REVIEW ARTICLES - Anesthesia and Pain Medicine

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KSNACC KSAP KSOA KSPA KNRS KSCVA KSTA KSPS KSRA KSAM

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o. 1 Jan. 2021

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REVIEW ARTICLES

1 Who are at high risk of mortality and morbidity among children with congenital heart disease undergoing noncardiac surgery?8 Perioperative glucocorticoid management based on current evidence16 Safety of epidural steroids: a review

pISSN: 1975-5171eISSN: 2383-7977

Vol. 16/No. 1Jan. 2021

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THE K

OREA

N SOCIETY OF OBSTETRIC A

NES

THES

IOLO

GI S

T S

Aims and ScopeAnesthesia and Pain Medicine (APM) is the official scientific journal of Korean Society of Neuroscience in Anesthesiology and Critical Care (KSNACC), The Korean Society for Anesthetic Pharmacology (KSAP), The Korean Society of Obstetric Anesthesiologists (KSOA), The

Korean Society of Pediatric Anesthesiologists (KSPA), Korean Neuromuscular Research Society (KNRS), Korean Society of Cardiothoracic

and Vascular Anesthesiologists (KSCVA), Korean Society of Transplantation Anesthesiologists (KSTA), The Korean Spinal Pain Society

(KSPS), Korean Society of Regional Anesthesia (KSRA), and Korean Society for Airway Management (KSAM). The abbreviated title is

"Anesth Pain Med". It is published four times a year on the last day of January, April, July, and October in English.

The mission of APM is to improve safety and quality of care of related patients and clinical practice of anesthesiologists by publishing

definitive articles in the field of anesthesiology including practice of perioperative management, critical care, and pain medicine. The

scopes of APM are as follows : anesthesia-related issues from affiliated neuroanesthesiology (KSNACC), experimental, laboratory

works or clinical relevance of anesthetic pharmacology (KSAP), anesthesia for operative delivery, pain relief in labor, care of the

critically ill parturient, perinatal physiology and pharmacology (KSOA), anesthetic care, perioperative management, and alleviation

of pain in children (KSPA), physiology of neuromuscular transmission and block, pharmacology of neuromuscular blocking agents

and their reversal agents, principles and applications of neuromuscular monitoring, and drug interaction between neuromuscular

blocking agents and other substances (KNRS), anesthesia for cardiothoracic and vascular surgery and management of patients

undergoing various surgeries for patients with cardiac, pulmonary, and vascular diseases (KSCVA), perioperative anesthesia care

of transplantation surgery, physiology or pharmacology related with transplantation anesthesiology (KSTA), pathophysiology,

pharmacology, and all respects of spine related pain (KSPS), clinical techniques of regional blocks, anatomy, patient safety issues,

basic sciences such as pharmacology of local anesthetics or sedative drugs (KSRA), all fields of airway management including difficult

airway and complications (KSAM). 

All or part of the Journal is indexed/tracked/covered by PubMed, PubMed Central (PMC), KoreaMed, KoMCI, Google Scholar, Science

Central.

Full text is freely available from http://anesth-pain-med.org

The circulation number per issue is 400.

Anesthesia and Pain Medicine January 2021; Volume 16, Number 1, Serial No. 59ⓒ 2021 the Korean Society of Anesthesiologists.

Korean Society of Neuroscience in Anesthesiologyand Critical Care

The Korean Society for Anesthetic Pharmacology

Korean Neuromuscular Research Society Korean Society of Cardiothoracic and VascularAnesthesiologists

The Korean Society of Obstetric Anesthesiologists The Korean Society of Pediatric Anesthesiologists

Korean Society of Transplantation Anesthesiologists The Korean Spinal Pain Society

Korean Society for Airway ManagementKorean Society of Regional Anesthesia

pISSN: 1975-5171eISSN: 2383-7977

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iAnesth Pain Med

Vol.16 No.1 January 2021

PublisherJae-Hwan Kim (Korea University, Korea)

Editor-in-ChiefYoung-Cheol Woo (Chung-Ang University, Korea)

Associate EditorChong Wha Baek (Chung-Ang University, Korea)

Jung-Won Hwang (Seoul National University, Korea)Hyun Kyo Lim (Yonsei University, Korea)

Editorial BoardHyunjoo Ahn (Sungkyunkwan University, Korea)

Randal S. Blank (University of Virginia, USA)Yong Seon Choi (Yonsei University, Korea)

Woo-jong Choi (University of Ulsan, Korea)Yang Hoon Chung (Soonchunhyang University, Korea)Seongtae Jeong (Chonnam National University, Korea)

Jae Hun Kim (Konkuk University, Korea)Ju Hwan Lee (Wonkwang University, Korea)

Jeong-Rim Lee (Yonsei University, Korea)

Wonjin Lee (Inje University, Korea)Chaeseong Lim (Chungnam National University, Korea)Jung Hyun Park (The Catholic University of Korea, Korea)Hyungseok Seo (Kyung Hee University, Korea)Young Duck Shin (Chungbuk National University, Korea)Peter D. Slinger (University of Toronto, Canada)Weipeng Wang (Shanghai Deltahealth Hospital, China)Laurence Weinberg (University of Melbourne, Australia)Young Ju Won (Korea University, Korea)

Ethics EditorYoung Yoo (Korea University, Korea)

Statistics EditorEun-Jin Ahn (Chung-Ang University, Korea), Junyong In (Dongguk University, Korea),

Jong Hae Kim (Daegu Catholic University, Korea), Dong-Kyu Lee (Korea University, Korea)

Illustrated EditorYong Beom Kim (Gachon University of Medicine and Science, Korea)

Manuscript EditorJi Youn Ha (The Korean Society of Anesthesiologists, Korea), Se Jueng Kim (MEDrang Inc., Korea)

Contacting the Anesthesia and Pain Medicine

All manuscripts must be submitted online through the APM e-Submission system (http://submit.anesth-pain-med.org).Electronic files of the manuscript contents must be uploaded at the web site.Items pertaining to manuscripts submitted for publication, as well as letters or other forms of communication regarding the editorial

management of APM should be sent to:

Editor-in-Chief

Young-Cheol Woo

Publishing/Editorial Office

The Korean Society of Anesthesiologists101-3503, Lotte Castle President, 109 Mapo-daero, Mapo-gu, Seoul 04146, KoreaTel +82-2-795-5129, Fax +82-2-792-4089, E-mail [email protected]

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Anesth Pain Medii

Vol.16 No.1 January 2021

Table of Contents

Reviews

1 Who are at high risk of mortality and morbidity among children with congenital heart disease undergoing noncardiac surgery?In-Kyung Song, Won-Jung Shin

8 Perioperative glucocorticoid management based on current evidence Kwon Hui Seo

16 Safety of epidural steroids: a review Min Soo Lee, Ho Sik Moon

Neuroanesthesia

Clinical Research

28 Pharmacological strategies to prevent postoperative delirium: a systematic review and network meta-analysisJun Mo Lee, Ye Jin Cho, Eun Jin Ahn, Geun Joo Choi, Hyun Kang

Obstetric Anesthesia

Clinical Research

49 Comparison of the effect of general and spinal anesthesia for elective cesarean section on maternal and fetal outcomes: a retrospective cohort studyTae-Yun Sung, Young Seok Jee, Hwang-Ju You, Choon-Kyu Cho

pISSN: 1975-5171eISSN: 2383-7977

Neuromuscular Research

Case Report

56 Treatment of rocuronium-induced anaphylaxis using sugammadexSun-Min Kim, Sei-hoon Oh, Seung-Ah Ryu

Cardiothoracic and Vascular Anesthesia

Clinical Research

60 Comparison of postoperative pulmonary complications between sugammadex and neostigmine in lung cancer patients undergoing video-assisted thoracoscopic lobectomy: a prospective double-blinded randomized trialTae Young Lee, Seong Yeop Jeong, Joon Ho Jeong, Jeong Ho Kim, So Ron Choi

http://anesth-pain-med.orghttp://anesth-pain-med.orghttp://anesth-pain-med.orghttp://anesth-pain-med.orghttp://anesth-pain-med.orghttp://anesth-pain-med.org

KSNACC KSAP KSOA KSPA KNRS KSCVA KSTA KSPS KSRA KSAM

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iiiAnesth Pain Med

General Article

Clinical Research

108 An exploratory study of risk factors for pressure injury in patients undergoing spine surgeryDaeHee Suh, Su Yeon Kim, Byunghoon Yoo, Sangseok Lee

Spinal Pain

Clinical Research

81 Prolotherapy for the patients with chronic musculoskeletal pain: systematic review and meta-analysisGeonhyeong Bae, Suyeon Kim, Sangseok Lee, Woo Yong Lee, Yunhee Lim

Case Report

96 Paraplegia after transforaminal epidural steroid injection in a patient with severe lumbar disc herniation Seok Ho Jeon, Won Jang, Sun-Hee Kim, Yong-Hyun Cho, Hyun Seok Lee, Hyun Cheol Ko

103 Unexpected extrusion of the implantable pulse generator of the spinal cord stimulator Eun-Ji Choi, Hyun-Su Ri, Hyeonsoo Park, Hye-Jin Kim, Ji-Uk Yoon, Gyeong-Jo Byeon

Transplantation Anesthesia

Clinical Research

68 Changes in the allocation policy for deceased donor livers in Korea: perspectives from anesthesiologists Seung Yeon Yoo, Gaab Soo Kim

Case Report

75 Capillary leak syndrome and disseminated intravascular coagulation after kidney transplantation in a patient with hereditary angioedema Jeong Wook Park, Jinyoung Seo, Sang Hun Kim, Ki Tae Jung

Letters to the Editor

116 Change of inspired oxygen concentration and temperature in low flow anesthesia To The editorHong Seuk Yang, Dong Ho Park, Chang Young Jeong

117 In replyJiwook Kim, Hochul Lee, Sungwon Ryu, Donghee Kang, Siejeong Ryu, Doosik Kim

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나제아_리플렛(2p)_A4(출력용).pdf 1 2019. 12. 9. 오후 5:42

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INTRODUCTION

The incidence of congenital heart disease (CHD) is re-

ported to be about 6 per 1,000 full-term live births in the

United States [1]. With advances in the perinatal diagnosis

of CHD and improvement in surgical and medical man-

agement, the survival rate and life expectancy in children

with CHD have been increasing [2]. These children fre-

quently require noncardiac surgeries, including laparo-

scopic, urogenital, and otolaryngological surgeries. During

the first year of life, 41% of infants who underwent congen-

ital heart surgery had undergone noncardiac surgery by

the age of 5 years [3]. With an increasing demand for surgi-

cal procedures under general anesthesia in these patients,

it is not uncommon for anesthesiologists to encounter chil-

dren with an unrepaired CHD or residual pathologic con-

ditions, as well as children with a repaired CHD. Therefore,

it is important to identify children at risk of perioperative

Corresponding author Won-Jung Shin, M.D., Ph.D.Department of Anesthesiology and Pain Medicine, Laboratory for Cardiovascular Dynamics, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea Tel: 82-2-3010-5644 Fax: 82-2-3010-6790E-mail: [email protected]

With advances in the development of surgical and medical treatments for congenital heart disease (CHD), the population of children and adults with CHD is growing. This population requires multiple surgical and diagnostic imaging procedures. Therefore, general anesthesia is inevitable. In many studies, it has been reported that children with CHD have increased anesthesia risks when undergoing noncardiac surgeries compared to children without CHD. The highest risk group included patients with functional single ventricle, suprasystemic pul-monary hypertension, left ventricular outflow obstruction, and cardiomyopathy. In this re-view, we provide an overview of perioperative risks in children with CHD undergoing noncar-diac surgeries and anesthetic considerations in patients classified as having the highest risk.

Keywords: Anesthesia; Child; Congenital heart defect; Risk.

Who are at high risk of mortality and morbidity among children with congenital heart disease undergoing noncardiac surgery?

In-Kyung Song and Won-Jung Shin

Department of Anesthesiology and Pain Medicine, Laboratory for Cardiovascular

Dynamics, Asan Medical Center, University of Ulsan College of Medicine, Seoul,

Korea Received November 25, 2020Accepted December 7, 2020

ReviewAnesth Pain Med 2021;16:1-7https://doi.org/10.17085/apm.20090pISSN 1975-5171 • eISSN 2383-7977

morbidity and mortality and to understand their patho-

physiologic and hemodynamic status when preparing their

general anesthetic plan. In the following review, we discuss

the current knowledge regarding children with CHD who

have high anesthesia and surgical risks and also focus on

the perioperative considerations for these high-risk pa-

tients.

RISKS OF NONCARDIAC SURGERIES IN CHILDREN WITH CHD

Recently, mortality and perioperative adverse events re-

lated to noncardiac surgeries have been reported in chil-

dren studies with large sample populations, including

those with and without CHD. Baum et al. [4] showed that

the overall 30-day mortality after noncardiac procedures

was higher in patients with CHD (6.0%) than in those with-

out CHD (3.8%). They also found that age, complexity of

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Copyright © the Korean Society of Anesthesiologists, 2021

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the operation, and CHD, were associated with periopera-

tive mortality. In the Pediatric Perioperative Cardiac Arrest

(POCA) Registry, causes of anesthesia-related cardiac ar-

rest were reported from nearly 80 voluntarily enrolled

North American institutions that provide anesthesia for

children over a period of 10 years [5]. In this study, children

with CHD had a higher mortality rate (33%) than those

without CHD (26%). Cardiac arrest was strongly associated

with surgical complexity and the patient’s underlying func-

tional status. Among the types of CHD, single ventricular

physiology, aortic stenosis, and cardiomyopathy were as-

sociated with the highest mortality following a cardiac ar-

rest. In another study, the incidence of perioperative cardi-

ac arrest was 2.9 per 10,000 anesthetic episodes among pa-

tients undergoing noncardiac surgeries, and of these, 27%

had CHD [6]. In addition, they found that the most com-

mon causes of cardiac arrest during noncardiac surgeries

were hypovolemia, bleeding, and massive transfusion.

