma 117(18.9%) 37(22.7%) 36(22.1%) 37(22.7%)
Adenosquamouscarcinoma (4.2%) 5(3.1%) 5(3.1%) 5(3.1%)
Differentiation:Well 119(19.3%) 37(22.7%) <0.001 38(23.3%) 37(22.7%) 0.96
Moderate 227(36.7%) 30(18.4%) 30(18.4%) 30(18.4%)
Poorly 153(24.8%) 61(37.4%) 64(39.3%) 61(37.4%)
Unknown 119(19.3%) 35(21.5%) 31(19.0%) 35(21.5%)
InitialHb 11.5(1.8) 11.6(1.6) 0.38 11.5(1.9) 11.6(1.6) 0.76
Hydronephrosis:No 550(89.0%) 143(87.7%) 0.68 143(87.7%) 143(87.7%) 1.00
Yes 68(11.0%) 20(12.3%) 20(12.3%) 20(12.3%)
approximately the same when we categorized to cisplatin
and carboplatin (Supplementary Table S1). e other
toxicities appeared to be very similar in both groups in
terms of white blood count, platelet and creatinine. e
compliance towards chemotherapy in both groups was
very good (79.14% in ve cycles or more in the weekly
group and 89.6% in two cycles or more in the tri-weekly
group).
DISCUSSION
e standard treatment for locally advanced cervical
cancer is concurrent platinum-based chemotherapy
and radiotherapy.
1
e frequency of the chemotherapy
regimen is either weekly or tri-weekly administration
according to clinical practice guideline of some institution
in ailand.
20
e weekly regimen is easy to manage in
terms of no requirements for patient admission and
possibly fewer side eects, however, there is still the
concern that the weekly regimen might not be enough
in terms of tumor control. erefore, any additional
evidence may potentially provide a benet in routine
management of chemotherapy in this setting.
Our results show that the tri-weekly group
experienced 8% more neutrophil count grade 2 or greater
toxicity than the weekly group. is eect led to no
signicant reduction in compliance. Interestingly, our
results also showed a potential 6%-7% benet in local
control and possibly a small benet (2%-3%) in overall
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Fig 1. Kaplan-Meier survival estimate comparison between weekly and tri-weekly chemotherapy, unadjusted curve (le) and adjusted by
chemotherapy regimen (carboplatin or cisplatin) (right).
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Supplementary Fig S1. Absolute dierence of overall survival with 95% condence interval.
Absolute difference
3-yrOS 0.03%(-0.7%to1.2%)
5-yrOS 0.03%(-0.8%to1.3%)
Absolute difference
3-yrOS 0.04%(-0.04%to0.12%)
5-yrOS 0.04%(-0.04%to0.13%)
Absolute difference
3-yrOS -0.01%(-0.06%to0.05%)
5-yrOS -0.04%(-0.11%to0.03%)
Supplementary Fig S2. Absolute dierence of local recurrence-free survival with 95% condence interval.
Supplementary Fig S3. Absolute dierence of regional recurrence-free survival with 95% condence interval.
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Supplementary Fig S4. Absolute dierence of distant metastasis-free survival with 95% condence interval.
Absolute difference
3-yrOS -0.01%(-0.11%to0.08%)
5-yrOS -0.03%(-0.13%to0.08%)
TABLE 2. Toxicity and compliance between weekly and triweekly chemotherapy.
Weekly Tri-weekly p-value
n=163 n=163
Compliance
Noofcycle 1 2(1%) 14(9%) Notapplicable
2 8(5%) 132(81%)
3 2(1%) 14(9%)
4 20 (12%) -
5 91 (56%) -
6 38(23%) -
7 1(1%) -
Missingdata 1(1%) 3(1%)
Toxicity
Hemoglobin 0 44(27.0%) 25(15.3%) 0.011
1 60(36.8%) 81(49.7%)
2 51(31.3%) 40(24.5%)
3 4(2.5%) 8(4.9%)
Missingdata 4(2.5%) 9(5.5%)
Whitebloodcell 0 51(31.3%) 45(27.6%) 0.43
1 77(47.2%) 73(44.8%)
2 28(17.2%) 29(17.8%)
3 3(1.8%) 7(4.3%)
Missingdata 4(2.5%) 9(5.5%)
ANC 0 123(75.5%) 102(62.6%) 0.009
1 32(19.6%) 35(21.5%)
2 4(2.5%) 12(7.4%)
3 0 5(3.1%)
Missingdata 4(2.5%) 9(5.5%)
Platelet 0 109(66.9%) 145(89.0%) <0.001
1 50(30.7%) 14(8.6%)
2 1 (0.6%) 1 (0.6%)
3 0 0
Missingdata 3(1.8%) 3(1.8%)
Creatinine 0 139(85.3%) 141(86.5%) 0.80
1 19(11.7%) 14(8.6%)
2 1 (0.6%) 2 (1.2%)
3 0(0.0%) 1(0.6%)
Missingdata 4(2.5%) 5(3.1%)
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SUPPLEMENTARY TABLE S1. Toxicity and compliance between weekly and triweekly cisplatin and carboplatin.
Cisplatin Carboplatin
Weekly Tri-weekly Weekly Tri-weekly
n=92 n=157 P value n=71 n=6 p-value
Compliance
Noofcycle 1 0(0%) 13(8%) NA 2(3%) 1(17%) NA
2 3(3%) 128(82%) 5(7%) 4(67%)
3 2(2%) 13(8%) 0(0%) 1(17%)
4 11(12%) - 9(13%) -
5 49(53%) - 42(59%) -
6 26(28%) - 12(17%) -
7 0(0%) - 1(1%) -
Missingdata 1(1%) 3(2%) 0(0%) 0(0%)
Toxicity
Hemoglobin 0 28(30%) 24(15%) 0.003 16(23%) 1(17%) 0.553
1 30(33%) 78(50%) 30(42%) 3(50%)
2 31(34%) 39(25%) 20(28%) 1(17%)
3 1(1%) 8(5%) 3(4%) 0(0%)
Missingdata 2(2%) 8(5%) 2(3%) 1(17%)
WBC 0 22(24%) 44(28%) 0.417 29(41%) 1(17%) 0.085
1 43(47%) 71(45%) 34(48%) 2(33%)
2 23(25%) 27(17%) 5(7%) 2(33%)
3 2(2%) 7(4%) 1(1%) 0(0%)
Missingdata 2(2%) 8(5%) 2(3%) 1(17%)
ANC 0 66(72%) 99(63%) 0.285 57(80%) 3(50%) 0.025
1 20(22%) 34(22%) 12(17%) 1(17%)
2 4(4%) 11(7%) 0(0%) 1(17%)
3 0(0%) 5(3%) 0(0%) 0(0%)
Missingdata 2(2%) 8(5%) 2(3%) 1(17%)
Platelet 0 61(66%) 141(90%) <0.001 48(68%) 4(67%) 1.000
1 29(32%) 12(8%) 21(30%) 2(33%)
2 1(1%) 1(1%) 0(0%) 0(0%)
3 0(0%) 0(0%) 0(0%) 0(0%)
Missingdata 1(1%) 3(2%) 2(3%) 0(0%)
Creatinine 0 81(88%) 137(87%) 0.842 58(82%) 4(67%) 0.413
1 9(10%) 12(8%) 10(14%) 2(33%)
2 1(1%) 2(1%) 0(0%) 0(0%)
3 0(0%) 1(1%) 0(0%) 0(0%)
Missingdata 1(1%) 5(3%) 3(4%) 0(0%)
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survival. ese results could lead to potential benets in
individual clinical judgment, especially in the context
of a university hospital in ailand while we wait for
stronger evidence.
Nowadays, strong evidence to clearly support
weekly or tri-weekly platinum-based chemotherapy
with radiotherapy in locally advanced cervical cancer
is limited. Two famous randomized controlled trials
from Korea provide conicting results and dierent
points (Table 3). e rst study from Korea
13
showed a
comparable tumor control eect and more compliance
with weekly chemotherapy. e reasons behind this
could be that the tri-weekly combined chemotherapy
regimen with cisplatin and 5FU has poor compliance
due to 15% grade 4 hematological toxicity, compared
with only 2% in the weekly group. erefore, the weekly
group in this study might display a similar eect because
of inadequate chemotherapy in the tri-weekly group due
to toxicity. On the other hand, the second randomized
controlled trial from Korea
12
showed that the tri-weekly
regimen was 20% more eective in terms of overall
survival and had less grade 3-4 neutropenia than the
weekly regimen. Less toxicity can be explained by the fact
that the regimen in this study was only cisplatin without
5FU. Interestingly, even with planned randomization,
the baseline characteristics in this second study were not
well-balanced. e patients in the weekly chemotherapy
group had much poorer prognosis. For example, the
patients in the weekly group had an advanced stage of
disease (stage III and stage IVA 45.1%), compared with
TABLE 3. Comparison of two Korean randomized controlled trials and this study.