These findings suggest that intrinsic surgical factors and

the associated hemodynamic deterioration are important

for estimating the risk of cardiac arrest. In a study investi-

gating 101,885 anesthetic cases, the overall 24-h mortality

after anesthesia was 13.4 per 10,000 [7]. The highest inci-

dence of death was in children younger than 30 days. Col-

lectively, children with CHD are faced with a high risk of

mortality and adverse events related to anesthesia when

undergoing noncardiac surgeries. In particular, the com-

plexity of CHD is regarded as an important factor influenc-

ing high risk of mortality. Therefore, children with CHD

may be at higher risk of mortality and morbidity during

and after noncardiac surgeries. In addition, age, anatomi-

cal and functional status according to CHD complexity,

and intrinsic surgical risks are points that must be consid-

ered with care when estimating the risks of mortality and

morbidity.

The other issue to consider is how to define and stratify

the risk factors. According to the American College of Sur-

geons who collected data on noncardiac surgeries as a part

of its National Surgical Quality Improvement Program for

the classification of CHD, CHD can be stratified as minor,

major, and severe, based on the residual lesion burden and

the functional status of the heart [8]. According to this clas-

sification, children who have maintained good cardiac

conditions with or without medication and children with a

repaired CHD are classified as having minor CHD; patients

with a repaired CHD but who have residual abnormalities

in hemodynamic status are considered to have major CHD;

patients with an unrepaired cyanotic CHD, pulmonary hy-

pertension, or ventricular dysfunction or children awaiting

transplantation are classified to have severe CHD. After

propensity matching for age, sex, physical status, surgical

emergency, and surgical complexity, severe CHD was sig-

nificantly associated with 30-day mortality and overall

mortality [8]. However, there was no difference between

children with minor CHD and their matched controls. In

addition to perioperative mortality, morbidities including

postoperative reintubation, infections, renal failure, neuro-

logic complications, thrombotic events, reoperation, and

readmission were more frequent in patients with major

and severe CHD. In a recent study regarding surgical com-

plexity, children with CHD younger than 1 year showed a

greater risk of postoperative complications, with an incre-

mental increase in odds ratios in the order of minor, major,

and severe CHD [9]. In another study of 3,010 children with

CHD undergoing noncardiac surgeries, major and severe

CHD remained significant risk factors for perioperative

cardiovascular events after adjusting for the American So-

ciety of Anesthesiologists physical status, emergency cases,

and surgical types [10].

In a previous study using a risk stratification tool to clas-

sify risk levels for perioperative cardiac complications, re-

paired atrial defects and ventricular septal defects were

considered low risk, maintenance cardiac medications;

and repaired cyanotic or complex CHD were classified as

moderate risk; and unrepaired cardiac anomalies, Williams

syndrome, pulmonary hypertension, valvular heart disease

with significant valvular gradients, hypertrophic cardiomy-

opathy with obstruction, congestive heart failure, or chil-

dren with ventricular-assisted devices were considered

high risk [11]. To further determine the anesthesia risk, age

less than 1 year, comorbidities, and surgical complexity

were included as the next step. Similarly, results from

non-validated data of anesthesia for noncardiac surgeries

indicated that children with CHD were classified as low,

intermediate, and high risk, and further discriminated

based on physiological decompensation, complexity of the

CHD, major surgery, age under 2 years, emergency, preop-

erative hospital stay more than 10 days, and American So-

ciety of Anesthesiologists physical status [12,13].

To date, only one study has reported a risk assessment

model using a validation cohort. This study identified eight

preoperative factors that were significant in determining

in-hospital mortality: 1) emergency procedure, 2) severe

CHD, 3) previous surgery within the last 30 days, 4) single

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ventricular physiology, 5) inotropic use, 6) cardiopulmo-

nary resuscitation, 7) kidney injury, and 8) mechanical

ventilation [14]. Based on the variables obtained from mul-

tivariable logistic regression analyses, scores from 0 to 10

were determined. This scoring system showed good dis-

crimination and calibration with an area under the receiver

operating characteristic curve of 0.831 (95% confidence in-

terval: 0.787–0.875) in the validation cohort. Briefly, scores

≤ 3 were associated with low risk, scores of 4–6 were asso-

ciated with medium risk, and scores ≥ 7 were associated

with a high risk for mortality (odds ratios 1.54, 4.19, and

22.15, respectively) [14]. Notably, major and severe CHD,

including single ventricular physiology, were found to be

major determinants of perioperative outcomes [14]. In

contrast, surgical complexity was not significant [14]. They

also highlighted that scoring-based risk stratification for

mortality may be necessary to help guide the perioperative

management of patients with high-risk CHD.

Herein, we reviewed the perioperative considerations of

children undergoing noncardiac surgeries who were classi-

fied as having high-risk CHD, in common with most of the

previously reported studies.

SINGLE VENTRICULAR PHYSIOLOGY

It is critical that anesthesiologists understand the physi-

ology of each palliative stage of a single ventricle, which in-

cludes truncus arteriosus, large and multiple ventricular

septal defects, and hypoplastic left heart syndrome

(HLHS). Patients who have not undergone completion of

superior cavopulmonary anastomosis (SCPA) are known to

have the highest risks during noncardiac surgeries and

congenital heart surgery. Especially in HLHS, the mortality

rate of patients younger than 2 years has been reported to

be up to 19% after noncardiac surgeries [15]. Hemodynam-

ic derangement is caused by excessive pulmonary blood

perfusion and poor systemic perfusion from imbalanced

circulation, decreased coronary perfusion, impairment of

the systemic right ventricle, and atrioventricular valve dys-

function. As the single ventricle concurrently operates both

the pulmonary and systemic circulations, hemodynamic

balance is frequently disrupted by alterations in pulmo-

nary and systemic vascular resistance (PVR and SVR, re-

spectively), ventilatory strategy including hypoxia and hy-

percapnia, acid-base balance, and intravascular volume

status. Therefore, postponing elective noncardiac proce-

dures under after SCPA is recommended. If the patient

could not postpone due to an emergent condition, Pulmo-

nary-to-systemic blood flow ratio should be at or just below

1 to maintain systemic perfusion and optimize oxygen de-

livery, consequently resulting in arterial oxygen saturation

of 80–90% [16].

After the SCPA, the single ventricle is no longer operating

with the volume overloading required to sustain parallel

circulations. Accordingly, cardiac output and systemic per-

fusion are not entirely dependent on pulmonary blood

flow, which makes the hemodynamic performance rela-

tively stable. However, hypercarbia, acidosis, and elevated

airway pressure should be avoided because pulmonary

blood flow remains dependent on PVR. However, hypocar-

bia may exacerbate a decrease in cerebral blood flow and

reduce venous return from the brain and upper body [17].

If there is high pressure in the superior vena cava, the head

and the tongue may become congestive due to disturbance

in venous return. In these patients, the goal of anesthetic

management is to maintain systemic oxygenation with ad-

equate pulmonary blood flow, which is secured by opti-

mizing intravascular volume, minimizing airway pressure,

and ensuring a low PVR.

Finally, the destination of single ventricular physiology is

the completion of successful Fontan circulation, in which all

systemic venous return is composed of pulmonary blood

flow. Even though systemic arterial saturation is maintained

above 90%, cardiac output relies on pulmonary blood flow

that runs down passively because there is no pump func-

tion producing a pulsatile driving pressure. Pulmonary

blood flow and cardiac output are strictly influenced by

mechanical ventilation with positive end-expiratory pres-

sure [18,19]. In addition, the pressure of the systemic ve-

nous system is elevated, and its capacitance is decreased,

and accompanied by diminished recruitment reserve of

the vascular volume [20]. Consequently, patients with a

Fontan circulation are intolerant of vasodilation from anes-

thetic agents, surgical bleeding, and dehydration. It may be

beneficial to prepare inotropic agents and vasopressors for

the treatment of hypotension and avoid excessive volume

challenges [20]. Unfortunately, bleeding tendency may be

increased due to persistent high venous pressure and anti-

coagulant therapy. However, they also have thrombosis

risks [21]. Along with preloading, other factors are required

to achieve the perfect Fontan circulation as follows: low

PVR, sinus rhythm, normal atrioventricular valve function,

good ventricular performance, and the absence of inflow

and outflow tract obstruction [22] (Fig. 1). After surgery, it

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Risks associated with congenital heart disease

Page 12

can be favorable for patients with Fontan physiology to ex-

tubate as early as possible and restore spontaneous breath-

ing.

SUPRASYSTEMIC PULMONARY HYPERTENSION

Pulmonary hypertension is one of the factors associated

with a high perioperative mortality rate. The perioperative

mortality risk has been reported to be at least 20-fold great-

er in children with pulmonary hypertension than in those

without among children undergoing noncardiac proce-

dures [23]. Suprasystemic pulmonary hypertension is de-

fined as the ratio of mean or systolic pulmonary artery

pressure to systemic artery pressure (PAP/SAP) of > 100%.

As pulmonary hypertension progresses, perioperative out-

comes worsen. Thus, it is crucial to determine the severity

of pulmonary hypertension during preoperative evalua-

tion. Features that distinguish the severity of pulmonary

hypertension are as follows: right ventricular (RV) dysfunc-

tion on echocardiography, decreased functional capacity,

growth failure, significantly elevated brain natriuretic pep-

tide (BNP) or N-terminal pro-BNP levels, and poor cathe-

terization indices [24]. In these children who are chronical-

ly exposed to suprasystemic PAP, acute RV failure and pul-

monary hypertensive crisis may occur given the limited

functional reserve of the RV. If coronary hypoperfusion oc-

curs simultaneously, catastrophic results such as myocar-

dial ischemia, fatal arrhythmia, and cardiac arrest may oc-

cur even if the increase in PAP is small [25].

Whenever patients undergo surgery and general anes-

thesia, pulmonary hypertensive crisis can develop due to

various causes including hypoxia, hypercarbia, acidosis,

hypothermia, and sympathetic stimulation. Particularly in

children whose PVR increases but remains responsive and

modifiable, any causes that induce an increase in PVR can

trigger a vicious cycle of pulmonary hypertensive crisis [25]

(Fig. 2). During anesthesia, clinical signs manifest as arteri-

al desaturation and low end-tidal CO2 levels due to im-

paired pulmonary blood flow, sudden cardiovascular col-

lapse, hypotension, and tachy- or brady-arrhythmia. Pul-

monary hypertensive crisis should be treated promptly.

Management of pulmonary hypertensive crisis may involve

ventilation with 100% inspired O2, mild hyperventilation,

inhaled nitric oxide, alkalinization using sodium bicarbon-

ate infusion, and inotropic support.

LEFT VENTRICULAR OUTFLOW TRACT OBSTRUCTION

According to the POCA registry, 16% of anesthesia-relat-

ed cardiac arrest was caused by obstruction to ventricular

outflow such as supravalvular, subaortic, or aortic stenosis

[5]. After cardiac arrest in these patients, the mortality rate

was 62%, suggesting that anesthesiologists should be me-

ticulous in perioperative management. In patients with

Williams syndrome, cardiovascular abnormalities are char-

acterized by supravalvular aortic and pulmonary stenoses

No inflow obstruction

Fontan pathway

Pulmonary vascular

bed

Perfect Fontan circulation requires

Common atrium

Single ventricle

Systemic resistance

Central venous system

Sinus rhythmPreload

Absence of LVOTO

No valvular regurgitation,

stenosis

Good contractility

PVR ↓

Fig. 1. Requirements for a perfect Fontan circulation. Factors at each anatomical structure are essential to secure successful Fontan circulation: an adequate preload, low pulmonary vascular resistance (PVR), normal sinus rhythm, normal atrioventricular valve function, good ventricular contractility, and absence of inflow and left outflow tract obstruction (LVOTO).

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Anesth Pain Med Vol. 16 No.1

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with elastin arteriopathy. Ventricular outflow obstruction

is followed by myocardial hypertrophy. Worsening biven-

tricular hypertrophy may lead to sudden cardiovascular

collapse in patients undergoing anesthesia. Moreover, fac-

tors related to coronary blood flow may also contribute to

cardiovascular events during the perioperative period in-

cluding 1) Anatomical abnormalities and coronary artery

stenosis, 2) compromise of diastolic blood pressure caused

by loss of aortic distensibility, and 3) myocardial oxygen

imbalance from increased demand of hypertrophied myo-

cardium [26]. Prolongation of the corrected QT interval is

present in 13% of patients with Williams syndrome, and

this is associated with sudden cardiac arrests [27]. Accord-

ing to examinations conducted as a part of preoperative

evaluation, children with Williams syndrome can be classi-

fied to have a low, moderate, or high risk. However, regard-

less of the risk classification, anesthetic management is

performed while attempting to maintain sinus rhythm, and

ensuring the maintenance of contractility, restoration of

intravascular volume deficit, and preservation of SVR [27].

Therefore, the choice of anesthetic agents must be guided

by whether a drug induces abrupt hemodynamic perturba-

tion.