Study Kim et al
13
(RCT) Ryu et al
12
(RCT) Our study (PS matched)
Weekly Tri-weekly Weekly Tri-weekly Weekly Tri-weekly
(Cis) (Cis+5FU) (Cis) (Cis) (Cis, carbo) (Cis, carbo)
(n=77) (n=78) (n=51) (n=53) (n=163) (n=163)
Patient StageII StageII StageII StageII StageI-II StageI-II
characteristics =58(75%) =52(67%) =28(55%) =34(64%) =51(31.3%) =51(31.3%)
StageIII-Iva StageIII-Iva StageIII-Iva StageIII-Iva StageIII-Iva StageIII-Iva
=19(25%) =26(33%) =23(45%) =19(36%) =112(68.7%) =112(68.7%)
PelvicLN+ PelvicLN+ PelvicLN+ PelvicLN+ PelvicLN+ PelvicLN+
=31(40%) =32(41%) =29(57%) =27(51%) =33(20%) =33(20%)
PAN+ PAN+ PAN+ PAN+
=7(14%) =5(9%) =24(15%) =20(12%)
Chemotherapy >80% >80% >=5cycles >=2cycles >=5cycles >=2cycles
compliance planned planned =98% =94% =80% =90%
dose dose
=64(83%) =47(60%)
Hematological Grade3-4 Grade3-4 Neutropenia Neutropenia Neutropenia Neutropenia
toxicity =19(25%) =32(41%)
Grade4 Grade4 Grade3-4 Grade3-4 Grade3-4 Grade3-4
=2(3%) =15(19%) =20(39%) =12(23%) =0(0%) =5(3%)
Thrombocytopenia Thrombocytopenia Thrombocytopenia Thrombocytopenia
Grade3-4 Grade3-4 Grade3-4 Grade3-4
=4(8%) =3(6%) =0(0%) =0(0%)
Overall survival 4year:67% 4year:70% 5year:67% 5year:89% 5year:64% 5year:66%
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the tri-weekly group (stage III and stage IVA 35.9%).
Moreover, positive pelvic and paraaortic lymph nodes
were more frequent in the weekly group (70.6%) than
in patients in the tri-weekly group (61.3%). is also
could be a reason why the weekly group had poorer
tumor control.
Our study had some strengths. First, it included real-
world data from a multi-centered study from university
hospitals in ailand, meaning it was more generalized
than a single-institute study. Second, we used advanced
statistical analysis to match patients who showed well-
balanced baseline characteristics. ird, this study had
adequately long-term follow-up time. However, there
were several limitations of this study as well. First, our
data came from the two-dimensional brachytherapy
era. Nowadays, many hospitals use three-dimensional
brachytherapy, which likely leads to more local control
of the primary site. erefore, the benet of tri-weekly
chemotherapy might be less than that seen in this study.
Also, our sample size was not large enough to detect any
actual dierence.
CONCLUSION
In summary, the tri-weekly chemotherapy regimen
showed a non-statistically potential benet over the
weekly regimen in terms of local control and overall
survival but with more neutrophil toxicity. Further
evidence with adequate sample size could validate this
result. In the meantime, individual judgment using this
data can be discussed with patients.
ACKNOWLEDGMENTS
Lalita Chunkoh as the main patient-data collector
at SI, RA and CU Hospitals; Ladathip Suwan as the
patient-data collector and supervisor of data collection
at RA Hospital; Buntipa Netsawang as the supervisor of
patient-data collection at CU Hospital; Siriporn Wong as
an additional patient-data collector at CU Hospital; Dr.
Poompis Pattaranutaporn as the supervisor of laboratory
data collection at RA Hospital.
Conict of interest: None to declare
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256
Nisachon Khorwanichakij, M.D.*, Smith Kungwankiattichai, M.D.**, Weerapat Owattanapanich, M.D.**
*Division of Hematology, Department of Medicine, Chaophraya Yommarat Hospital, Suphanburi 72000, ailand, **Division of Hematology,
Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, ailand.
Validation of Several Formulas to Differentiate
Thalassemia from Iron Deciency Anemia and
Proposal of a Thalassemia–Iron Deciency
Discrimination (TID) Predictive Score
ABSTRACT
Objective: is study aimed to validate the sensitivity analysis of all the available formulas for their ability to
dierentiate between IDA and thalassemia and propose a novel formula to improve the sensitivity of all thalassemia
subtypes screening.
Materials and Methods: We conducted a 5-year, single-center, Cohort study on 227 microcytic anemia patients
diagnosed between June 2015 and September 2020 at Chaophraya Yommarat Hospital, Suphanburi, ailand to
validate the sensitivity of all the available formulas and invent the novel predictive score.
Results: Approximately three-quarters of our cases were all subtypes of thalassemia diseases while 26.9% were IDA.
e sensitivity of almost all the previous formulas for thalassemia prediction ranged between 13.9%-44.0%, while
the specicity varied between 0%–98.4%. Nevertheless, the sensitivity of the formulas that had favorable sensitivity
was quite low. Here, a novel thalassemia–iron deciency discrimination (TID) predictive score is proposed, which
demonstrated a sensitivity of 90.4% the specicity of 78.7%, the positive predictive value of 92.0 %, the negative
predictive value of 75.0%, and the accuracy of 87.2%.
Conclusion: e proposed TID predictive score is a novel uncomplicated formulation which oers high sensitivity
for all thalassemia subtypes prediction.
Keywords: Iron deciency anemia; microcytic anemia; predictive score; thalassemia (Siriraj Med J 2022; 74: 256-265)
Corresponding author: Weerapat Owattanapanich
E-mail: weerapato36733@gmail.com
Received 27 January 2022 Revised 18 February 2022 Accepted 23 February 2022
ORCID ID: https://orcid.org/0000-0002-1262-2005
http://dx.doi.org/10.33192/Smj.2022.32
INTRODUCTION
According to the World Health Organization, iron
deciency anemia (IDA) is the major cause of nutritional
anemia worldwide.
1
e incidence of IDA in ai women
of reproductive age was reported to be 28.7%, 30.2%, and
31.8%, in 2013, 2014, and 2015, respectively.
1
Another
study reported an anemia rate of 21% in educated young
ai women, with the two most prevalent causes among
those cases being thalassemia (28%) and IDA (21%).
2
Patients with IDA and thalassemia may both
present with microcytic anemia (defined as a mean
corpuscular volume (MCV) < 80 fL), which should be
further investigated to distinguish between these two
entities due to their dierent treatment approaches.
Iron supplementation and the correction of occult blood
loss remain the standard treatments for IDA. On the
other hand, certain types of thalassemia diseases, such
as hemoglobin (Hb) E/β-thalassemia and homozygous
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β-thalassemia, require regular blood transfusion and iron
chelation to prevent iron deposition in various organs,
which could lead to multiple organ dysfunction, i.e.,
liver cirrhosis, endocrinopathies, and heart failure.
3
Detailed evaluation to conrm IDA involves an
iron study test, consisting of measuring the levels of
serum ferritin, serum iron, total iron-binding capacity
(TIBC), and transferrin saturation (TSAT). If the serum
ferritin value is ≤30 ng/mL or the TSAT value is <16%,
IDA diagnosis can be conrmed with high sensitivity
and high specicity.
4
Meanwhile, Hb typing is employed
for the diagnosis of thalassemia.
5
However, in developing
countries, some primary hospitals have limited resources
to manage iron studies and Hb typing test. As a result, to
make a diagnosis, blood samples have to be transferred
to a comprehensive laboratory center, which can be a
time-consuming process. As such, other available tools
to initially discriminate these conditions could be of
value. For thalassemia diagnosis, a range of associated
factors can be assessed to develop a thalassemia predictive
score.
According to the extensive literature review we
performed, several formulas exist for thalassemia prediction
among microcytic anemic patients, including the Red
Blood Cell Count (RBC), Red Cell Distribution Width
(RDW), Red Cell Distribution Width Index (RDWI),
Green and King formula, Srivastava formula, Mentzer
formula, Ehsani formula, Ricerca formula, England
and Fraser formula, Sirdah formula, and Shine and Lal
formula.
6-14
e reported sensitivity and specicity of these
formulas range from 40% to 100%.
6-18
Another formula,
the 11T score is an interesting formula that combines
11 other formulas to calculate its score, providing a
higher discrimination ability.
15-18
In a previous study that
attempted to validate this score among a ai population,
the 11T score showed a sensitivity of 82.1% and specicity
of 91.7% for thalassemia prediction. However, it should
be noted that only β-thalassemia subtype was included
in previous studies. In addition, IDA in those trials was
diagnosed when serum ferritin was <10 ng/mL.
18
In the present study, we aimed to validate the sensitivity
assessment of all the available formulas for their ability to
dierentiate between IDA and all thalassemia subtypes.
In addition, we propose a novel formula to improve
the sensitivity of thalassemia screening. In addition,
to increase the diagnostic sensitivity in our study, the
diagnosis of IDA could be established when ferritin was
<30 ng/mL and TSAT was <16%.