CARDIOMYOPATHY

Children with cardiomyopathy and ventricular dysfunc-

tion are classified to have high perioperative mortality and

morbidity risks related to anesthesia [8]. Based on the

POCA registry, cardiomyopathy contributed to 13% of

perioperative cardiac arrests [5]. The etiology of cardiomy-

opathy includes idiopathic causes (hypertrophic, restric-

tive, and dilated), structural heart disease (such as CHD

including single ventricular physiology), and secondary

disorders (such as end-stage renal disease and congenital

heart block) [28]. Among these children, there may be an

increased risk of preoperative morbidity and mortality

when ventricular dysfunction is caused by dilated cardio-

myopathy, failing Fontan circulation, left ventricular out-

flow obstruction, and pulmonary hypertension. General

anesthesia may induce hemodynamic instability even at

regular doses of anesthetic agents because ventricular

functional reserve is severely compromised. Ketamine is

recommended as the choice of induction agent because

the sympathetic tone is preserved. In addition, balanced

anesthesia is beneficial for achieving hemodynamic stabil-

ity using opioids, volatile agents, neuromuscular blockade,

or a combination of these agents [29]. In children with car-

diomyopathy, the anesthetic goal is to maintain the pre-

load, sinus rhythm, SVR, ventricular contractility, and cor-

onary perfusion. Inotropic and vasoactive drugs may be

frequently required to manage hypotension and low cardi-

ac output. It is important that an excessively elevated SVR

be avoided because an impaired ventricle with limited

Anesthesia Surgical stimulationMechannical ventilation

HypoxiaHypercarbia

AcidosisSympathetic stimulation

Rapid increase PAP and PVR

Right heart failure, Rt-Lt shunting further

hypoxia

Myocardial ischemia, low cardiac output, increased

airway resistance

Shock,Cardiac arrest and

death

Pulmonary hypertension:mean PAP > 25 mmHg or > 50% of SAP

Fig. 2. A vicious cycle of pulmonary hypertensive crisis. During general anesthesia and surgical procedures, conditions of hypoxia, hypercarbia, acidosis, hypothermia, and sympathetic stimulation can induce a further increase in pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR), thereby triggering a vicious cycle of pulmonary hypertensive crisis. SAP: systemic artery pressure.

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Risks associated with congenital heart disease

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contractile reserve is not tolerant of a high afterload [30].

CONCLUSION

Children with CHD, particularly single ventricular physi-

ology, suprasystemic pulmonary hypertension, left ventric-

ular outflow obstruction, and cardiomyopathy with ven-

tricular dysfunction, have the highest morbidity and mor-

tality risks following noncardiac surgeries. During the pre-

operative evaluation of these patients, it is necessary to

identify whether residual functional or anatomical impair-

ment is present at the time of surgery. To prevent poor out-

comes and avoid worse-case scenarios, anesthesiologists

should be fully acquainted with the pathophysiology of

CHD and be able to respond to intraoperative events and

complications during surgery in a timely manner.

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article

was reported.

AUTHOR CONTRIBUTIONS

Conceptualization: Won-Jung Shin, In-Kyung Song. Writ-

ing - original draft: In-Kyung Song. Writing - review & edit-

ing: Won-Jung Shin.

ORCID

In-Kyung Song, https://orcid.org/0000-0002-7699-2005

Won-Jung Shin, https://orcid.org/0000-0002-6790-3859

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Risks associated with congenital heart disease

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INTRODUCTION

Synthetic glucocorticoids were first introduced in 1949

after the development of a purified preparation, known as

cortisone, and became a revolutionary treatment for pa-

tients with primary adrenal failure and other acute-chronic

inflammatory and autoimmune diseases. In anesthesiolo-

gy, it is widely used to treat reactive airway diseases, acute

nerve injury, nausea or vomiting, inflammatory diseases,

and excessive immunosuppression during organ trans-

Corresponding author Kwon Hui Seo, M.D., Ph.D. Department of Anesthesiology and Pain Medicine, Hallym University Sacred Heart Hospital, Hallym University School of Medicine, 22 Gwanpyeong-ro 170beon-gil, Dongan-gu, Anyang 14068, Korea Tel: 82-31-380-5959 Fax: 82-31-385-3244 E-mail: [email protected]

Glucocorticoid preparations, adreno-cortical steroids, with strong anti-inflammatory and im-munosuppressive effects, are widely used for treating various diseases. The number of pa-tients exposed to steroid therapy prior to surgery is increasing. When these patients present for surgery, the anesthesiologist must decide whether to administer perioperative steroid supplementation. Stress-dose glucocorticoid administration is required during the perioper-ative period because of the possibility of failure of cortisol secretion to cope with the in-creased cortisol requirement due to surgical stress, adrenal insufficiency, hemodynamic in-stability, and the possibility of adrenal crisis. Therefore, glucocorticoids should be supple-mented at the same level as that of normal physiological response to surgical stress by eval-uating the invasiveness of surgery and inhibition of the hypothalamus-pituitary-adrenal axis. Various textbooks and research articles recommend the stress-dose of glucocorticoids during perioperative periods. It has been commonly suggested that glucocorticoids should be administered in an amount equivalent to about 100 mg of cortisol for major surgery be-cause it induces approximately 5 times the normal secretion. However, more studies, with appropriate power, regarding the administration of stress-dose glucocorticoids are still re-quired, and evaluation of patients with possible adrenal insufficiency and appropriate gluco-corticoid administration based on surgical stress will help improve the prognosis.

Keywords: Adrenal glands; Adrenal insufficiency; Glucocorticoids; Hypothalmus; Periopera-tive period; Pituitary gland; Steroids.

Perioperative glucocorticoid management based on current evidence

Kwon Hui Seo

Department of Anesthesiology and Pain Medicine, Hallym University Sacred Heart

Hospital, Hallym University School of Medicine, Anyang, KoreaReceived November 16, 2020Accepted November 30, 2020

ReviewAnesth Pain Med 2021;16:8-15https://doi.org/10.17085/apm.20089pISSN 1975-5171 • eISSN 2383-7977

plantation or cardiopulmonary bypass [1]. Shortly after the

development of synthetic cortisone, there were two case

reports of perioperative secondary adrenal crisis. The two

young patients on chronic cortisone therapy stopped ste-

roids before the surgery; they suddenly died after the sur-

gery, and the result of the autopsy showed bilateral adrenal

atrophy [2,3]. Since then, it has become common practice

to perioperatively administer glucocorticoids at a su-

pra-physiological dose, the so-called stress-dose, to pa-

tients on steroid therapy for long duration and in suspected

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Copyright © the Korean Society of Anesthesiologists, 2021

8

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adrenal failure cases.

The number of patients exposed to steroid therapy prior

to surgery is increasing as corticosteroids are widely used

for systemic administration and as inhalation and topical

drugs [4]. Accordingly, clinical trials and retrospective

analyses have been conducted regarding stress-dose glu-

cocorticoids administration in the perioperative period for

patients on steroid therapy [5,6]. However, many clinical

trials had a low level of evidence, including unclear criteria

for adrenal failure with a limited number of patients, re-

sulting in various proposed recommendations for the ad-

ministration of glucocorticoids in the perioperative periods

[7]. Therefore, this article reviews the physiology of adre-

no-cortical hormones and indications and applications of

stress-dose glucocorticoids in the perioperative periods

based on recently published recommendations [7,8].

PHYSIOLOGY OF ADRENOCORTICAL HORMONE SECRETION:

HYPOTHALAMUS-PITUITARY-ADRENAL AXIS

Adrenocorticosteroids are steroid derivatives produced in

the adrenal cortex and include three endogenous hormones:

glucocorticoid, mineralocorticoid, and androgen. All of

them are synthesized when cholesterol is converted to preg-

nenolone by the cytochrome P450 enzyme [1]. Of these, glu-

cocorticoids are secreted from the zona fasciculata of the

adrenal cortex and the most important glucocorticoid is cor-

tisol. Cortisol is an essential hormone for maintaining life. It

mediates carbohydrate and protein metabolism, fatty acid

transfer, electrolyte and fluid balance, and anti-inflammato-

ry reactions. Cortisol enables the synthesis and release of

catecholamines and contributes to normal vascular perme-

ability, vascular tone, and myocardial contraction by regu-

lating β-receptor synthesis and regulation [1].

The secretion of adrenal cortical hormones is regulated

by the hypothalamic-pituitary-adrenal (HPA) axis. The cor-

ticotropin-releasing hormone (CRH) secreted from the hy-

pothalamus stimulates the secretion of adrenocortico-

tropic hormone (ACTH) in the anterior pituitary gland, and

ACTH stimulates the adrenal gland. This positive feedback

for cortisol secretion and negative feedback for inhibiting

the secretion of CRH and ACTH due to increased cortisol

concentration regulates the secretion of cortisol [1].

The secretion of cortisol changes depending on the pul-

satile secretion of CRH and ACTH according to the circadi-

an rhythm. Serum cortisol concentration reaches the high-

est concentration of about 15 μg/dl around 6–9 am, then

drops to the lowest concentration of below 2 μg/dl around

11 pm to 1 am. The median value of the 24-h period is ap-

proximately 5.2 μg/dl [9]. In normal adults, the adrenal

glands produce approximately 5 to 10 mg/m2/day (body

surface area per day) of cortisol, which is equivalent to 5 to

7 mg of oral prednisone or 20 to 30 mg of hydrocortisone

[10,11]. In plasma, approximately 90% of circulating corti-

sol binds to corticosteroid-binding globulin (CBG), an

α2-globulin binding protein synthesized in the liver [12].

The remaining 5–10% binds to albumin or circulates freely

and exerts an effect on target cells. When plasma cortisol

concentration exceeds 20–30 μg/dl, CBG is saturated, and

the concentration of free cortisol increases rapidly [12].

Sudden physiological and mental stress such as trauma,

burns, major surgery, hypoglycemia, high fever, low blood

pressure, severe exercise, and cold exposure activates the

HPA axis and increases blood ACTH and cortisol levels. In

a normal response to stress, the blood cortisol concentra-

tion increases to 18–20 μg/dl and adrenal cortisol secretion

increases up to 30–45 μg/dl during moderately stressful sit-

uations and about 260 μg/dl in a highly stressful life-threat-

ening situation. Increased cortisol levels normalize within

approximately 24 to 48 h after the stress is resolved [11].

ADRENAL INSUFFICIENCY

Adrenal insufficiency (AI) is the inability of the adrenal

glands to produce adequate amounts of corticosteroids in

response to various pathophysiologic states; this condition

can be classified into primary, secondary, and tertiary AI

depending on the cause [11]. Primary AI is an abnormality

in the adrenal gland itself and is caused by the destruction

of the adrenal cortex due to autoimmune diseases, viral

and tuberculosis infection, hemorrhage, metastatic cancer,

and sepsis. Secondary AI is rare but is caused by impaired

production of ACTH or CRH due to damage or dysfunction

caused by diseases of the pituitary gland or hypothalamus.

Tertiary AI is the most common form, widely included in

secondary AI, and is typically caused by inhibition of the

hypothalamus or pituitary due to iatrogenic corticosteroid

therapy; the degree of adrenal dysfunction is variable and

sometimes reversible. In these patients, mineralocorticoid

secretion is not affected and only cortisol production is re-

versibly inhibited [13]. Tertiary AI rarely occurs when oral

prednisone dosage is less than 5 mg or when steroid is tak-

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Perioperative glucocorticoid management

Page 18

en for a short period of less than 2 weeks, regardless of the

dosage. However, AI has been reported to occur in more

than 60% of patients taking high-dose oral prednisone ( >

40 mg) even after only about 6 days [11,14].

Clinical signs of adrenal crisis

Patients with long-term steroid administration or severe

illness have a reduced cortisol response to stress, which

causes risk of an acute adrenal crisis. Symptoms of acute

adrenal crisis in awake patients are presented in Table 1

[15]. In patients under anesthesia, hypotension, which

does not respond to fluid administration, has been consid-

ered the most important sign of perioperative adrenal crisis

[7]. Symptoms and signs that occur earlier than hypoten-

sion include non-specific changes in consciousness and

cognitive decline and persistent fever [8]. Laboratory ex-

aminations may show hypoglycemia, hyponatremia, and

hyperkalemia. Since most of these symptoms are non-spe-

cific, it is necessary to exclude causes other than AI. How-

ever, since adrenal crisis is a life-threatening condition, it

should be immediately recognized and corrected by the

administration of stress-doses of steroids, fluids, and vaso-

pressors [8].

SURGERY INDUCED CORTISOL STRESS RESPONSE

Surgery causes a stress response with a wide range of en-

docrine, immune, and cardiovascular effects. During major

surgery, proinflammatory cytokines, CRH, ACTH, and cor-

tisol levels increase proportionally, resulting in an increase

in cortisol secretion up to approximately 5–10 times the

normal secretion, that is, 75–150 mg/day [16,17]. After sur-

gery, the diurnal secretion of cortisol malfunctions tempo-

rarily, and the serum concentration of cortisol rises due to

surgical stress [11].

In a recent meta-analysis, the change in serum cortisol

concentration before and after surgery in patients without

steroid therapy was analyzed in 71 studies since the 1990s

[18]. In this study, the invasiveness of surgery was divided

into three stages from grade 1 to 3 according to the modi-

fied Johns Hopkins surgical criteria [19]. Minor to moder-

ately invasive procedures with less bleeding (potential

blood loss < 500 ml) were included in grade 1; for example,

breast biopsy, removal of minor skin or subcutaneous le-

sions, myringotomy tubes, hysteroscopy, cystoscopy, va-

sectomy, circumcision, fiberoptic bronchoscopy, diagnos-

tic laparoscopy, dilatation, and curettage. Moderately to

significantly invasive procedures (potential blood loss 500–

1,500 ml) were included in grade 2; for example, thyroidec-

tomy, hysterectomy, myomectomy, cystectomy, cholecys-

tectomy, laminectomy, hip/knee replacement, nephrecto-

my, and major laparoscopic procedures. Highly invasive

procedures (potential blood loss > 1,500 ml) were included

in Grade 3, for example, major reconstruction of the gas-

trointestinal tract, major genitourinary surgery, cardiotho-

racic procedures, and intracranial procedures. In this re-

view, it was found that the grade of surgery significantly af-

fected cortisol secretion [18]. Patients undergoing grade 1

surgery did not show an intraoperative cortisol peak, and

postsurgical cortisol concentrations were similar to those

at baseline. Nevertheless, when compared to published

data on healthy, unstressed adults, the mean cortisol out-

put over the first 24 h after grade I surgical procedure was

approximately doubled. Patients undergoing grade 2 and 3

surgery had 3.5–4 times higher cortisol output than that of

healthy, unstressed individuals within the first 24-h post-

operative period. Moreover, in both grade 2 and 3 surger-

ies, mean cortisol values remained elevated in comparison

with the baseline measurements up to postoperative day 7.

Due to ethical issues, only a few studies have investigated

the change in cortisol concentration and the incidence of

AI after discontinuation of steroids in patients taking ste-

roids. In 1973, Kehlet and Binder [16] investigated the oc-

currence of acute AI after steroid discontinuation in 73 pa-

tients undergoing major surgery, including splenectomy

and colon resection. Patients took 5–80 mg of prednisone

for various periods in this study. As a result, about 10% of

patients developed perioperative hypotension, but only 3

patients showed low blood cortisol levels, and most of

them were treated by fluid administration. They also mea-

sured cortisol concentration in patients undergoing major

Table 1. Signs of Adrenal Crisis [15]

Signs of adrenal crisis

Dehydration, hypotension

Nausea and vomiting with a history of weight loss and anorexia

Abdominal pain (“acute abdomen”)

Unexplained hypoglycemia

Unexplained fever

Hyponatremia, hyperkalemia, azotemia, hypercalcemia, eosinophilia

Hyperpigmentation or vitiligo

Other autoimmune endocrine deficiencies (hypothyroidism or gonad-al failure)

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abdominal surgery and minor procedures such as hand

surgery or uterine curettage, and estimated cortisol secre-

tion due to surgical stress was found to be 75–150 mg/day

and 50 mg/day for major and minor surgeries, respectively.

The results of this study formed the rationale for subse-

quent recommendations of perioperative glucocorticoid

supplementation [7,20].

De Lange and Kars [5] and Khazen and El-Hussuna [6]

investigated the incidence of AI following administration of

stress-doses or conventional maintenance doses of gluco-

corticoids based on prospective and retrospective studies.

The randomized controlled trials included in their me-

ta-analysis mostly targeted minor to moderate surgery with

a limited number of patients, and both meta-analyses con-

cluded that the incidence of perioperative AI was very low

[5,6]. These studies reported that patients taking less than

5–10 mg/day of prednisone did not have adverse side effect

of AI, even if only the daily dose was maintained during

relatively less invasive surgery [21–23].

PHYSIOLOGICAL RATIONALE FOR PERIOPERATIVE GLUCOCORTICOID

SUPPLEMENTATION

Despite the low incidence of surgery-induced AI, several

major pathophysiologic mechanisms support the necessity

of glucocorticoid administration in the perioperative period.

Vascular tone and maintenance of blood pressure

Glucocorticoids have a permissive effect on vascular

tone and maintenance of blood pressure [24]. Glucocorti-

coids alone do not increase blood pressure, but when ad-

ministered with a vasopressor, glucocorticoids enhance

vascular reactivity to vasopressors. The effect of glucocorti-

coid on vascular tone is exerted by inhibition of the synthe-

sis of prostacyclin I2 (PGI2), a potent vasodilator, in the vas-

cular endothelium [25]. If the inhibitory effect on vascular

tone disappears due to a decrease in cortisol response, it

may lead to increased production of PGI2, vasodilation,

and hypotension.

Catecholamine synthesis and secretion

Cortisol is involved in catecholamine synthesis and me-

diates the release of catecholamine from sympathetic

nerve cells by directly regulating the activity of phenyletha-

nolamine N-methyltransferase, an enzyme that catalyzes

the conversion of norepinephrine to epinephrine in the

adrenal medulla [26]. Cortisol also mediates catechol-

amine release from sympathetic cells [27].

Myocardial contractility

Cortisol helps the myocardium adapt to perioperative

stress [28]. In animal studies, acute adrenal failure caused

reduced myocardial contractility due to a decrease in the

activity of myofibrillar adenosine triphosphatase, which is

directly dependent on glucocorticoids [29]. In patients with

hemodynamically unstable secondary AI, bolus intrave-

nous hydrocortisone increases the stroke work index of the

left ventricle [30].

SYNTHETIC ADRENOCORTICOIDS

All synthetic glucocorticoids are derivatives of cortisol,

an endogenous glucocorticoid. Drugs used as therapeutic

glucocorticoids include hydrocortisone, prednisolone, and

dexamethasone (Table 2) [1]. Among these drugs, hydro-

cortisone, which has the same structure as cortisol, is the

most commonly used synthetic glucocorticoid. Prednisone

is an inactive prodrug that is activated to prednisolone by

11β-hydroxysteroid dehydrogenase after administration

[31]. Synthetic corticosteroids have different glucocorticoid

and mineralocorticoid activities. Table 2 shows the relative

efficacy of commonly used corticosteroids compared to

Table 2. Relative Potency of Synthetic Steroids [1]

Drugs Glucocorticoid activity Mineralocorticoid activity Equivalent dose (mg) Duration of action (h)

Hydrocortisone (cortisol) 1 1 20 8–12

Prednisone 4 0.8 5 12–36

Prednisolone 4 0.8 5 12–36

Methylprednisolone 5 0.5 4 12–36

Dexamethasone 30–40 0 0.5–0.75 36–54

Fludrocortisone 10 250 2 24

Aldosterone 0 3000

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Perioperative glucocorticoid management

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that of hydrocortisone [1]. When adrenal gland function is

reduced, corticosteroids are used to replace both glucocor-

ticoids and mineralocorticoids. Therefore, in patients with

primary AI in which mineralocorticoids are not secreted,

dexamethasone is not appropriate and synthetic mineralo-

corticoids, fludrocortisone, and hydrocortisone should be

administered [7]. Secondary and tertiary AI are caused by a

lack of glucocorticoids, so the administration of drugs with

mineralocorticoid activity may cause side effects such as

dose-dependent edema, fluid retention, and hypokalemia

[7]. Therefore, when a high dose of hydrocortisone of 100

mg or more is required in patients with secondary and ter-

tiary AI, switching to a drug with a higher glucocorticoid

activity ratio than that of mineralocorticoid such as meth-

ylprednisolone should be considered [24].

Side effects of prolonged administration of high dose of glucocorticoid

Continuous administration of high doses of glucocorti-

coids after surgery can cause unwanted side effects [31].

Glucocorticoids promote gluconeogenesis in the liver and

proteolysis and adipolysis in muscles, resulting in hyper-

glycemia. In addition, continuous glucocorticoid adminis-

tration results in sodium retention, subsequent plasma

volume increase, and intensifies vasopressor response to

angiotensin II and catecholamines, leading to hyperten-

sion [32]. Glucocorticoids inhibit cytokine signaling and

the synthesis of matrix metalloproteinases and collagen,

which play an important role in wound healing [33]. In ad-

dition, it can cause gastrointestinal bleeding and various

psychiatric symptoms [7]. However, most side effects occur

in proportion to the duration of glucocorticoid administra-

tion, therefore, the incidence of side effects after short-

term treatment is low even with high doses.

PERIOPERATIVE STRESS-DOSE GLUCOCORTICOID

Glucocorticoids should be administered during the

perioperative period because cortisol secretion in response

to surgical stress may fail, resulting in AI, hemodynamic

instability, and adrenal crisis. Therefore, the dose of gluco-

corticoid should be administered at the same level as that

of normal physiological response to the surgical stress after

evaluating the invasiveness of surgery and inhibition of the

HPA axis [24]. If there is no suppression of the HPA axis or

the requirement due to surgical stress does not exceed the

maintenance dose of glucocorticoids already being taken,

a perioperative stress-dose of glucocorticoid is not re-

quired unless the patient shows signs of AI [7]. However,

when glucocorticoid requirement increases rapidly due to

surgical stress, and the inhibition of the HPA axis is clini-

cally important, the administration of stress doses should

be considered [7,8].

Approach according to HPA axis suppression

1. Nonsuppressed HPA axis

Steroid dose and duration affect HPA axis suppression.

Regardless of duration, the risk of HPA axis suppression is

low if the prednisone dose taken in the morning does not

exceed 5 mg/day (≈ methylprednisolone 4 mg/day, dexa-

methasone 0.5 mg/day, hydrocortisone 20 mg/day) or 10

mg of prednisone every other day. In addition, if any dose

of glucocorticoid is administered for less than three weeks,

the HPA axis is less likely to be suppressed. These patients

do not require additional administration of glucocorticoids

or tests to assess the HPA axis [7].

2. Patients with suppressed HPA axis

Patients on daily dose of prednisone exceeding 20 mg for

a period of more than three weeks and patients with symp-

toms of Cushing syndrome who are taking glucocorticoids

are at high risk of HPA axis suppression [7]. These patients

should be administered perioperative supplemental gluco-

corticoids according to the invasiveness of surgery [7].

3. Unknown HPA axis suppression

Besides these patients, patients taking prednisone at

5–20 mg/day or equivalent doses over a period of three or

more weeks may experience various ranges of HPA axis

suppression depending on their age, and dosage and dura-

tion of administration [34]. Even in cases with discontin-

ued exposure of steroids, patients who inhaled high-dose

steroids or high-potency topical steroids should be tested

for adrenal function preoperatively and supplemental glu-

cocorticoids should be administered based on the results

of the test. There is a risk of HPA axis inhibition when in-

haled glucocorticoid fluticasone ≥ 750 μg/day (or beclo-

methasone ≥ 1,500 μg/day ≈ prednisolone ≥ 10 mg/day) is

administered for more than 3 weeks before surgery [35,36].

The absorption rate of topical steroids varies depending on

the period of use, strength, and application site, but when

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topical steroids with high potency are used for > 2 g/day

for more than 2 weeks, suppression of the HPA axis may

occur [37]. In addition, patients who have received three or

more intra-articular or spinal glucocorticoid injections

within three months prior to surgery, have symptoms of AI,

or Cushing's syndrome, the HPA axis needs to be evaluated

[38].

Assessment of HPA axis suppression

1. Morning serum cortisol

Measurement of morning serum cortisol concentrations

before 8 am after stopping glucocorticoids for 24 h is a

good screening test for assessing secondary and tertiary AI

symptoms [39]. If the morning serum cortisol concentra-

tion is lower than 5 μg/dl, suppression of the HPA axis may

be suspected and the administration of additional gluco-

corticoids is required [7]. If the morning cortisol concen-

tration is greater than 10 μg/dl, it can be considered that

there is no inhibition of the HPA axis, and the usual dose of

glucocorticoid is taken until the day of surgery and no ad-

ditional administration is required [7]. If the morning corti-

sol concentration is 5 to 10 μg/dl, ACTH stimulation tests

are conducted, or glucocorticoids are administered based

on experience.

2. Short ACTH stimulation tests

The ACTH stimulation test determines whether adrenal

function is inhibited by administering synthetic ACTH (co-

syntropin 250 μg); the concentration of serum cortisol are

measured 30 min after the administration of ACTH [24]. If

cortisol concentration is higher than 18 μg/dl, it can be deter-

mined that proper adrenal function is maintained and addi-

tional administration of glucocorticoid is not required [7].

RECOMMENDED DOSE OF GLUCOCORTICOID ACCORDING TO

SURGICAL STRESS

Based on recent studies, recommendations were pub-

lished in Anesthesiology in 2017 and Anaesthesia in 2020

[7,8]. As presented in Table 3, Liu et al. proposed recom-

mendations based on estimated daily cortisol secretions

according to the invasiveness of surgery [7,16,17].

Recently, the Royal College of Anaesthetists and the En-

docrinology Society of the United Kingdom also published

guidelines in Anaesthesia [8], but they are different from

those of Liu et al. [7]. They have similarity in that they rec-

ommend administering stress-dose steroids to patients

with primary and secondary AI and HPA axis suppression.

However, they recommended 100 mg of hydrocortisone for

all patients undergoing minor procedures as well as major

surgeries [8]. After the publication of this recommendation,

when questions arose about administering the same dose

for a relatively simple operation [40], the authors respond-

ed that this dose may not be appropriate for simple proce-

Table 3. Surgical Stress according to Procedures and Recommended Dosing of Glucocorticoid [7]

Type of surgery Estimated cortisol secretion rate Examples Recommended dosing

Superficial 8–10 mg/day Dental surgery Usual daily dose

Biopsy

Minor 50 mg/day Inguinal hernia repair Usual daily dose plus

Colonoscopy

Uterine curettage Hydrocortisone 50 mg IV before incision

Hand surgery Hydrocortisone 25 mg IV every 8 h × 24 h

Moderate 75–150 mg/day Lower extremity revascularization Then usual daily dose

Total joint replacement

Cholecystectomy

Colon resection

Abdominal hysterectomy

Major 75–150 mg/day Esophagectomy Usual daily dose plus

Total proctocolectomy Hydrocortisone 100 mg IV before incision

Major cardiac/vascular surgery Followed by continuous IV hydrocortisone 200 mg (> 24 h)

Hepaticojejunostomy or

Delivery Hydrocortisone 50 mg IV every 8 h × 24 h

Trauma Taper dose by half per day until usual daily dose reached

IV: intravenously.