4
MATERIALS AND METHODS
Study design and population
We conducted a 5-year, retrospective, single-
center, cohort study on microcytic anemia patients
diagnosed between June 1, 2015, and September 30,
2020, at Chaophraya Yommarat Hospital, Suphanburi,
ailand. e inclusion criteria were: (1) patients aged
15 years old or older, and (2) patients with microcytic
anemia. (3) patients who had the result of iron study
in the IDA group and Hb typing and/or PCR in the
thalassemia group. e exclusion criteria were patients
receiving erythropoiesis-stimulating agents or receiving
iron supplementation before blood testing. We categorized
patients into 2 groups by dierent timeframes; a group
for internal validation using patients during June 2015
- August 2017 and a group for calculation score using
patients during September 2017 - September 2020.
e study was approved for registration in the ai
Clinical Trial Registry with the identication number
TCTR20210725003.
Instrument and evaluation parameters
All blood samples were collected by using 3-ml
dipotassium ethylenediaminetetraacetic acid tubes
(K
2
EDTA) for a complete blood count (CBC) test and
analyzed within 2 hours aer taking the samples by
Mindray BC-6200 automated blood counter (Mindray
Bio‐Medical Electronics Co., Ltd, Shenzhen, China).
is device used impedance technology to count and
size RBC and platelet (PLT) together with cyanotic-free
colorimetric method for Hb. MCV and % RDW were
calculated based on the RBC histogram. In addition, mean
corpuscular hemoglobin (MCH) and mean corpuscular
hemoglobin concentration (MCHC) was also calculated
from RBC, Hb, and hematocrit parameters. e patient’s
demographic data and initial laboratory results were collected.
Patients with microcytic anemia were classied into two
groups: the IDA group and the thalassemia group. In the
thalassemia group, three included thalassemia disease
subtypes were as follows: α-thalassemia, β–thalassemia
disease, and α- combined β-thalassemia disease.
Study size consideration
At least 200 microcytic anemia cases were required
to validate the formulas and develop a novel predictive
score. Furthermore, 150 patients (40 patients with IDA and
110 patients with thalassemia) were separately assigned
for an internal validation of this score.
Handing of continuous predictors
e proposed predictive score was developed followed
by the predictive model study Risk of Bias Assessment
Tool (PROBAST). Four red blood cell parameters were
incorporated for this predictive score calculation including
MCH, RDW, RBC and PLT.
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258
Terminology
Anemia is dened by a hemoglobin (Hb) level <
13/dL in males or Hb < 12 g/dL in females.
19
Anemia
with small red blood cells (MCV < 80 fL) is termed
microcytic anemia.
4
A diagnosis of IDA is established if
a patient has microcytic anemia with serum ferritin < 30
ng/mL and transferrin saturation < 16%.
4
e 11T score
is a summary score from 11 formulas, comprising RBC
(×10
12
/L), RDW, RDWI (RDW × MCV/RBC), Green
and King formula (MCV2 × RDW/Hb × 100), Srivastava
formula (MCH/RBC), Mentzer formula (MCV/RBC),
Ehsani formula [MCV - (10 × RBC)], Ricerca formula
(RDW/RBC), England and Fraser formula [MCV - RBC
- (5 × Hb) - 3.4], Sirdah formula [MCV - RBC - (3 ×
Hb)], and Shine and Lal formula (MCV2 × MCH/100).
18
Statistical analysis
PASW Statistics for Windows, version 18.0 (SPSS
Inc., Chicago, IL, USA) was applied for the data analyses.
e patients’ demographic and clinical characteristics were
summarized descriptively by causes of microcytic anemia.
Continuous variables were reported as the mean±standard
deviation for normally distributed continuous variables,
and the median with interquartile ranges (Q1, Q3) for
nonnormally distributed continuous variables. Categorical
variables were reported as the frequency and percentage
and were compared using Fisher’s exact test or chi-square
test. Continuous variables were compared using the
Student’s t-test or Mann–Whiney U test. e univariate
and multivariate predictors of thalassemia were estimated
using Cox proportional hazards analysis (backward
stepwise method) and presented as an odds ratio (OR)
and 95% condence interval (CI). e receiver operating
characteristic (ROC) curve for the cuto score and for
thalassemia diagnosis was presented as the area under the
curve (AUC), accuracy, sensitivity, specicity, positive
predictive value (PPV), and negative predictive value
(NPV). For all the tests performed, a two-tailed p-value
< 0.05 was considered to be statistically signicant. e
calibration belt model was used for model calibration.
e model was attended by the Hosmer –Lemeshow χ
2
goodness-of-t test.
Ethics approval and consent to participate
is study was approved by the Ethics Committee for
Research in Human Subjects at Chaophraya Yommarat
Hospital, Suphanburi, ailand. All procedures followed
were in accordance with the ethical standards of the
responsible committee on human experimentation and
with the Helsinki Declaration of 1975, as revised in 2008.
Informed consent was waived due to a retrospective
study.
RESULTS
Baseline patient characteristics
In total, 227 microcytic anemic patients were included
in this study. Approximately three-quarters (73.1%)
were diagnosed with thalassemia disease, including
Hb E/β-thalassemia, homozygous β-thalassemia, Hb
H disease, Hb H/CS disease, AE Bart’s disease, and EF
Bart’s disease, whereas 61 patients (26.9%) were IDA.
In the thalassemic group, the mean patient age
was 42.1±20.5 years old. e mean Hb and MCV were
8±1.7 g/dL and 61.7±9.2 fL, respectively. e median
PLT count was 308,000/µL (range, 189,000-413,000/
µL). Among the IDA group, the mean patient age was
57.6±18.3 years old. e mean Hb was 6.1±1.7g/dL and
the mean MCV was 62.9±8.3 fL. e median PLT count
and serum ferritin were 384,000/µL (range, 263,000-
478,000/µL) and 16.7 ng/mL (range, 4-22.2 ng/mL),
respectively. Several factors were signicantly dierent
between the thalassemic and the IDA groups, such as age,
body mass index, Hb level, MCH, MCHC, red blood cell
distribution width (RDW), red blood cell counts, PLT
count, and iron proles. Table 1 displays the baseline
patient features and initial laboratory results of the
thalassemic and IDA patients.
Validation of the previous formulas predicting thalassemia
We analyzed the sensitivity, specificity, PPV,
NPV, and accuracy of each previous formula to predict
thalassemia, including RBC, % RDW, RDWI, Green and
King, Srivastava, Mentzer, Ehsani, Ricerca, England,
and Fraser, Shine and Lal, and 11T score, by using the
included patient’s data in this study. e sensitivity of
almost all the formulas ranged between 13.9% - 44%.
Only the RDW and Shine and Lal formulas yielded
high sensitivity (97.6%), but with low specicity results,
with gures of 0% and 3.3%, respectively. e specicity
of each formula varied between 0%-98.4%. e high
specicity of above 90% was found with several formulas,
including RDWI, Green and King, England and Fraser,
Sirdah, and 11T score; unfortunately, the sensitivity of
these formulas was quite low. e PPV of almost all the
formulas provided high results, which were above 90%.
In contrast, the NPV of all the formulas was as low as
approximately 30% (range, 0%-36.3%). e accuracy
of each formula varied between 36.1%-72.3%. Table 2
demonstrates the sensitivity, specicity, PPV, NPV, and
accuracy of each formula for predicting thalassemia.
Subgroup analysis of the formulas for predicting each
type of thalassemia
We performed a subgroup analysis of each thalassemia
subtype, including β-thalassemia disease, α-thalassemia
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TABLE 1. Baseline patient features and initial laboratory results of the thalassemic and iron deciency anemia patients.