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Perioperative glucocorticoid management

Page 22

dures [41]. Therefore, we can only refer to their recommen-

dations for major surgery. According to this guideline, for

patients undergoing major surgery, hydrocortisone 100 mg

or dexamethasone 6–8 mg should be administered at time

of induction of anesthesia, followed by immediate initia-

tion of a continuous infusion of hydrocortisone 200 mg/

day until the patients can be administered double the

pre-surgical oral dose [8].

CONCLUSION

Cortisol has a variety of critical physiological actions,

and an increase in concentration due to surgical stress is

important for maintaining hemodynamic stability during

surgery. Although studies with more appropriate evidence

are still required, evaluation of patients with possible AI

and glucocorticoid administration according to surgical

stress is crucial and can improve prognosis.

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article

was reported.

ORCID

Kwon Hui Seo, https://orcid.org/0000-0003-4397-9207

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INTRODUCTION

Corticosteroids are very attractive as drugs for many

musculoskeletal diseases because of their potent anti-in-

flammatory effect. Epidural steroid injection (ESI) is widely

used to treat various back pain conditions such as herniat-

ed intervertebral disc and spinal stenosis. Corticosteroids

have been used to treat spinal diseases for a long time. Ini-

tially, they were delivered into intrathecal space in 1954 [1].

However, because of the transient pharmacological effect,

the injection route of corticosteroids was changed into epi-

dural space. Several studies have supported the efficacy of

ESI in spinal disease [2–4]. Transforaminal epidural steroid

injection (TFESI) is used to relieve pain and reduce the po-

tential need for surgery [5,6]. Radicular pain is caused not

only by mechanical compression but also due to inflam-

Corresponding author Ho Sik Moon, M.D., Ph.D. Department of Anesthesiology and Pain Medicine, Eunpyeong St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 1021 Tongil-ro, Eunpyeong-gu, Seoul 03312, Korea Tel: 82-2-2030-3864Fax: 82-2-2030-3861E-mail: [email protected]

Spine disease is one of the most common musculoskeletal diseases, especially in an aging society. An epidural steroid injection (ESI) is a highly effective treatment that can be used to bridge the gap between physical therapy and surgery. Recently, it has been increasingly used clinically. The purpose of this article is to review the complications of corticosteroids administered epidurally. Common complications include: hypothalamic-pituitary-adrenal (HPA) axis suppression, adrenal insufficiency, iatrogenic Cushing’s syndrome, hyperglyce-mia, osteoporosis, and immunological or infectious diseases. Other less common complica-tions include psychiatric problems and ocular ailments. However, the incidence of complica-tions related to epidural steroids is not high, and most of them are not serious. The use of nonparticulate steroids is recommended to minimize the complications associated with epi-dural steroids. The appropriate interval and dosage of ESI are disputed. We recommend that the selection of appropriate ESI protocol should be based on the suppression of HPA axis, which reflects the systemic absorption of the corticosteroid.

Keywords: Drug-related side effects and adverse reactions; Epidural injections; Glucocorti-coids; Guideline; Review; Safety.

Safety of epidural steroids: a review

Min Soo Lee and Ho Sik Moon

Department of Anesthesiology and Pain Medicine, College of Medicine, The Catholic

University of Korea, Seoul, Korea

Received January 1, 2021Revised January 18, 2021 Accepted January 18, 2021

ReviewAnesth Pain Med 2021;16:16-27https://doi.org/10.17085/apm.21002pISSN 1975-5171 • eISSN 2383-7977

mation of the affected nerve roots because the nucleus

pulposus of the intervertebral disc evokes an immune re-

action mediated via inflammatory molecules [7]. Thus the

rationale for using corticosteroids in epidural block is es-

tablished [8].

The complications associated with corticosteroid use are

as many as their therapeutic effects. However, most com-

plications related to ESI are not serious. Lee et al. [9] ana-

lyzed 52,935 ESI procedures performed in 22,059 patients

and found no major adverse events. Similarly, no major

adverse events were detected in another single-center

study of 1,300 lumbar transforaminal epidural injections.

Kang et al. [10] surveyed complications of 825 patients who

were treated with dexamethasone epidurally. Forty pa-

tients (4.8%) showed systemic but minor and transient side

effects of corticosteroids including facial flushing (1.5%),

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Copyright © the Korean Society of Anesthesiologists, 2021

16

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urticaria (0.8%), and insomnia (0.8%). Serious complica-

tions such as adrenal insufficiency (AI), Cushing's syn-

drome, neurological accidents, and osteonecrosis have

been reported rarely [11,12]. Because these complications

cause irreversible sequelae, pain physicians need to be

cognizant of the side effects of corticosteroids and their

prevention.

ESI is a valuable procedure used to treat spinal pain. Al-

though systemic side effects of treatment with long-term

oral administration of steroids are well established, the

pharmacology and side effects associated with ESI are

poorly understood. This review summarizes the complica-

tions of epidural steroids and techniques as well as related

mechanical injury.

PHARMACOLOGIC PROPERTIES OF EPIDURAL STEROIDS

Pathophysiology of radiculopathy

Radiculopathy is caused by inflammation and the me-

chanical compression of the nerve root. Inflammation

plays a major role in the evolution of radiculopathy [13].

Clinically, a large herniation of an intervertebral disc asso-

ciated with significant neural compression may be asymp-

tomatic, whereas severe radicular pain may exist without

detectable root compression. Also, the size or shape of her-

niation, and eventual change in size or shape does not cor-

relate with clinical presentation or course [14,15]. This

shows the importance of inflammation in the pathophysi-

ology of radiculopathy. The damaged structures release

various inflammatory mediators, which trigger inflamma-

tory reaction in the spine. For instance, the damaged facet

joints release bradykinin, serotonin, norepinephrine, and

interleukin (IL)-1. Also, the nerve endings of the posterior

longitudinal ligament, outer annulus, facet capsule, or

periosteum release substance P, vasoactive intestinal pep-

tide, and calcitonin gene-related peptide. The nucleus pul-

posus generates inflammatory mediators, including phos-

pholipase A2 (PLA2), prostaglandin E2, IL-1α, IL-1β, IL-6,

tumor necrosis factor, and nitric oxide, and it is well known

that discogenic pain is mediated by these inflammatory

mediators and neovascularization induced by chemical

signaling [8,16]. PLA2 is the rate-limiting factor involved in

the synthesis of arachidonic acid, which is the principal

substrate in the cyclo-oxygenase and lipo-oxygenase path-

ways. Prostaglandins, along with other arachidonic acid

byproducts, can cause or exacerbate pain mediated via in-

flammatory mechanisms and sensitization of peripheral

nociceptors [17,18]. Among the inflamed structures, the

dorsal root ganglion is more sensitive to mechanical pres-

sure than the nerve root [16].

Rationale for the use of epidural corticosteroids in radiculopathy

The therapeutic effects of corticosteroids in radiculopa-

thy are yet to be fully understood. Until now, several mech-

anisms have been proposed: inhibition of leukocyte func-

tion; alleviation of inflammatory events such as edema, fi-

brin deposition, capillary dilatation, leukocyte aggregation,

phagocytosis, capillary and fibroblast proliferation, colla-

gen deposition and cicatrization; inhibition of the synthe-

sis of pro-inflammatory substances like PLA2; inhibition of

the activity of lymphokines; inhibition of the display of

chemotactic molecules on the surface of the endothelial

cells; and minimization of endothelial injury [16]. In addi-

tion to their anti-inflammatory effects, corticosteroids may

inhibit pain via suppression of ectopic discharges from in-

jured nerves and decreased conduction in normal unmy-

elinated C fibers [19].

Pharmacokinetics of epidural steroids

The elimination half-life of triamcinolone acetonide 80

mg following interlaminar epidural injection is 506 ± 255

h, and the time to maximum concentration (Tmax) is 37.5 ±

37.5 h [20]. These pharmacokinetic properties of epidural

steroids vary depending on the route of administration.

The elimination half-life after oral, intravenous, intraartic-

ular, and intravitreal injection of triamcinolone varies: oral,

2.6 h [21]; intravenous, 2.0 h [21]; intraarticular knee injec-

tion, 77–154 h [22]; and intravitreal, 446 h [23]. The differ-

ences between oral/intravenous and intraarticular/intrav-

itreal/epidural administration of triamcinolone appear to

be due to its particulate form. Interestingly, in the case of

cervical interlaminar epidural injection with triamcinolone

acetonide 80 mg, the elimination half-life was 310 ± 212 h

and Tmax was 22.8 ± 13.1 h, which was shorter than that of

lumbar ESI due to the cervical epidural vasculature [24].

Current evidence suggests that more soluble glucocorti-

coids have shorter duration of systemic effect than less sol-

uble glucocorticoids [25]. Intramuscular administration of

dexamethasone is followed by partial absorption into the

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Safety of epidural steroid injection

Page 26

systemic circulation and the biological half-life of dexa-

methasone is 5.2 ± 0.4 h [26]. Unfortunately, there has

been no study on the pharmacokinetic features of epidural

dexamethasone, and further research is required.

ENDOCRINOLOGICAL COMPLICATIONS

HPA axis suppression, AI, and iatrogenic Cushing’s syndrome

Glucocorticoids are synthesized in the adrenal cortex

under the regulation of the HPA axis. They are produced on

demand and not stored in body. The glucocorticoid syn-

thesis is inhibited by three mechanisms. First, the rapid

feedback (less than 10 min) is sensitive to changes in circu-

lating glucocorticoids and not to the absolute levels of ste-

roid. Second, early delayed feedback (30 min to 2 h) is as-

sociated with the suppression of adrenocorticotropic hor-

mone (ACTH) synthesis, which is affected by the concen-

tration of circulating glucocorticoids. Third, late delayed

feedback (about a day) is related to high concentration of

glucocorticoids, persisting for days or weeks [27].

HPA axis suppression occurs in most of the patients who

receive ESI, and most of them recover within 2–4 weeks

[28–32]. This complication is likely to be asymptomatic and

does not require treatment in most cases. Studies involving

orally administered corticosteroids have shown that the

treatment dose or duration is not correlated with the sever-

ity of HPA axis suppression and reported substantial indi-

vidual variation in clinical effects depending on age and

co-existing disease [33]. However, the results of ESI differed

from the effects of oral corticosteroid intake. Sim et al. [30]

conducted a randomized controlled trial comparing the

HPA axis suppression under different dosages of epidural

triamcinolone (40 mg vs. 20 mg) and showed that the HPA

suppression in the triamcinolone 40 mg group (19.7 ± 3.1

days) was longer than in the group treated with triamcino-

lone 20 mg (8.0 ± 2.4 days), and the recovery rate of the tri-

amcinolone 40 mg group was lower than in the triamcino-

lone 20 mg group (P = 0.015). However, the extent of HPA

axis reduction, i.e., the difference between salivary cortisol

(SC) concentration before ESI and SC concentration on

day 1 after ESI was not affected by the dosage of corticoste-

roid [30]. The type of corticosteroid also affects the HPA

axis suppression. Friedly et al. [25] reported that HPA axis

suppression was more likely with longer-acting insoluble

corticosteroid formulations such as methylprednisolone or

triamcinolone than betamethasone and dexamethasone.

However, patient demographics did not influence the du-

ration of HPA axis suppression [25].

Secondary AI is known as a rare disease (0.00015–

0.00028%) [34]. Its mortality is two-fold higher than in gen-

eral population, which is associated with infection or adre-

nal crisis [34]. The common symptoms of AI are fatigue,

loss of appetite, weight loss, nausea, vomiting, abdominal

pain, and muscle and joint pain, which are nonspecific and

therefore do not facilitate easy diagnosis. Moreover, specif-

ic symptoms such as hyperpigmentation, salt craving, and

postural hypotension are uncommon in AI induced with

exogenous glucocorticoids because of intact mineralocor-

ticoid axis [35]. Therefore, an early diagnosis of iatrogenic

AI is challenging for physicians. Park et al. reported that

11.8% of patients who were treated with long-term ESI be-

yond 6 months developed secondary AI, although they did

not show AI symptoms [28]. The average number of ESIs

per year in the AI group was 7.7 ± 1.3/yr and in the Non-AI

group was 7.4 ± 3.3/yr.

The risk of iatrogenic Cushing's syndrome after ESI is

unknown. No well-controlled study about its incidence af-

ter ESI is available, and only several cases have been re-

ported [36–38]. Interestingly, a few cases were associated

with ritonavir treatment of patients with human immuno-

deficiency virus [37,38]. Park et al. [28] reported that none

of the 18 subjects who were treated long-term with ESI be-

yond 6 months manifested iatrogenic Cushing's syndrome.

The authors used the late-night salivary cortisol (LNSC)

test, which is usually performed between 23:00 and 24:00,

and is known to be very sensitive and specific for the diag-

nosis of Cushing's syndrome [39]. Sim et al. [30] also con-

ducted an LNSC test in 30 subjects who received triamcin-

olone acetate 40 mg or 20 mg and showed the absence of

iatrogenic Cushing's syndrome in either group.

Effects on glucose metabolism & hyperglycemia

Glucocorticoids decrease insulin sensitivity and periph-

eral glucose uptake as well as hepatic gluconeogenesis.

Hyperglycemia may be one of the annoying side effects af-

ter ESI, especially in patients with diabetes.

In a study by Ward et al. [40], 10 healthy volunteers were

administered 80 mg of triamcinolone (equivalent to dexa-

methasone 16 mg) via caudal ESI. Fasting insulin and glu-

cose levels rose significantly one day after ESI and returned

to normal by 1 week. In a study of patients receiving ESI or

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glenohumeral joint injection, serum glucose was elevated

for approximately 1 day [41]. Maillefert et al. [42] followed

nine healthy subjects for 21 days after a single epidural in-

jection of dexamethasone 15 mg and found no changes in

fasting glucose. These studies dispute the hypoglycemic ef-

fect of ESIs in healthy individuals.

ESIs appear to have a greater effect on glucose control in

diabetics. Diabetic patients may have significantly reduced

cytochrome p450 3A4 expression and activity [43]. There-

by, a decreased clearance of glucocorticoids and increased

duration of systemic side effects are observed. Gonzalez et

al. [44] followed 12 patients with diabetes after epidural in-

jection of betamethasone 12–18 mg via transforaminal and

caudal route and reported statistically significant eleva-

tions in blood glucose levels in diabetic subjects. This ef-

fect peaked on the day of the injection and lasted approxi-

mately 2 days. A study of 100 patients with pre-existing dia-

betes by Kim et al. [45] reported that ESIs were associated

with significant elevations in postprandial blood glucose in

diabetic patients for up to 4 days after the procedure. The

higher dose of triamcinolone increased the glucose levels

greater than the lower dose regardless of pain control, em-

ployment status, or clinical outcome. Thus, they recom-

mended lower doses in patients with diabetes [45]. Based

on the above studies, the elevation in blood glucose among

diabetic subjects was observed for two to three days fol-

lowing ESI, and therefore diabetic patients are advised to

control their blood sugar levels tightly until three days after

the procedure.

Effects on bone metabolism & osteoporosis

In general, corticosteroid therapy results in bone loss

and osteoporosis, which could be a challenge, especially in

postmenopausal women. Corticosteroids affect bone re-

modeling by increasing bone resorption via apoptosis of

osteocytes and enhanced osteoclast activity. Many studies

have investigated bone mineral density (BMD) in patients

taking oral corticosteroids. However, orally administered

corticosteroids exhibit different absorption characteristics

and effects compared with those associated with epidural

injections. Therefore, a direct comparison between the two

is difficult.

Dubois et al. [46] reported the absence of a relationship

between cumulative epidural steroid dose and BMD in

healthy men and women pretreated with at least 3 g of

methylprednisolone. However, in postmenopausal wom-

en, an ESI with triamcinolone 80 mg induced a significant

decrease in hip BMD at 6 months compared with baseline

(P = 0.002) and an age-matched control group (P = 0.007)

[47]. Similarly, Kim and Hwang [48] reported a retrospec-

tive study in which multiple ESIs with an approximate cu-

mulative dose of triamcinolone 400 mg reduced hip BMD

in postmenopausal women. The average duration between

the first and last ESIs was 34.4 ± 2.6 months. The risk of os-

teoporotic fracture appears to increase due to ESI. Mandel

et al. [49] conducted a large retrospective cohort study

comparing 3,415 patients who received at least one ESI

with 3,000 patients who did not receive any ESI. ESI in-

creased the risk of fractures by a factor of 1.21 (95% confi-

dence interval, 1.08–1.30) after adjustment for covariates (P

= 0.003). Therefore, physicians should keep in mind that

ESI increases the risk of osteoporosis and fracture in post-

menopausal women.

Abnormal uterine bleeding

Abnormal uterine bleeding (AUB) is not infrequent in

women treated with ESI. The incidence of AUB in women

(70% premenopausal and 30% postmenopausal) who re-

ceived ESI was 2.5% of 8,166 ESIs [50]. However, the exact

relationship between AUB and ESI was not revealed exactly

and sex hormone levels after ESI have yet to be measured.

In the case of intra-articular injection, corticosteroid thera-

py induces a temporary, but considerable suppression of

sex hormone secretion [51].

IMMUNOLOGICAL/INFECTIOUS COMPLICATIONS

Immunosuppression and infection

Immunosuppression is one of the most serious side ef-

fects associated with iatrogenic corticosteroid use. Cortico-

steroids suppress inflammatory genes, upregulate anti-in-

flammatory genes, decrease the production of proinflam-

matory cytokines, and inhibit phagocyte function [52]. Pre-

operative intra-articular corticosteroid injection is associ-

ated with an increased risk of postoperative periprosthetic

infection [53]. Preoperative ESI also appears to be related

to infection after spine surgery. The overall rate of postop-

erative infection related to single-level lumbar decompres-

sion after ESI was reported to vary between 0.8% and 1.7%,

which was more common within 1 month and 1–3 months

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Safety of epidural steroid injection

Page 28

before surgery than within 3–6 months and 6–12 months

before surgery [54]. Therefore, the optimal interval be-

tween the last preoperative ESI and surgery should be at

least 3 months to prevent postoperative infection. Singla et

al. [55] also reported similar results suggesting that preop-

erative ESI within 3 months of lumbar fusion was associat-

ed with an increased rate (1.6%) of postoperative infection

in a retrospective cohort of 88,540 patients.

Allergic reaction & anaphylaxis

Despite the anti-inflammatory and anti-allergic effects of

corticosteroids, no systemic hypersensitivity was detected,

paradoxically [56]. The allergic reactions or hypersensitivi-

ty usually occur due to exposure to preservatives or ste-

roids. The incidence of anaphylaxis was 0.5% in the study

of patients injected with intravenous corticosteroids [57].

However, no study analyzed the incidence of anaphylaxis

in patients using epidural corticosteroids except in a few

cases. Most of the cases are associated with triamcinolone

or methylprednisolone treatment and symptoms include

sneezing, angioedema, tachycardia, marked hypotension,

itching, redness, and peri-orbital edema [58–60].

Facial flushing is a common side effect of ESI, and is as-

sociated immunoglobulin E and histamine-mediated reac-

tion [61]. Most types of corticosteroids used in ESI cause

facial flushing. Cicala et al. [61] reported that 9.3% of pa-

tients who received cervical ESI with methylprednisolone

acetate manifested facial flushing. In the retrospective co-

hort study of Kim et al. [62], the overall incidence of facial

flushing was 28% among 150 subjects who received ESI

with 16 mg of dexamethasone. In this study, the female

subjects were vulnerable to facial flushing (64%) and all

cases of flushing were resolved within 48 h.

MISCELLANEOUS COMPLICATIONS

Psychiatric complications

Corticosteroid-induced psychiatric complications are

not infrequent. Wada et al. [63] reported that corticoste-

roid-induced psychiatric syndrome including depression,

mania, psychosis, and delirium occurred in 0.87% of 2,069

patients (15 patients with a mood disorder and 3 patients

with a psychotic disorder), who showed a relatively good

outcome with full remission within 1–3 months. However,

the pathophysiology of this complication was not clear.

Corticosteroid is suggested to affect dopaminergic or cho-

linergic systems, reduce serotonin release, and induce tox-

ic effects in the hippocampus or other brain regions [64].

Most of the studies involved oral or intravenous adminis-

tration of corticosteroid, but not ESI. Benyamin et al re-

ported a case of a 67-year-old male who received multiple

corticosteroid injections including ESI, and developed psy-

chotic symptoms such as racing thoughts, anger, agitation,

pressured hyper-verbal speech, and paranoia, which spon-

taneously resolved in 7–10 days [65].

Ocular complications

Corticosteroid therapy can increase intraocular pressure

(IOP), which is known as steroid-induced ocular hyperten-

sion, steroid-induced glaucoma (SIG), and at worst blind-

ness. The prevalence of SIG is not reported yet, but non-re-

sponders to corticosteroid was accounted for 61–63% (IOP

elevation < 5 mmHg), moderate responders 33% (IOP ele-

vation ranging 6 to 15 mmHg), and high responders consti-

tuted 4–6% (IOP elevation > 15 mmHg) [66]. However,

these results are based on corticosteroid administration

through the topical, intraocular, periocular, oral, intrave-

nous, inhaled, nasal, and transcutaneous routes. A single

case report involved a patient who experienced sudden bi-

lateral blurred vision due to increased IOP after ESI, war-

ranting immediate ophthalmic intervention. The symptom

resolved within three and one half months [67]. In addi-

tion, a few case reports involved other ophthalmological

complications such as retinal venous hemorrhage, ambly-

opia, transient bilateral vision defect, central serous cho-

rioretinopathy, and subcapsular cataracts after ESI [68,69].

Steroid-induced myopathy

Steroid-induced myopathy is a rare complication charac-

terized clinically by proximal lower extremity weakness,

normal creatine kinase, normal electromyogram, and loss

of type IIa fibers [52]. There is no research or case report on

steroid-induced myopathy associated with ESI. Therefore,

further research is needed to address this problem.

Epidural lipomatosis

A few case reports suggest epidural lipomatosis, which is

characterized by excessive accumulation of unencapsulat-

ed fat in the spinal canal [70–72]. This complication is usu-

20 www.anesth-pain-med.org

Anesth Pain Med Vol. 16 No.1

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KS

PS

ally associated with long-term ESI and can cause symp-

toms of spinal cord or nerve root compression. The prog-

nosis of epidural lipomatosis is not good. Two of the cases

required spine surgery [71,72].

MISCELLANEOUS ISSUES FOR SAFE ESI

Corticosteroids: particulate vs. nonparticulate steroids

The corticosteroids for ESI are divided into particulate

(triamcinolone and methylprednisolone) and nonparticu-

late (dexamethasone and betamethasone) formulations.

Several cases of spinal cord ischemia after ESI have been

reported since they were first described in 2002 by Houten

and Errico [73]. Reports of spinal cord ischemia, paralysis,

permanent blindness, and death after ESI have raised con-

cerns about the potential embolization of particulate corti-

costeroids. Proposed mechanisms include direct injury to

the spinal arteries and embolization. Specifically, the

transforaminal approach entails needle insertion in close

proximity to the spinal cord arteries. Inadvertent arterial

injection of a particulate corticosteroid may result in em-

bolic infarction and subsequent permanent neurologic

compromise. Recent investigations demonstrate an alter-

native mechanism of injury. Several particulate steroids

have been shown to exert immediate and massive effect on

microvascular perfusion in a mouse model via formation

of red blood cell (RBC) aggregates associated with the

transformation of RBCs into spiculated RBCs [74,75].

However, dexamethasone does not form particles or ag-

gregates large enough to cause an embolism, based on

published case reports of paraplegia, quadriplegia, or

stroke following ESI [74]. However, a mixture of dexameth-

asone or betamethasone and ropivacaine induced a

pH-dependent crystallization in vitro [76,77]. In 2011, the

Food and Drug Administration (FDA) required a label

change for triamcinolone, stating that it should not be used

for ESI. Nonetheless, particulate steroids continue to be

used because of a theoretical advantage of pain relief sec-

ondary to delayed clearance from the spinal canal [78].

Three randomized studies investigated the effectiveness of

different steroid preparations. Two studies reported no evi-

dence that nonparticulate steroids such as dexamethasone

at 10 mg were less effective than particulate steroids such

as methylprednisolone, triamcinolone, or betamethasone

in lumbar TFESI [79,80]. Conversely, Park et al. [81] report-

ed that the nonparticulate steroid dexamethasone was sta-

tistically less effective than the particulate steroid in terms

of pain relief. In 2020, Donohue et al. [82] reported that

there was no significant difference in pain relief at any

point between nonparticulate and particulate steroids and

recommended the use of nonparticulate corticosteroids in

ESI given the safety concerns associated with particulate

corticosteroids. Considering the potential risk of cata-

strophic complications, nonparticulate steroid prepara-

tions should be considered as first-line agents when per-

forming ESI. Further studies are necessary to compare cor-

ticosteroid preparations.

Optimal interval and dosage of ESI

Unfortunately, there is no definite consensus on what

constitutes the appropriate regimen of ESIs, and little in-

formation concerning recommendations or practice guide-

lines is available to date. A significant variation in dose, fre-

quency, and ESI interval was attributed to physician pref-

erence. In a survey conducted by Vydra et al. [2], most phy-

sicians (56.0%) preferred 10 mg of dexamethasone for ESI,

followed by 8 mg (12%), 4 mg (9%), 15 mg (8%), 20 mg

(6%), 6 mg (6%), and 12 mg (3%). Also, many of the doctors

(40%) allowed 4 ESIs annually, followed by 3 (29%), 6

(17%), 5 (6%), 2 (3%), 8 (2%), 10 (2%), 9 (1%), and > 10 in-

jections (1%) [2]. Kim et al. [83] published a survey of 122

pain centers adopting the current ESI regimen. More than

half (55%) of Korean pain physicians used dexamethasone

for ESIs. The minimum interval of subsequent ESIs is 3.1

weeks at academic institutions and 2.1 weeks at private

pain clinics [83].

Determining the optimal steroid dose, duration, and in-

terval for ESIs is essential to develop a treatment protocol

with minimal complications without compromising the

treatment effectiveness. Above all, a consensus is needed

to determine the major complications associated with ste-

roids indicating limited corticosteroid use. Rare complica-

tions, such as epidural lipomatosis, steroid-induced myop-

athy, and iatrogenic Cushing’s syndrome or complications

that are patient-specific such as allergic reactions cannot

be used as a criterion for limited ESI use. Most epidural

steroid complications are associated with systemic absorp-

tion of corticosteroids, which is reflected by HPA axis sup-

pression. The HPA axis suppression as an indicator of a ESI

limitation has several advantages. First, it is observed in all

patients who receive ESI [28,30–32]. Second, the recovery

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Safety of epidural steroid injection

Page 30

curve of HPA function after ESI is similar to that of the

elimination of epidurally injected steroid [20,24]. Third, it

represents a dose-response relationship, which provides

important information about minimal dosage of epidural

steroids [30]. Finally, the recovery of HPA axis function is

closely related to AI, one of the serious complications of

ESI [28].