Parameters Total Thalassemia β-thalassemia α-thalassemia α-thalassemia Irondeciency P-valueformultiplecomparisons
(N=227) (All) (1)(N=89) (2)(N=62) combinedwith anemia(0)
(N=166) (39.2%) (27.3%) β-thalassemia (N=61)
(73.1%) (3)(N=15) (26.9%) 1vs.0 2vs.0 3vs.0 Allvs.0
(6.6%)
Age(mean±SD) 46.3±21 42.1±20.5 42.8±20.4 41.5±21.5 40.9±17.1 57.6±18.3 <0.001 <0.001 0.002 <0.001
(years)
Sex(Male) 74(32.6%) 54(32.5%) 33(37.1%) 18(29%) 3(20%) 20(32.8%) 0.589 0.652 0.531 0.971
BMI 21.4±4.1 20.8±3.6 20.8±3.9 20.3±3.1 22.5±3.3 23.2±4.9 0.001 <0.001 0.602 0.001
Hemoglobintyping 181 (79.7%) 166(100%) 89(100%) 62(100%) 15(100%) 15(24.6) <0.001 <0.001 <0.001 <0.001
PCRfor 14(6.2%) 14(8.4%) 4(4.5%) 3(4.8%) 7(46.7%) 0(0%) 0.146 0.244 <0.001 0.024
α-thalassemia
Comorbidities 77(33.9%) 44(26.5%) 26(29.2%) 15(24.2%) 3(20%) 33(54.1%) 0.002 0.001 0.018 <0.001
Hypertension 34(15%) 16(9.6%) 12(13.5%) 3(4.8%) 1(6.7%) 18(29.5%) 0.016 <0.001 0.097 <0.001
Diabetes 22(9.7%) 12(7.2%) 10(11.2%) 1(1.6%) 1(6.7%) 10(16.4%) 0.361 0.004 0.682 0.039
Dyslipidemia 15(6.6%) 6(3.6%) 5(5.6%) 0(0%) 1(6.7%) 9(14.8%) 0.059 0.001 0.676 0.005
CAD 11(4.8%) 10(6%) 4(4.5%) 5(8.1%) 1(6.7%) 1(1.6%) 0.649 2.07 0.358 0.296
CKD 11(4.8%) 9(5.4%) 8(9%) 1(1.6%) 0(0%) 2(3.3%) 0.202 0.619 1.00 0.732
Liver disease 8(3.5%) 7(4.2%) 5(5.6%) 1(1.6%) 1(6.7%) 1(1.6%) 0.402 1.00 0.358 0.686
Arthritis 7(3.1%) 6(3.6%) 4(4.5%) 2(3.2%) 0(0%) 1(1.6%) 0.649 1.00 1.00 0.678
Others 19(8.4%) 7(4.2%) 2(2.2%) 5(8.1%) 0(0%) 12(19.7%) <0.001 0.062 0.109 <0.001
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TABLE 1. Baseline patient features and initial laboratory results of the thalassemic and iron deciency anemia patients. (Continue)
Parameters Total Thalassemia β-thalassemia α-thalassemia α-thalassemia Irondeciency P-valueformultiplecomparisons
(N=227) (All) (1)(N=89) (2)(N=62) combinedwith anemia(0)
(N=166) (39.2%) (27.3%) β-thalassemia (N=61)
(73.1%) (3)(N=15) (26.9%) 1vs.0 2vs.0 3vs.0 Allvs.0
(6.6%)
Laboratory
CBC
Mean±SD
Hemoglobin (g/dl) 7.5±1.9 8±1.7 7.9±1.9 8±1.5 8.5±1.7 6.1±1.7 <0.001 <0.001 <0.001 <0.001
Hematocrit (%) 25±14.3 26.4±16.2 26.2±21.7 26.9±4.4 25.9±6.3 21.2±5 0.082 <0.001 0.003 0.015
MCV (fL) 62±8.9 61.7±9.2 61.3±8.9 63.7±9.5 56.1±7.3 62.9±8.3 0.286 0.605 0.005 0.404
MCH (pg) 18.8±3 19.2±2.8 19.9±3 18.6±2.2 17.3±2.4 17.7±3.3 <0.001 0.066 0.674 0.001
MCHC (g/dl) 31.3±14.7 32.5±17 32.3±2.5 33.2±27.8 30.9±2.5 28.0±2.2 <0.001 0.148 <0.001 0.042
RDW (%) 23.6±5.4 24.7±5.7 24.5±6.3 25.2±5 23.8±4.7 20.4±3 <0.001 <0.001 0.016 <0.001
RBC (x10
12
/L) 4±1 4.2±1 4±1 4.3±0.9 4.9±0.9 3.4±0.8 <0.001 <0.001 <0.001 <0.001
Median±IQR
WBC (cells/µL) 7,410 7,595 7,860 6,900 7,750 6,320 0.009 0.495 0.096 0.031
Platelet(/µL) 316,000 308,000 307,000 298,000 353,000 384,000 0.015 0.006 0.759 0.006
(224,000- (189,000- (172,000- (202,000- (298,000- (263,000-
436,000) 413,000) 409,000) 401,000) 470,000) 478,000)
Ironstudy
Median±IQR
serum ferritin 249 590 882.5 383.6 548 16.7 <0.001 <0.001 <0.001 <0.001
(ng/ml) (8.96-859) (259-1,427) (323-2387.5) (184-759) (268.7-1499) (4-22.2)
serum iron (µg/dl) 17 69 66 70.5 79 12 <0.001 <0.001 0.004 <0.001
(11-51) (44-104) (41-104) (47.0-89) (49.0-105) (10-15)
Transferrin 4.9 27.5 26.3 32.9 36 3.5 <0.001 <0.001 <0.001 <0.001
saturation (%) (3.2-24.2) (19.1-44) (16.6-46.8) (23-44) (23-38.6) (2.5-4.6)
Mean±SD
TIBC (µg/dl) 322.7±90.2 250.6±80.3 258.1±96.8 241.9±57.7 235.7±31.8 371.3±58.6 <0.001 <0.001 0.027 <0.001
Abbreviations: MCV = Mean corpuscular volume, MCH = Mean corpuscular hemoglobin, MCHC = Mean corpuscular hemoglobin concentration, RDW = Red blood cell
distribution width, RBC = Red blood cell, WBC = White blood cell, TIBC = Total iron binding capacity (µg/dL), TSAT = Transferin saturation (%).
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TABLE 2. Sensitivity, specicity, positive predictive value, negative predictive value, and accuracy of each formula
to predict thalassemia.
Formula Cutoff Thalassemia Iron Sensitivity Specicity PPV NPV Accuracy
n(%) deciency (95%CI) (95%CI) (95%CI) (95%CI) (95%CI)
anemia
n (%)
RBC(x10
12
/L) ≥5 36(97.3) 1(2.7) 21.7% 98.4% 97.3% 31.6% 42.3%
<5 130(68.4) 60(31.6) (15.7-28.7) (91.2-100) (85.8-99.9) (25-38.7) (35.9-48.7)
RDW(%) ≥14 162(72.6) 61(27.4) 97.6% 0% 72.6% 0% 71.4%
<14 4(100) 0(0) (93.9-99.3) (0-5.9) (66.3-78.4) (0-60.2) (65.48-77.25)
RDWI[6] <220 23(92) 2(8) 13.9% 96.7% 92% 29.2% 36.1%
≥220 143(70.8) 59(29.2) (9-20.1) (88.7-99.6) (74-99) (23-36) (29.9-42.4)
GreenandKing[7] <72 27(96.4) 1(3.6) 16.3% 98.4% 96.4% 30.2% 38.3%
≥72 139(69.8) 60(30.2) (11-22.8) (91.2-100) (81.7-99.9) (23.9-37) (32-44.7)
Srivastava[8] <3.8 56(84.8) 10(15.2) 33.7% 83.6% 84.8% 31.7% 47.1%
≥3.8 110(68.3) 51(31.7) (26.6-41.5) (71.9-91.8) (73.9-92.5) (24.6-39.5) (40.6-53.6)
Mentzer[9] <13 65(90.3) 7(9.7) 39.2% 88.5% 90.3% 34.8% 52.4%
≥13 101(65.2) 54(34.8) (31.7-47) (77.8-95.3) (81-96) (27.4-42.9) (45.9-58.9)
Ehsani[10] <15 73(90.1) 8(9.9) 44% 86.9% 90.1% 36.3% 55.5%
≥15 93(63.7) 53(36.3) (36.3-51.9) (75.8-94.2) (81.5-95.6) (28.5-44.7) (49-62)
Ricerca[11] <4.4 35(81.4) 8(18.6) 21.1% 86.9% 81.4% 28.8% 38.8%
≥4.4 131(71.2) 53(28.8) (15.1-28.1) (75.8-94.2) (66.6-91.6) (22.4-35.9) (32.4-45.1)
England[12] <0 24(96) 1(4) 14.5% 98.4% 96% 29.7% 37%
andFraser ≥0 142(70.3) 60(29.7) (9.5-20.7) (91.2-100) (79.6-99.9) (23.5-36.5) (30.7-43.3)
Sirdah[13] <27 63(94) 4(6) 38% 93.4% 94% 35.6% 52.9%
≥27 103(64.4) 57(35.6) (30.5-45.8) (84.1-98.2) (85.4-98.3) (28.2-43.6) (46.4-59.4)
ShineandLal[14] <1530 162(73.3) 59(26.7) 97.6% 3.3% 73.3% 33.3% 72.3%
≥1530 4(66.7) 2(33.3) (93.9-99.3) (0.4-11.3) (67-79) (4.3-77.7) (66.4-78.1)
11Tscore[16] ≥7 40(97.6) 1(2.4) 24.1% 98.4% 97.6% 32.3% 44.1%
<7 126(67.7) 60(32.3) (17.8-31.3) (91.2-100) (87.1-99.9) (25.6-39.5) (37.6-50.5)
11Tscore(cutoff5) ≥5 64(88.9) 8(11.1) 38.6 86.9 88.9 34.2 51.5
<5 102(65.8) 53(34.2) (31.1-46.4) (75.8-94.2) (79.3-95.1) (26.8-42.2) (45.0-58.0)
11Tscore(cutoff6) ≥6 58(95.1) 3(4.9) 34.9 95.1 95.1 34.9 51.1
<6 108(65.1) 58(34.9) (27.7-42.7) (86.3-99.0) (86.3-99.0) (27.7-42.7) (44.6-57.6)
11Tscore(cutoff8) ≥8 30(96.8) 1(3.2) 18.1 98.4 96.8 30.6 36.7
<8 136(69.4) 60(30.6) (12.5-24.8) (91.2-100.0) (83.3-99.9) (24.2-37.6) (33.3-46.0)
11Tscore(cutoff9) ≥9 20(95.2) 1(4.8) 12.0 98.4 95.2 29.1 35.2
<9 146(70.9) 60(29.1) (7.5-18.0) (91.2-100.0) (76.2-99.9) (23.0-35.8) (29.0-41.5)
Abbreviations: PPV = Positive predictive value, NPV = Negative predictive value, RBC = Red blood cell count interval, RDW = Red blood
cell distribution width, RDWI = Red blood cell distribution width index.