Before discussing appropriate ESI interval, physicians

should consider the need to repeat ESI multiple times. Re-

peated ESIs within 3 months provide cumulative benefit

[84]. If multiple ESIs are considered, an appropriate inter-

val between ESIs should be decided based on the average

duration of HPA axis suppression after ESI without affect-

ing the physiological restoration. Another rationale for an

appropriate interval is to wait until the peak effects of epi-

dural steroid treatment are detected to avoid needless ad-

ditional ESI [85]. Chon and Moon [31] reported that the

HPA axis suppression period after ESI with triamcinolone

40 mg was 19.9 ± 6.8 days, which was similar to that of Sim

et al. [30] (19.7 ± 3.1 days). Accordingly, the minimum rec-

ommended interval between ESIs using triamcinolone 40

mg might be 3 to 4 weeks for safety. The HPA axis suppres-

sion period is affected by the dose of epidural steroid ad-

ministered. In the study of Sim et al. [30], the HPA suppres-

sion period after the epidural injection of triamcinolone 20

mg was 8.0 ± 2.4 days. Therefore, the smaller the dose of

epidural steroid, the closer is the ESI minimum interval.

The type of corticosteroid also affects the duration of HPA

axis suppression. Friedly et al. [25] reported that particu-

late corticosteroids such as methylprednisolone and triam-

cinolone showed relatively longer HPA axis suppression

than the non-particulate forms like betamethasone and

dexamethasone. In the case of methylprednisolone and

triamcinolone, the HPA suppression lasted an average of 3

weeks; however, the serum cortisol concentrations follow-

ing 3-week treatment with betamethasone and dexameth-

asone was not significantly different from the control

group. Similarly, Chutatape et al. [86] reported that epidur-

al dexamethasone 8 mg decreased both ACTH and serum

cortisol concentrations below 7 days. These results may be

associated with the characteristics of the particulate steroid

formulations, suggesting that long-acting and insoluble

types can cause sustained systemic absorption of the corti-

costeroid. In summary, multiple ESIs using particulate ste-

roid require sufficient interval of about 3–4 weeks because

of long-lasting HPA axis suppression, while non-particulate

steroids require shorter periods.

The types of corticosteroids, treatment effectiveness and

duration, and the incidence of complications should be

considered to determine the optimal dosage of ESI. In the

case of oral corticosteroid intake, a multidisciplinary Euro-

pean League Against Rheumatism (EULAR) task force

group of experts recommended that the risk of long-term

corticosteroid therapy depended on dosage: treatment

with less than 5 mg prednisone equivalent per day had low

risk, whereas patient-specific characteristics should be

considered between 5 mg and 10 mg/day, and levels great-

er than 10 mg/day could increase the risk of harm [87].

However, in the case of ESI, it is controversial whether

there is a relationship between systemic complications and

the dosage of corticosteroids. Habib et al. [88] conducted a

randomized, single-blind, controlled trial that showed no

significant difference between the two ESI doses of methyl-

prednisolone (80 mg and 40 mg) in terms of the rate of sec-

ondary AI (P = 0.715) at 3 weeks, except for the visual ana-

log scale (VAS) (P = 0.049) at 3 weeks. However, in the

double-blind, randomized controlled trial of Sim et al. [30],

there was a significant difference between ESIs with 40 mg

and 20 mg doses of triamcinolone in terms of HPA sup-

pression period (19.7 ± 3.1 days vs. 8.0 ± 2.4 days, P =

0.0005) and the slope in the linear mixed-effects model de-

noting the recovery rate of HPA axis (0.00431 ± 0.00043 vs.

0.00647 ± 0.00069, P = 0.015) at 4 weeks. However, there

were no differences in VAS (P > 0.99) and AI incidence (P

= 0.220) at 4 weeks between the two groups in Sim's study.

The World Institute of Pain (WIP) Benelux working group

recommended that the number of ESIs should be adjusted

according to the clinical response, suggesting that a 2-week

interval for additional ESI may be appropriate for proper

evaluation and minimization of endocrine side effects, and

the lowest effective dose should be used for ESI (40 mg for

methylprednisolone, 10 to 20 mg for triamcinolone acetate,

and 10 mg for dexamethasone phosphate) [68].

ESI for a pregnant or breastfeeding patient

Approximately 50% of pregnant women experience low

back pain. Despite its prevalence, low-back pain (LBP) in

pregnancy is considered normal by many patients and

physicians. Also, safe treatment options in pregnancy are

still disputed. Concerns regarding maternal and fetal

well-being restrict the use of interventional treatment regi-

mens by pain physicians, resulting in a higher incidence of

obstetric complications.

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Sehmbi et al. [89] reviewed 56 studies investigating man-

agement strategies for LBP in pregnancy. According to this

review, three case reports involved ESI to alleviate symp-

toms of LBP, but all pregnant patients eventually required

operative intervention due to recurrence or progression of

neurological symptoms. In brief, there is weak evidence

supporting the analgesic and surgery-delaying effect of ESI

in pregnant patients with LBP, which is consistent with ob-

servations involving non-pregnant patients. Although a

single dose of epidural steroid appears to be associated

with a low risk to the fetus, it is recommended that ESI

should be reserved for pregnant patients with new onset of

signs or severe symptoms of lumbar nerve root compres-

sion before surgery.

The use of ESI during breastfeeding has yet to be investi-

gated comprehensively. The secretory function of prolactin

in humans is sensitive to changes in the activity of the HPA

axis in a dose-dependent manner [90]. McGuire reported a

case of 35-year-old mother treated with ESI and facet joint

injection with triamcinolone 80–120 mg resulting in tem-

porary reduction of lactation [91]. Although a detailed

study is needed, patients should be informed that the

amount of breast milk may decrease from day 3 to day 9 af-

ter ESI. Karahan et al. [92] reported that methylpredniso-

lone concentrations in breast milk and maternal serum fol-

lowing high-dose (1,000 mg) methylprednisolone IV pulse

therapy showed a similar trend at all time points. Eight

hours after the injection, the concentrations of methyl-

prednisolone in the milk and maternal serum were low; the

transfer of methylprednisolone into breast milk is low.

They recommended that mothers need to wait for 2–4 h to

further limit the level of exposure although the risk to the

infant seems low. Currently, no information on the effect of

epidural steroids on breast milk or breastfed infants is

available.

CONCLUSIONS

The complications caused by epidural corticosteroids

are relatively rare and rarely serious. However, pain physi-

cians should be aware of the complications because a

growing number of patients with various diseases are treat-

ed with ESI. Although the relationship between the degree

of systemic absorption and the side effects of ESI are not

well known, and most ESI-related complications appear to

be associated with systemic absorption of corticosteroids.

Thus, the complications of ESI differ from those adminis-

tered via oral or venous routes and depend on the type of

steroids used. The duration of HPA axis suppression ade-

quately reflects the systemic absorption of epidural corti-

costeroids. In terms of safety, non-particulate steroids are

preferred over particulate steroids. The ESI interval should

be at least 3–4 weeks for a particulate steroid, but non-par-

ticulate steroids may be administered more frequently. The

ESI dosage is controversial and should be designed to min-

imize HPA axis suppression for each drug.

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article

was reported.

AUTHOR CONTRIBUTIONS

Conceptualization: Min Soo Lee, Ho Sik Moon. Formal

analysis: Min Soo Lee. Writing - original draft: Min Soo

Lee, Ho Sik Moon. Writing - review & editing: Ho Sik Moon.

Supervision: Ho Sik Moon.

ORCID

Min Soo Lee, https://orcid.org/0000-0002-9968-1998

Ho Sik Moon, https://orcid.org/0000-0003-2298-7734

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Corresponding author Hyun Kang, M.D., Ph.D.Department of Anesthesiology and Pain Medicine, Chung-Ang University College of Medicine, 84 Heukseok-ro, Dongjak-gu, Seoul 06974, Korea Tel: 82-2-6299-2586 Fax: 82-2-6299-2585 E-mail: [email protected]

Background: Postoperative delirium (POD) is a condition of cerebral dysfunction and a com-mon complication after surgery. This study aimed to compare and determine the relative ef-ficacy of pharmacological interventions for preventing POD using a network meta-analysis.

Methods: We performed a systematic and comprehensive search to identify and analyze all randomized controlled trials until June 29, 2020, comparing two or more pharmacological interventions, including placebo, to prevent or reduce POD. The primary outcome was the in-cidence of POD. We performed a network meta-analysis and used the surface under the cu-mulative ranking curve (SUCRA) values and rankograms to present the hierarchy of the pharmacological interventions evaluated.

Results: According to the SUCRA value, the incidence of POD decreased in the following or-der: the combination of propofol and acetaminophen (86.1%), combination of ketamine and dexmedetomidine (86.0%), combination of diazepam, flunitrazepam, and pethidine (84.8%), and olanzapine (75.6%) after all types of anesthesia; combination of propofol and acetamin-ophen (85.9%), combination of ketamine and dexmedetomidine (83.2%), gabapentin (82.2%), and combination of diazepam, flunitrazepam, and pethidine (79.7%) after general anesthesia; and ketamine (87.1%), combination of propofol and acetaminophen (86.0%), and combination of dexmedetomidine and acetaminophen (66.3%) after cardiac surgery. However, only the dexmedetomidine group showed a lower incidence of POD than the con-trol group after all types of anesthesia and after general anesthesia.

Conclusions: Dexmedetomidine reduced POD compared with the control group. The combi-nation of propofol and acetaminophen and the combination of ketamine and dexmedetomi-dine seemed to be effective in preventing POD. However, further studies are needed to de-termine the optimal pharmacological intervention to prevent POD.

Keywords: Delirium; Network meta-analysis; Pharmacology; Surgical procedures, operative.

Pharmacological strategies to prevent postoperative delirium: a systematic review and network meta-analysis

Jun Mo Lee1, Ye Jin Cho1, Eun Jin Ahn1, Geun Joo Choi1,2, and Hyun Kang1,2

1Department of Anesthesiology and Pain Medicine, Chung-Ang University College

of Medicine, 2The Institute of Evidence Based Clinical Medicine, Chung-Ang University,

Seoul, Korea

Received September 25, 2020 Revised October 15, 2020 Accepted October 16, 2020

Clinical ResearchAnesth Pain Med 2021;16:28-48https://doi.org/10.17085/apm.20079pISSN 1975-5171 • eISSN 2383-7977

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Copyright © the Korean Society of Anesthesiologists, 2021

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CINTRODUCTION

Postoperative delirium (POD) is a condition of cerebral

dysfunction and a common complication after surgery that

occurs in 15–35% patients [1]. Old age, a history of stroke,

use of narcotic analgesics, poor physical condition, alco-

holism, preexisting cognitive impairment, and type of sur-

gery are known risk factors for POD [2,3]. Especially pa-

tients undergoing major surgery, including cardiac surgery,

are at increased risk of developing POD because of the

complexity of the surgical procedure, the administration of

intraoperative and postoperative anesthetic and other

pharmacological agents. For this reason, POD is reported

to affect up to 57% of cardiac-surgery patients [4].

POD is characterized by altered consciousness, disorien-

tation, impaired memory, perceptual disturbance, altered

psychomotor activity, and altered sleep-wake cycles after

surgery. POD increases the rate of mortality, length of hos-

pital stay, risk of placement to long-term care institutions,

or functional disability, thus increasing hospitalization

costs [2,5]. Therefore, appropriate prevention and treat-

ment of POD is important for enhancing postoperative re-

covery and quality of life in elderly patients [6].

The treatment strategies for POD are well organized

compared to the prevention strategies. The treatment for

POD includes treating the underlying cause; correcting flu-

id and electrolyte imbalance or hypoxia; removing cathe-

ters if present, and treating patients who are restless, ag-

gressive, agitative, and harm to themself or others with an-

tipsychotics such as haloperidol, chlorpromazine, olanzap-

ine, and risperidone [7,8].

However, it is unclear which strategies are effective for

preventing POD. Therefore, various strategies to prevent

POD, especially variable pharmacological interventions,

such as dexmedetomidine, propofol, midazolam, ket-

amine, and acetaminophen, have been applied and com-

pared. However, each study only compared two or three

drugs and reported diverse results.

Recently, a few systematic reviews and meta-analyses

have demonstrated and integrated the preventive effect of

various interventions [9–14]. However, each study was lim-

ited to pair-wise meta-analysis and examined only two

pharmacological interventions. No previous network me-

ta-analysis (NMA) has compared the effectiveness of all

available pharmacological interventions. Further, the

aforementioned studies included studies conducted prior

to 2017.

NMA complements traditional pair-wise meta-analysis

by combining direct and indirect comparisons of treat-

ments and provides objective ranking of various treatments

based on the corresponding surface under the cumulative

ranking curve (SUCRA) [15].

Thus, we reviewed all articles that investigated the effec-

tiveness of pharmacological interventions to prevent POD

and performed NMA to compare and quantify the rank or-

der of the effectiveness of pharmacological interventions to

prevent POD.