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disease, and β-thalassemia combined with α-thalassemia
disease. In the subgroup of the β-thalassemia group, the
results were not signicantly dierent from in the full
analysis. Similarly, the results remained similar to the full
analysis in the α-thalassemia disease group. However,
when we validated the formulas in the β-thalassemia
combined with α-thalassemia disease patients, the NPV
and the accuracy of almost all the formulas were better
than in the full analysis, with gures ranging between
79.0%-93.0%, while the sensitivity and specicity were
not dierent from in the full analysis.
Proposed novel thalassemia–iron deciency discrimination
(TID) predictive score
Because the validation of each previous formula
was imperfect, we attempted to determine the signicant
factors to dierentiate between thalassemic and IDA
patients. We found that MCH, % RDW, RBC, and PLT
were signicant factors related to thalassemia. erefore,
the predictive score is calculated by using these factors
as the following:
y = (-4.643) + (2.273 if MCH 17 to 20) + (3.888 if
MCH > 20) + (2.025 if RDW 21 to 25) + (4.986 if RDW
> 25) + (0.485 if RBC 3.5 to 4.5) + (4.787 if RBC > 4.5) +
(0.785 if PLT < 265,000) + (1 if PLT 265,000 to 400,000)
Subsequently the TID predictive score was simplied
by multiplying with 2 as the following:
y = (-9) + (5 if MCH 17 to 20) + (8 if MCH > 20)
+ (4 if RDW 21 to 25) + (10 if RDW > 25) + (1 if RBC
3.5 to 4.5) + (10 if RBC > 4.5) + (2 if PLT < 265,000) +
(2 if PLT 265,000 to 400,000) (Fig 1)
We used the ROC analysis for the TID predictive
score. e most appropriate cuto level for predicting
thalassemia was ≥2, in which the AUC was 0.93 (95%
CI: 0.890 - 0.969; Fig 2). e sensitivity and specicity
of the score were 90.4% and 78.7%, respectively (Table 3).
Internal validation of the TID predictive score
e split 150 sample proles were utilized for the
internal validation study of the TID predictive score. e
AUC was 0.88 (95% CI: 0.815 - 0.947). e sensitivity
to predict thalassemia from the internal validation was
96.4%, with the specicity and the accuracy of 50.0%
and 84.0%, respectively. ere was a non-statistically
signicant dierence in AUCs between the predictive
TID predictive score creation and the internal validation
(P-value = 0.805).
DISCUSSION
e most common cause of microcytic anemia
in developed countries is IDA. However, thalassemia
should not be overlooked in patients with microcytic
anemia, especially in Asian populations.
20-21
In Southeast
Asian subjects, the prevalence of α-thalassemia among
anemic patients is 20%–30%, and β-thalassemia is about
3%–9%.
20-21
A CBC is a worthwhile initial investigation
that can be performed in every hospital. Although CBC
is a simple test, it gives an instant result, but it cannot
totally dierentiate the cause of microcytic anemia.
Hence, conrmation tests, such as iron study, Hb typing,
and PCR for α-thalassemia, are still mandatory for a
denitive diagnosis. However, such conrmation tests
are invariably more sophisticated, quite expensive, and
can take several days to several weeks to get the results
back. So these are not always practical in developing
countries with limited resources.
Several formulas have been developed to predict
thalassemia and used as a screening tool for thalassemia
diagnosis. For example, predictive formulas, such as
Green and King, Srivastava, and Mentzer have shown a
sensitivity of 87.7%–93.8% and specicity of 82.5%–95%
according to the previous results.
7-9,15
e 11Tscore was
developed to improve the sensitivity and specicity for
improving thalassemia diagnosis.
15
It is composed of 11
predictive formulas.
15-18
A previous study from France
found it had a sensitivity of 85.7% and specicity of 97.5%,
15
while the study from ailand reported a sensitivity of
82.1% and specicity of 91.7%.
18
However, the 11Tscore
has been applied for predicting only the β-thalassemia
subtype.
15-18
Another study reported that the Jayabose
RDW index, the Green and King formula, and the Janel
11T score are good formulas to dierentiate thalassemia
trait from IDA among their population.
22
Moreover,
the serum ferritin cuto value from previous studies
for IDA diagnosis varied between <10 ng/ml and <16
ng/ml.
16-18
Currently, the denition for IDA diagnosis is
serum ferritin < 30 ng/ml and TSAT < 16 %.
4
therefore,
we dened IDA according to this recent suggestion in
this study.
In our study, we validated all the previous formulas
with all subtypes of thalassemia, including α-thalassemia
disease, β-thalassemia disease, α-thalassemia combined
with β-thalassemia disease, and IDA patients. In contrast
to the previous results, the sensitivity and specicity
to predict thalassemia disease among these included
patients were not high. Therefore, we proposed a
novel TID predictive score composed of 4 red blood
cell indices, namely % RDW, RBC, and PLT count.
e TID predictive score had a sensitivity of 90.4%
and specicity of 78.7% to dierentiate all thalassemia
subtypes from IDA. Although, the specicity from the
internal validation was insignicantly lower compared
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Original Article
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Fig 1. e thalassemia–iron deciency discrimination (TID) predictive score and their values.
Fig 2. Receiver operating characteristic curve and the area under the curve for obtaining the cut o value for thalassemia prediction using
the TID predictive score (A) all thalassemia subtypes (B) β-thalassemia disease (C) α-thalassemia disease (D) α-thalassemia combined with
β-thalassemia
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to the gure from the predictive score generation, the
sensitivity remained satisfying. e TID predictive score
applies % RDW for calculation because in ailand CBC
report is practically presented with % RDW. However, a
recent study showed that absolute RDW is more specic
to dierentiate thalassemia from IDA in microcytic
anemia comparing with relative RDW.
23
This score might be beneficial for thalassemia
screening, whereby patients who have a score ≥2 can be
selected for further investigation to conrm thalassemia
disease. is could reduce unnecessary expenses from
over investigation, which would be especially important
in resource-limited countries. In other words, patients
who have a lower likelihood of having thalassemia as
assessed from the predictive score could be treated as
IDA while waiting for their iron study.
ere are some limitations of this study to note.
First, because this was a retrospective study, some
information may have been missing. Second, the TID
predictive score demonstrated a specicity of 50.0% from
the internal validation, some IDA patients who have high
TID predictive scores might experience a treatment delay
while awaiting for Hb typing result. ird, IDA patients
from this cohort had signicantly more severe anemia
than the thalassemia subjects. is factor might inuence
the sensitivity/specicity of discriminant formulas. Lastly,
in the subgroup analysis, the size of some subgroups is
quite small which leads to imprecise formula validation.
CONCLUSION
alassemia and IDA are the most common causes
of microcytic anemia. Here, a TID predictive score
was proposed that demonstrated higher sensitivity for
thalassemia prediction while remaining uncomplicated
to be applied due to its few involved parameters.
ACKNOWLEDGEMENTS
The authors are grateful to the Department of
Medicine, Chaophraya Yommarat Hospital, Suphanburi,
ailand and the Faculty of Medicine Siriraj Hospital,
Mahidol University, ailand for grant support. We
also thank Assoc.Prof. Preechaya Wongkrajang and Dr.
Ratikorn Anusorntanawat for their valuable consultation
and advice and thank Ms. Pattaraporn Tunsing and
Ms. Kemajira Karaketklang for the data collection and
statistical analyses.
Conicts of interest: e authors conrm that there
are no known conicts of interest associated with this
publication.
Funding: is study was funded by grants from the
Department of Medicine, Chaophraya Yommarat Hospital,
Suphanburi, ailand and the Faculty of Medicine Siriraj
Hospital, Mahidol University, Bangkok, ailand.
REFERENCES
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gho/data/indicators/indicator-details/GHO/prevalence-of-
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2. Brimson S, Suwanwong Y, Brimson JM. Nutritional anemia
predominant form of anemia in educated young ai women.Ethn
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diagnosis of thalassemia.Int J Lab Hematol. 2016;38 Suppl
1:32-40. doi:10.1111/ijlh.12527
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TABLE 3. Sensitivity, specicity, positive predictive value, negative predictive value, and accuracy of the TID predictive
score.
Logisticmodel Cutoff Thalassemia Iron Sensitivity Specicity PPV NPV Accuracy
n(%) deciency (95%CI) (95%CI) (95%CI) (95%CI) (95%CI)
anemia
n (%)
Logisticmodelscore ≥2 150(92) 13(8) 90.4% 78.7% 92.0% 75.0% 87.2%
<2 16(25) 48(75) (84.8-88.1) (66.3-88.1) (86.7-95.7) (62.6-85.0) (82.9-91.6)
Abbreviations: PPV = Positive predictive value, NPV = Negative predictive value.
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6. JayaboseS,GiavanelliJ,Levendoglu O, Sandoval C, Ozkayak F,
Visintainer P. Dierentiating iron deciency anemia from
thalassemia minor by using an RDW-based index.J Pediatr
Hematol Oncol. 1999;21:314.
7. Green R, King R. A new red cell discriminant incorporating
volume dispersion for dierentiating iron deciency anemia
from thalassemia minor.Blood Cells. 1989;15(3):481-95.
8. Srivastava PC, Bevington JM. Iron deciency and-or thalassaemia
trait.Lancet. 1973;1(7807):832. doi:10.1016/s0140-6736(73)
90637-5
9. Mentzer WC Jr. Dierentiation of iron deciency from thalassaemia
trait.Lancet. 1973;1(7808):882. doi:10.1016/s0140-6736(73)
91446-3
10. Ehsani M, Darvish A, Eslani A, Seighali F. A new formula for
dierentiation of iron deciency anemia (IDA) and thalassemia
trait (TT). Turk J Hematol 2005;22(Suppl): 268.
11. Ricerca BM, Storti S, d’Onofrio G, Mancini S, Vittori M,
Campisi S, et al. Dierentiation of iron deciency from thalassaemia
trait: a new approach.Haematologica. 1987;72(5):409-13.
12. EnglandJM,BainBJ,FraserPM.Dierentiation of iron deciency
from thalassemia trait by routine blood‐count.Lancet.1973;1:449-
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13. SirdahM,TaraziI,Al NajjarE,Al HaddadR.Evaluation of
the diagnostic reliability of dierent RBC indices and formulas
in the dierentiation of theβ‐thalassemia minor from iron
deciency in Palestinian population.Int J Lab Hematol2007;30:
324-30.
14. Shine I, Lal S. A strategy to detect beta‐thalassemia
minor.Lancet1977;1:692-4.
15. Janel A, Roszyk L, Rapatel C, Mareynat G, Berger MG, Francois
A, et al. Proposal of a score combining red blood cell indices for
early dierentiation of beta-thalassemia minor from iron
deciency anemia.Hematology. 2011;16(2):123-7. doi:10.11
79/102453311X12940641877849.
16. Chandra H, Shrivastava V, Chandra S, Rawat A, Nautiyal R.
Evaluation of Platelet and Red Blood Cell Parameters with
Proposal of Modied Score as Discriminating Guide for Iron
Deciency Anemia and β-alassemia Minor.J Clin Diagn
Res. 2016;10(5):EC31-EC34. doi:10.7860/JCDR/2016/17672.
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17. Plengsuree S, Punyamung M, Yanola J, Nanta S, Paiping K,
Maneewong K, et al. Red Cell Indices and Formulas Used in
Dierentiation of β-alassemia Trait from Iron Deciency
in ai Adults.Hemoglobin. 2015;39(4):235-9. doi:10.3109/
03630269.2015.1048352
18. Pornprasert S, ongsat C, Panyachadporn U. Evaluation
of Applying a Combination of Red Cell Indexes and Formulas
to Dierentiate β-alassemia Trait from Iron Deciency
Anemia in the ai Population.Hemoglobin. 2017;41(2):116-9.
doi:10.1080/03630269.2017.1323763
19. WHO. Haemoglobin concentrations for the diagnosis of
anaemia and assessment of severity. Vitamin and Mineral
Nutrition Information System. Geneva, World Health Organization,
2011 (WHO/NMH/NHD/MNM/11.1). Available from: http://
www.who.int/vmnis/indicators/haemoglobin. pdf, accessed
[date].
20. Goh LPW, Chong ETJ, Lee PC. Prevalence of Alpha (α)-
alassemia in Southeast Asia (2010-2020): A Meta-Analysis
Involving 83,674 Subjects.Int J Environ Res Public Health.
2020;17(20):7354. doi:10.3390/ijerph17207354
21. Kattamis A, Forni GL, Aydinok Y, Viprakasit V. Changing
patterns in the epidemiology of β-thalassemia.Eur J Haematol.
2020;105(6):692-703. doi:10.1111/ejh.13512
22. Urrechaga E, Homann JJML. Critical appraisal of discriminant
formulas for distinguishing thalassemia from iron deciency in
patients with microcytic anemia. Clin Chem Lab Med. 2017;
55(10):1582-91. doi:10.1515/cclm-2016-0856
23. Homann JJML, Urrechaga E. Role of RDW in mathematical
formulas aiding the differential diagnosis of microcytic
anemia.Scand J Clin Lab Invest. 2020;80(6):464-9. doi:10.10
80/00365513.2020.1774800
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Voramon Teranasthiarphan, M.D., Thakerng Pitakteerabundit, M.D., Nan-ak Wiboonkhwan, M.D.,
Tortrakoon ongkan,
M.D.
Department of Surgery, Prince of Songkla University, Hat Yai, Songkhla 90110, ailand.
The Evolution of Associating Liver Partition with
Portal Vein Ligation for Staged Hepatectomy
ABSTRACT
Associating Liver Partition with Portal Vein Ligation for Staged Hepatectomy is a cutting-edge surgical technique
for resection of hepatic malignancies that has piqued the interest of the international hepatobiliary community.
Patients with insucient future liver remnants, many of whom are considered unresectable via other methods,
have the possibility of being cured with this treatment. e main issues; howbeit include, increased perioperative
morbidity and mortality as well as both early and rapid disease recurrence. However, with continuous improving
of patient selection, optimizing stage 2 operation times and rened operative techniques this has led to reduced
morbidity and mortality rates. As for its usage, the most frequent indication is colorectal liver metastasis (CRLM);
in which, the results in CRLM have shown higher resectability; however, it has a comparable complication rate
to two-stage hepatectomy. Conversely, perihilar cholangiocarcinoma and hepatocellular carcinoma have terrible
outcomes; although, with technical renement and better patient selection good outcomes are achievable.
Herein, we summarized the current evidence based of the application of ALPPS in real-life practice, including
the potential complications related to this procedure.
Keywords: ALPPS; Future liver remnant; hepatectomy (Siriraj Med J 2022; 74: 266-273)
Corresponding author: Tortrakoon ongkan
E-mail: Ttortrak@medicine.psu.ac.th
Received 2 December 2021 Revised 20 February 2022 Accepted 7 March 2022
ORCID ID: https://orcid.org/0000-0002-8210-1459
http://dx.doi.org/10.33192/Smj.2022.33
INTRODUCTION
An insucient future liver remnant is a factor
excluding patients from curative intent liver resection,
as the low hepatic functional reserve of the small, future
liver remnant (FLR) can lead to post-hepatectomy liver
failure (PHLF). Portal vein embolization (PVE) results in
compensatory hypertrophy of FLR; however, the biggest
drawback of PVE is insucient FLR hypertrophy, or
subsequent disease progression; which aects roughly
20% of patients.
1
Recently, Two-stage hepatectomy (TSH) has been
introduced for patients with bilateral multinodular colorectal
liver metastases.
2
is can be used in conjunction with
Portal vein occlusion (PVO); either portal vein ligation
(PVL) or percutaneous PVE. e main idea being that the
liver grows in the interval between sequential resection,
and the risk of PHLF is presumably reduced due to
this staged approach.
3,4
However, although TSH is well
established, failure to proceed to stage 2 is reported as
being a problem in up to one-third of patients.
Dr. Hans Schlitt discovered the Associating
Liver Partition with Portal Vein Ligation for Staged
Hepatectomy (ALPPS) by chance. He noticed a small
liver remnant during an extended right hepatectomy for
hilar cholangiocarcinoma. So, he decided to perform a
hepaticojejunostomy and right PVL aer parenchymal
Teranasthiarphan et al.
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transection for enhancing exposure. Fortunately, computed
tomography (CT) scanning revealed extensive hypertrophy
of the remnant segments one week later. Hence, the right
liver was subsequently removed.
5
ALPPS is based on the
fast hypertrophy of remnant segments. It can enhance the
remaining liver by up to 80% over an average duration
of 1-2 weeks compared to 20-45% in 2-8 weeks in PVE
patients.
6,7
e possible mechanism of rapid hypertrophy
in ALPPS is based on the increase of portal ow in the
disconnection of the interlobar perfusion, accompanied
by the increased level of inammatory cytokines that
induce liver regeneration. e disadvantage is a high
procedure-related morbidity and mortality rate of roughly
40% and 15%, respectively, mainly from liver failure
and bile leakage.
8
As a result, the safety of ALPPS in
comparison to standard techniques is still debatable.
Pathophysiology of liver regeneration in ALPPS
There are two proposed mechanisms for rapid
hypertrophy aer the rst stage of ALPPS. Firstly, the
parenchymal transection will not allow communication
of interlobar collateral circulation. e portal ow can
maximize the shearing force to the hepatocyte that causes
the liver to regenerate. e later mechanism is based on
the increased level of inammatory mediators that drive
liver regeneration.
9
e disparity between the size and function of a remnant
could explain the high risk of ALPPS complications. e
regenerate hepatocyte shows edema and expansion, but is
still partly immature within the rst two weeks aer the
procedure, albeit from unknown causes.
10
Histologically,
the hepatocyte has greater cell density, is smaller in
size, brighter and has narrower sinusoidal compared to
PVE.
11
In electron microscopy, the FLR area is frequently
shown as being vacant in appearance. is is caused
by hepatocytic cytoplasm lled with glycogen granules
and fewer cytoplasmic organelles, lipofuscin granules.
To date, all of these properties can be interpreted as
immature cells.
Technical considerations (right trisectionectomy ALPPS)
The liver was examined with intraoperative
ultrasonography to conrm the number and location
of the tumor. e liver was fully mobilized, and the
hepatoduodenal ligament was skeletonized. e right portal
vein was ligated with non-absorbable suture material.
e parenchymal transection was carried down along the
falciform ligament (Fig 1). Most of the authors advocated
for using a plastic bag for covering the deportalized liver,
so as to control bile leakage. CT scanning was performed
at 9 days on average, postoperatively. e right hepatic
artery, right hepatic duct, right, and middle hepatic vein
were then divided in the second stage operation.
5,12
Modications to the initial techniques
Bile duct ligation
Recent studies have suggested against routine bile
duct ligation.
13,14
Many published reports have reported
complications; such as, a higher rate of bile leakage,
biloma formation and severe, dense adhesion at the porta
hepatis during second stage operations. e previous
hypothesis was that by increasing the biliary obstruction
response in obstructed livers, right bile duct ligation
could promote additional FLR hypertrophy.
Fig 1. Schematic overview of Associating Liver Partition with Portal Vein Ligation for Staged Hepatectomy (right trisectionectomy). (A)
e liver was occupied with multiple tumors on both sides. e potential procedure is right trisectionectomy with the lateral section as the
future remnant liver. (B) In the rst stage, complete parenchymal transection was carried out along the falciform ligament, the tumors in
the remnant liver were removed, and the right portal vein was ligated. (C) e future liver remnant shows signicant hypertrophy, and then
the deportalized lobe was removed.
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Preservation of the middle hepatic vein
e rst ALPPS series mentions ligation of the
middle hepatic vein during the rst stage of the procedure
5
however, a recent study
13
discovered its relation with
congestion of liver segments IV, V, VIII. is may result
in decreased outow, followed by a higher risk of ischemia
and hepatic necrosis as well as subsequent bile leakage.
e middle hepatic vein is now preserved as the venous
outow of segment IV, rather than being removed as
previously reported, without compromising parenchymal
hypertrophy. Most hepatobiliary surgeons currently use
this method.
6
Hybrid ALPPS (Non touch technique)
is modication aims to avoid manipulating the
right lobe of the liver in order to improve tumor tissue
handling and prevent hematologic malignancy spread.
13,15,16
e parenchymal transection is performed using an anterior
approach, without mobilization, and the hepatoduodenal
ligament is le intact. In the days following the operation,
interventional radiology performs right PVE. At the
second stage, there is less inammation around the liver;
according to reports. Nevertheless, some of the authors
are against this idea, due to the inability to achieve
optimal vascular control during a technically complex
procedure; especially via an anterior approach.
14,15
Partial ALPPS
is modied technique solely diers in the degree of
liver partition. In contrast to conventional ALPPS, where
parenchymal transection was complete, partial ALPPS
transected only 50% to 80% of the parenchyma in stage
I.
14
Anatomic outow structures (hepatic veins), and/
or tumor(s) lying inside or near the future transection
line, determine the degree of partial transection. e
main advantage of this modication in technique is
that it limits the deleterious congestion of the excluded
segments and segment IV necrosis, by preserving their
outow via the middle hepatic vein.
17,18
Partial ALPPS
generates equivalent FLR hypertrophy to complete ALPPS,
but with decreased morbidity and near-zero mortality.
16
However, Chan et al. demonstrated that complete ALPPS
can cause rapid FLR hypertrophy more so than partial
ALPPS, while having no impact on perioperative risks in
chronic liver disease.
19
In the meta-analysis by Wu et al,
they compared partial and complete ALPPS and showed
that FLR hypertrophy and time intervals between stages
were not substantially dierent for both techniques.
20
Although, the post-operative complication rate was
signicantly lower in partial ALPPS.
Mini-ALPPS
Mini-ALPPS simplies rst stage hepatectomy, by
using a partial parenchymal transection technique and
intraoperative portal vein embolization, without hilar
dissection or liver mobilization. is approach allows
for an accelerated FLR hypertrophy to be obtained at
a mean of 63% within 11 days.
19
is is similar to that
reported for classic ALPPS; but without the high rate of
mortality and morbidity.
5,6
Associating Liver Tourniquet and Portal Ligation for
Staged Hepatectomy
With this method, a tourniquet is used to replace the
completion of the parenchymal transection, this reduces
the complexity and time required in the rst stage of the
operation.
21
A thick suture material is applied around the
liver in the deep sulcus of the parenchymal transection
(an extra-glissonian approach). en the tourniquet
is subsequently tightened to completely obstruct all
interlobar collateral circulation.
Radiofrequency assisted liver partition
is is an application of radiofrequency ablation to
the parenchyma, aer right PVL at the site of demarcation.
e hypertrophic rate is increased by up to 62% over a
mean interval of 22 days, according to the study, and
that it also avoids the complications of liver partition.
22
ALPPS outcome
Primary outcomes
e studies that investigated the ecacy of ALPPS
have consistently revealed that ALPPS causes hypertrophy
of 60-90%, with the average duration of the stage being
9-14 days (Table 1). Most of the cases (95-100%) that
complete the rst stage could be undergoing a later
stage.
5,6,15,23,24
e international ALPPS registry consists
of 141 (70%) colorectal liver metastasis (CRLM) patients
among 202 patients.
25
Within 7 days, the median initial
standardized future liver remnant of 21% grew by 80%,
and ninety-day mortality was 9%. Severe complications
occurred in 27% of patients. Red blood cell transfusion,
an operative time of more than 300 minutes, patient ages
being greater than 60 years, and non-CRLM were all
independent risks for severe complications. Additionally,
the registry shows that many factors directly aect the
rate of liver hypertrophy; such as, age, intermittent
Pringle maneuver, and abnormal parenchyma.
25
According to meta-analysis,
26
ALPPS seems to be
more eective than the two-stage approach in causing
remnant hypertrophy, with signicantly higher resection
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TABLE 1. Success rate and outcome of Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy
compare with two-staged hepatectomy.
Author Year Primary tumor FLR volume Drop-out rate Morbidity*/
(reference) (N) increment(%)afterrststage(%) mortality
CRLM HCC CCA ALPPS TSH ALPPS TSH (%)
Schnitzbauer
5
2012 14 3 4 74 n/a n/a n/a 64/12
ShindohJ
8
2013 14 3 4 70 62 n/a 28 40/12
SchaddeE
25
2014 141 17 19 80 n/a 2 n/a 27/9
SchaddeE
6
2015 228 32 27 90 n/a 2 n/a 14/9
Sandstrom
31
2018 97 - - 68 36 8 43 43/8
WangZ
36
2020 - 45 - 57 n/a 9 n/a 12/11
ChanA
37
2021 - 46 - 49 38 2 32 21/6.5
Abbreviations: CRLM; Colorectal Liver Metastasis, HCC; Hepatocellular carcinoma, CCA; Cholangiocarcinoma, FLR; Future liver remnant,
ALPPS; Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy, TSH; two-stage hepatectomy
* Clavien-Dindo grade ≥ IIIB
n/a: non-available
rates of approximately 92-100%.
25–28
Additionally, there
is a shorter time interval of 1-2 weeks vs. 20-45% in
2-8 weeks following PVE. Furthermore, prolonged
periods between stages in TSH has caused up to 30%
of patients to be ineligible for a nal hepatectomy, due
to disease progression.
10,29,30
At the same time, ALPPS
faces the problem of most candidates having a higher
risk for micrometastasis in FLR aer a second stage
operation. Additionally, there is an argument concerning
the hypertrophic liver, in regards to cellular swelling
or complete functioning regeneration, and that liver
hypertrophy in such a short period of time may not
ensure its functional capacity.
9
In conclusion, despite
ALPPS having a greater resectability rate, there is no
signicant dierence in disease free survival between
ALPPS and TSH.
Morbidity and mortality
e major obstacle of the procedure is the signicant
rate of morbidity and mortality. e largest study, 202
patients, cited major morbidity of 28% and mortality of
9%.
6,15,25
Although, the reported mortality rate is variable,
the high complication rate is may have occurred from
the small sample size of the study. A German study
revealed a 12 percent 90-day death rate, triggering a
erce debate among international experts;
5
surgical
exploration, right portal vein ligation (PVL additionally,
other small studies found signicantly higher rates;
ranging from 22-29%. Conversely, there have been no
90-day mortalities recorded across multiple centers.
13,15,25
Comparison between ALPPS and Two-stage hepatectomy.
e retrospective comparative analysis of 140 patients
undergoing PVE to the 25 patients undergoing ALPPS
showed that the rates of hypertrophy were similar in both
groups: 70% in the ALPPS group and 60% in the PVE
group.
8
Overall, there was no signicant dierence in
major morbidity between the two groups (40% ALPPS
versus 30% PVE). However, for other complications
ALPPS had signicantly higher rates than PVE in all
causes; bile leak (24% versus 6%), re-laparotomy (30%
versus 3%) and sepsis (20% versus 0%); but was no
signicantly higher in liver-related mortality (12% versus
6%).
Data from the retrospective multicenter study
showed a trend towards higher morbidity and mortality
associated with ALPPS compared with PVE. e 90-day
mortality was 15% versus 6%, and post-hepatectomy
liver failure was 13% versus 9% for the ALPPS versus
the PVE group, respectively. Moreover, patients in the
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270
ALPPS group achieved more completion of resection
(83% versus 66%); however, the recurrence at one year
was comparable (54% versus 52%).
25
In contrast to Aloia et al, the PVE group had just a
34% increase in FLR compared to a 77% gain in the ALPPS
group.
28
e LIGRO was a landmark randomized controlled
trial that compared the resection rate between ALPPS and
TSH in CRLM patients. is study demonstrated that
ALPPS could oer a higher resection rate compared to
TSH, 92% to 57%, respectively, with comparable surgical
margins, complications, and short-term mortality.
31
A recent systematic review and meta-analysis of
ALPPS versus traditional staged hepatectomy, in 2019,
7
found that ALPPS increased FLR more than PVE and
TSH. However, the results of the study are limited due
to the high heterogeneity among the studies. As for
overall mortality and morbidity, the higher trend is
on the side of ALPPS over PVE/TSH; morbidity 30%
and 26%, respectively, without heterogeneity; mortality
10% and 4% consequently, without heterogeneity. e
feasible rate of stage 2 aer ALPPS and PVE were 94%
versus 63%, respectively, which is the same as between
ALPPS and TSH, 95% versus 72%, respectively.
ALPPS in CRLM
In the first international registry,
6
the 90-day
postoperative mortality among all patients who underwent
ALPPS was 9%. For patients with CRLM, the 2-year
overall survival (OS) and disease-free survival (DFS)
were 62% and 41%, respectively. Patients with CRLM
who were younger than 60 years of age had a better
chance of survival than patients with other malignancies.
A separate analysis of the international ALPPS registry
included 228 patients with CRLM, which comprised of
72% of the study population. In this report, the 90-day
mortality was 5%. e leading cause of mortality was liver-
related, for which it was recommended by the authors
to evaluate the patients underlying condition, using the
model of end-stage liver disease, and the international
study group for liver surgery criteria, so as to discriminate
against higher or lower risk.
27
Some of the suggested approaches to improve ALPPS
outcome include stratication of patients for developed
liver failure following rst stage hepatectomy, achieving
expertise in the learning curve, renement in patient
selection, modications to the original ALPPS procedure
to reduce liver traumatization, interval chemotherapy,
a shorter time o chemotherapy, and preservation of
segment IV.
9
e objective of oncologic liver surgery is
to achieve a tumor-free margin. In there meta-analysis,
Margonis et al,
29
found that a margin of >1 mm was
related with better overall survival, and a margin of >1
cm was even associated with better DFS. As a result, a
better oncologic outcome may even justify the removal
of signicant volumes of parenchyma. Furthermore,
regarding the numbers and sizes of metastases remaining
in the FLR, full tumor clearance of the FLR during the
rst stage is crucial for any two-stage strategy. ese
traditional markers; numbers and sizes of metastases
as well as intensity of oncologic pretreatment area are
important prognostic factors. KRAS mutation, which has
been linked to poor survival, and TP53 mutation have
both been linked to a higher chance of tumor relapse in
recent studies.
30
Hence, analysis by Schnitzbauer et al,
32
assumed
that there is a tendency for potential overuse of ALPPS.
Additionally, the role of major hepatectomy in CRLM has
become less, due to eective down-sizing of chemotherapy
being available. In this case, ALPPS must be viewed as
a last resort at the very end of the therapeutic spectrum
for CRLM.
ALPPS in Hepatocellular carcinoma (HCC)
e ALPPS registry’s initial report, which included
17 patients with HCC, and the second, which included
32 patients with HCC, reported 90-day mortality rates of
12% and 13%, respectively.
6,25
ese results appeared to
be the consequence of both an early learning curve and a
typically increased mortality of liver resection in altered
liver parenchyma. More devastating was when the rst
major analysis from the ALPPS registry, with 35 ALPPS
for intermediate-stage tumor, revealed a 90-day mortality
of 30%.
33
However, a thorough examination revealed
that ALPPS had been employed with broad inclusion
criteria and in an undierentiated manner. Fortunately,
aer careful selection, using the ALPPS technique in a
good patient candidate with HCC (Child A cirrhosis,
FLR volume > 30%, an indocyanine green clearance rate
at 15 minutes <20%, platelet count > 100,000/µL and no
complete right portal vein thrombosis), led to a decrease
in mortality of 7% and 0%.
23,34,35
A recent study, from
Wang et al, investigated their outcomes of conventional
ALPPS in 45 HCC patients.
36
e results showed that
the patients who received ALPPS had similar eects to
those who underwent one-stage hepatectomy,; with 1-
and 3-year OS rates of 64% and 60% and 1- and 3-year
DFS rates of 48% and 44%. Furthermore, the results
were far superior to those who received transarterial
chemoembolization. Recently, Chan et al. investigated
the role of ALPPS for hepatitis-related HCC. e study
shows ALPPS induced FLR volume increment by 48.8%,
without dierence in morbidity and mortality compared
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to PVE. Although, over 56.5% of patients that complete
stage 2 had cirrhosis.
37
ALPPS in cholangiocarcinoma
From the beginning, ALPPS was rstly used in a
case of hilar cholangiocarcinoma, even so, the latest
data reveals the highest perioperative complication risks
among all indicated diseases. e 90-day-mortality for
intrahepatic cholangiocarcinoma from the ALPPS registry
is about 13%.
6
e risk of perioperative complications
is higher in perihilar cholangiocarcinoma (PHC), most
likely from post rst stage parenchymal necrosis, possibly
infected bile, and biliary leakage. A matched case study
that compared data from the ALPPS registry to data
on PVE and right trisectionectomy for PHC found that
perioperative mortality was as high as 48% in the ALPPS
group versus 24% in the matched group.
38
ese results led
to unacceptable arguments over whether it is a homicidal
choice of treatment or not. However, from a closer
viewpoint, ALPPS in the research was performed with the
intention to improve resectability, by rapidly increasing
FLR; but at the same time some principles of surgery for
PHC were neglected. For example; performing the 1
st
stage
operation in the presence of infection and inammation
by conventional ALPPS; thereby causing a higher risk
of biliary leakage. Conversely, new techniques; such as:
“Mini-ALPPS” and “Hybrid ALPPS”, were introduced.
Both strategies aim to achieve appropriate FLR growth
in the shortest period possible, and both prevent hilar
dissection during the rst stage. As a result, in PHC
patients, ALPPS should not be deemed a categorical
contraindication.
Authors opinions
Aer the initial outcome of ALPPS demonstrated
the dramatic increment of FLR, this procedure became
famous among the hepatobiliary surgery community.
However, many patients have been through this procedure
without proper indication, which has lead to avoidable
complications. Even with the international ALPPS registry
results, the 90-day mortality was much higher than
conventional hepatectomy.
6
e authors suggest that the following issue should
be considered before selecting a patient for ALPPS.
1. For CRLM: the patient should receive episodes
of systemic chemotherapy, with or without
targeted therapy. Good response liver metastasis
could omit the need for this risky procedure.ALPPS
should only be used as a last measure in the
treatment of CRLM.
32
2. The CRLM patients who progress while on
systemic therapy are poor candidates for ALPPS.
3. Aer stage 1, preoperative liver evaluation is
crucial. Both quantitative and qualitative assessments
are essential. e second stage should be terminated,
or postponed for any patient that has good
FLR increase but impaired function. ere are
some discrepancies between the increased
volume and the remnant›s function because most
of the regenerated hepatocyte is still partly
immature.
10
4. In chronic viral hepatitis or cirrhosis there is
scant evidence of ALPPS; therefore, the surgeon
should select the most suitable patients for ALPPS.
5. Patients with cholangiocarcinoma should avoid
ALPPS. ALPPS in cholangiocarcinoma had the
highest risk of perioperative complication among
all indicated diseases. e 90-day-mortality for
intrahepatic cholangiocarcinoma is high as 13%,
and might be higher for perihilar cholangiocarcinoma.
6
CONCLUSION
ALPPS is one of the strategies to overcome inadequate
future liver remnants. Perioperative complications are
the main concern for ALPPS, because the tremendous
volume increment within 1-2 weeks is not well correlated
with the function of the remnant liver. As early results
from the ALPPS registry have shown, inappropriate
patient selection resulted in a high risk of PHLF and
postoperative mortality. Proper patient selection coupled
with a satisfactory pre-and interstage liver assessment
could improve outcomes; especially for CRLM, which
has comparable results to TSH.
ACKNOWLEDGEMENT
e authors would like to thank Woralux Phusoongnern,
M.D., FRCNST, for the illustrations.
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