MATERIALS AND METHODS

Protocol and registration

We developed the protocol for this systematic review and

NMA according to the preferred reporting requirements for

systematic review and meta-analysis protocol (PRISMA-P)

statement [16]. We registered the review protocol at the

International Prospective Register of Systematic Reviews

(registration no. CRD42020189363; www.crd.york.ac.uk/

prospero) on May 7, 2020.

This systematic review and NMA of pharmacological in-

terventions for preventing POD were performed according

to the protocol recommended by the Cochrane Collabora-

tion [17] and reported according to the PRISMA extension

for NMA guidelines [18].

Search strategy

We searched MEDLINE, EMBASE, Cochrane Central

Register of Controlled Trials (CENTRAL), and Google

Scholar from inception to June 29, 2020 using the search

terms related to pharmacological interventions for pre-

venting POD. The search terms used for MEDLINE and

EMBASE are presented in Supplementary Material. Two

investigators (GJC and HK) screened the titles and ab-

stracts of the retrieved articles. Reference lists were import-

ed to Endnote software 8.1 (Thompson Reuters, USA), and

duplicate articles were removed. Additionally, the refer-

ences of articles obtained from the original search were re-

viewed to identify relevant articles.

Inclusion criteria and exclusion criteria

We included only randomized controlled trials (RCTs)

that compared two or more pharmacological interventions

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Pharmacological strategies for POD

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to prevent POD.

The PICO-SD information included the following:

1. Patients (P): all patients receiving surgery under gen-

eral or regional anesthesia

2. Intervention (I): pharmacological interventions to pre-

vent POD

3. Comparison (C): other pharmacological interventions

to prevent POD, placebo, or no treatment

4. Outcome measurements (O): the incidence of POD

5. Study design (SD): RCTs

6. Subgroup analysis: general anesthesia and cardiac sur-

gery

Exclusion criteria contained the following features:

1. Review articles, case reports, case-series, letters to the

editor, commentaries, proceedings, laboratory science

studies, and all other non-relevant studies

2. Studies that failed to report the outcomes of interest

3. Studies that investigated the effect of inhalational an-

esthetics or patient-controlled analgesia (PCA) regi-

mens

There was on language limitations or date restrictions in

our study.

Study selection

Two reviewers (JML and YJC) independently screened

the titles and abstracts of the studies to identify trials that

met the inclusion criteria outlined above. For articles de-

termined to be eligible based on the title and/or abstract,

the full paper was retrieved. Potentially relevant studies

chosen by at least one author were retrieved, and the full

text was evaluated. Full-text articles were assessed sepa-

rately by two authors (JML and YJC), and any disagree-

ments were resolved through discussion. In cases where

agreement could not be reached, the dispute was resolved

with the help of a third investigator (HK). To minimize data

duplication owing to multiple reporting, articles from the

same author, organization, or country were compared.

Data extraction

Using a standardized extraction form, the following data

were extracted independently by two investigators (JML

and YJC): 1) title, 2) name of the first author, 3) name of the

journal, 4) year of publication, 5) study design, 6) type of

pharmacological interventions, 7) dose of pharmacological

agents, 8) country, 9) risk of bias, 10) inclusion criteria, 11)

exclusion criteria, 12) age, 13) number of subjects, and 14)

incidence of POD.

If the information was inadequate, attempts were made

to contact the study authors, and additional information

was requested. If unsuccessful, missing information was

calculated from the available data, if possible, or was ex-

tracted from the figure using the open source software Plot

Digitizer (version 2.6.8; http://plotdigitizer.sourceforge.

net).

The reference lists were divided into two halves. Two in-

vestigators completed data extraction, one for each half of

the reference list. Data extraction forms were cross-

checked to verify the accuracy and consistency of the ex-

tracted data.

The degree of agreement between the two independent

data extractors was computed using kappa statistics to

measure the difference between the observed and expect-

ed agreements, i.e., whether they were random or by

chance. Kappa values were interpreted as: 1) less than 0:

less than chance agreement; 2) 0.01 to 0.20: slight agree-

ment; 3) 0.21 to 0.40: fair agreement; 4) 0.41 to 0.60: mod-

erate agreement; 5) 0.61 to 0.80: substantial agreement;

and 6) 0.8 to 0.99: almost perfect agreement [19].

Risk of bias assessment

The quality of the studies was independently assessed by

two investigators (JML and YJC) using the Revised Co-

chrane risk of bias tool for randomized trials (RoB 2.0). Risk

of bias judgment was assessed in the following domains:

bias arising from the randomization process, bias due to

deviations from intended intervention, bias due to missing

outcome data, bias in measurement of the outcome, and

bias in selection of the reported results. Based on the re-

sults of risk of bias judgment, formal overall risk of bias

judgment was categorized as “low risk of bias,” “some con-

cern,” and “high risk of bias” [20].

Statistical analysis

Ad-hoc tables were designed to summarize data from the

included studies by showing their key characteristics and

any important questions related to the review objectives.

After extracting the data, the reviewers determined the fea-

sibility of a meta-analysis.

A multiple treatment comparison NMA is a meta-analy-

sis generalization method that includes both direct and in-

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Cdirect RCT comparison of treatments. A random-effects

NMA based on a frequentist framework was performed us-

ing STATA software (version 15, StataCorp LP, USA) based

on mvmeta with NMA graphical tools developed by

Chaimani et al. [21].

Before conducting the NMA, we evaluated the transitivi-

ty assumption by examining the comparability of the risk

of bias (all versus removing high risks of bias from the ran-

domization process and overall risk of bias), demograph-

ics, and types of pharmacological interventions as poten-

tial treatment-effect modifiers across comparisons.

A network plot linking the included pharmacological in-

terventions to prevent POD and their combination with

other pharmacological agents was formed to indicate the

types of agents, number of patients on different agents, and

the level of pair-wise comparisons. The nodes show com-

parisons of pharmacological agents being compared, and

the edges show the available direct comparisons among

the pharmacological agents. The nodes and edges are

weighed on the basis of the weights applied in NMA and

the inverse of the standard error of effect.

We evaluated the consistency assumption for the entire

network using the design-by-treatment interaction model.

We also evaluated each closed loop in the network to eval-

uate local inconsistencies between the direct and indirect

effect estimates for the same comparison. For each loop,

we estimated the inconsistency factor (IF) as the absolute

difference between the direct and indirect estimates and

95% confidence interval (CI) for each paired comparison in

the loop [22]. When the IF value with 95% CI started at 0, it

indicated that the direct evidence and the indirect evi-

dence were consistent.

Mean summary effects with CI were presented together

with their predictive intervals (PrIs) to facilitate interpreta-

tion of the results considering the magnitude of heteroge-

neity. PrIs provide an interval that is expected to encom-

pass the estimate of a future study.

A rankogram and a cumulative ranking curve were

drawn for each pharmacological intervention. Rankogram

plots are the probabilities for treatments to assume a possi-

ble rank. We used surface under the cumulative ranking

curve (SUCRA) values to present the hierarchy of pharma-

cological interventions to prevent the incidence of POD.

The SUCRA is a relative ranking measure that accounts for

the uncertainty in the treatment order, that is, accounts for

both the location and the variance of all relative treatment

effects. A higher SUCRA value is regarded as a more posi-

tive result for individual interventions [23].

We performed subgroup analysis based on all types of

anesthesia, general anesthesia, and cardiac surgery, be-

cause the incidence of POD is expected to be different ac-

cording to the type of anesthesia, and increase after cardiac

surgery.

Quality of evidence

The evidence grade was determined using the Grading of

Recommendations, Assessment, Development, and Evalu-

ation (GRADE) system, which uses a sequential assessment

of the evidence quality, followed by an assessment of the

risk-benefit balance and a subsequent judgment on the

strength of the recommendations [24].

RESULTS

Study selection

We initially retrieved 235 articles from MEDLINE, EM-

BASE, CENTRAL, and Google Scholar databases and 17 ar-

ticles through a manual search. After adjusting for dupli-

cates, 245 studies remained. Of these, 182 studies were dis-

carded after reviewing the title and abstracts for the follow-

ing reasons: related to other topics, designed as systematic

reviews, reviews or retrospective studies, and conference

abstracts. The full texts of the 63 remaining studies were re-

viewed in detail; 12 studies were excluded for the following

reasons: three were study protocols [25–27], two were edi-

torials [13,28], four were systematic reviews, [9–12] and

three did not report the outcome of our interest (two com-

pared an inhalational agent [13,29] and one was compared

in the PCA regimen [30]). Thus, 51 studies with a total of

22,565 patients that included 18 different pharmacological

interventions were included in this NMA (Fig. 1). The kap-

pa value for the selected articles between the two reviewers

was 0.844.

Characteristics of the included studies

The characteristics of the 51 studies are summarized in

Table 1. All the studies were performed on adults with

American Society of Anesthesiologists physical status clas-

sifications I, II, and III. The 51 studies were conducted in

various countries, such as Australia [31,32], Canada [33,34],

China [1,2,6,35–47], Denmark [48], Greece [49], India

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Pharmacological strategies for POD

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[50,51], Iran [52,53], Japan [54–57], the Netherlands [58–

61], South Korea [62,63], Switzerland [64], Taiwan [65,66],

Thailand [67], the United Kingdom [68], the United States

of America [4,69–76], and Saudi arabia [77].

Twenty-seven types of pharmacological agents, includ-

ing dexmedetomidine (Dexm) [2,4,6,31,33,35,36,38–45,47,

50,51,62,63,65,66,69,70], propofol (Prop) [4,33,42–44,

47,51,66,70], acetaminophen (AAP) [70], midazolam

(Mida) [4,6,77], remifentanil (Remi) [62], morphine (Morp)

[31], methylprednisolone (MPDL) [32,34,48], melatonin

(Mela) [58,77], dexamethasone (Dexa) [52,59,61], haloperi-

dol (Halo) [37,54,55,60], rivastigmine (Riva) [64], ketamine

(Keta) [39,71], olanzapine (Olan) [72], gabapentin (Gaba)

[73,76], nimodipine (Nimo) [1], cyproheptadine (Cypr)

[53], ondansetron (Onda) [49], risperoidone (Risp) [67],

L-tryptophan(L-tyr) [74], donepezil (Done) [68,75], Yoku-

kansan (TJ-54) [56], diazepam (Diaz) [57], flunitrazepam

(Flun) [57] and pethidine (Peth) [57], parecoxib (Pare) [46],

and clonidine (Clon) [77] were evaluated.

The types of surgery investigated included cardiovascular

surgery [4,31–35,42,43,47,50–52,59,61,62,64,67,70,71], ortho-

pedic surgery [1,2,6,39,40,44,46,48,49,54,58,60,68,72,73,75–

77], thoracoscopic and pulmonary surgery [41,56,65,74], ab-

dominal and laparoscopic surgery [54–57,63,66], vascular

and urology surgery [74], free flap [38], oral cancer surgery

[45], and non-cardiac surgery [36,37,53,69]. The anesthesia

method in the studies included only general anesthesia [1,

2,4,6,31–35,38,39,41–43,45,47,49–52,55–57,59,61–67,69–

71,76], general anesthesia + regional anesthesia [36,37,48,

54,72-74], type of anesthesia were not decribed [40,53,58,

60,68,75], and only regional anesthesia [44,46,77].

Study quality assessment

The risk of bias assessment in the included studies using

the Cochrane tool is presented in Table 2.

All types of anesthesia

A total of 51 studies (22,565 patients) measured the inci-

dence of POD. The pooled overall incidence of POD after

all types of anesthesia was 18.5% (95% CI: 16.2% to 21.0%,

Pchi2 < 0.001, I2 = 92.0%). The network plot of all eligible

comparisons for this endpoint is depicted in Fig. 2A.

Although all 27 management modalities (nodes) were

connected to the network, two comparisons (Control [Cont],

Dexm) were compared directly to the other 25 nodes.

The evaluation of the network inconsistency using the

design-by-treatment interaction model suggested no sig-

nificant inconsistency (χ2 [8] = 13.37, P = 0.100). Of the 14

closed loops in the network for the comparison of postop-

erative delirium, four loops (Dexm-Dexm + AAP-pro + AAP

[01-04-05] [70], Dexm-Keta-Keta + Dexm [01-09-22] [39],

Pro-Dexm + AAP-Prop + AAP [03-04-05] [70], Mida-Me-

la-Clon [06-11-25] [77]) were formed only by multi-arm tri-

als. Thus, local inconsistency was evaluated in 10 loops. Al-

though most loops showed no relevance in the local incon-

sistency between the direct and indirect point estimates,

235 records identified through database searching

245 records screened with titles and abstracts 182 records excluded

Excluded (n = 12):

• Study protocol (n = 3)• Editorial (n = 2)• Systematic review (n = 4)• Not report the outcome of interest (n = 3)

63 full-text articles assessed for eligibility

51 studies included in NMA (n = 22,565)

17 records identified through hand searching

Fig. 1. PRISMA flowchart of included and excluded trials. PRISMA: preferred reporting requirements for systematic review and meta-analysis, NMA: network meta-analysis.

245 records after 7 duplicates removed

32 www.anesth-pain-med.org

Anesth Pain Med Vol. 16 No.1

Page 41

KS

NAC

C

Tabl

e 1

. The

Cha

ract

eris

tics

of th

e In

clud

ing

Stud

ies

Stud

yYe

arCo

untr

ySu

rger

yAn

esth

esia

Asse

ssm

ent

tool

Asse

ssor

Man

agem

ent

Adm

inis

trat

ion

time

No.

of

patie

nts

Age

(yr)

Sex,

M/F

(%)

Dei

ner e

t al.

[69 ]

2017

USA

Non

card

iac

surg

ery

G/A

CAM

, CAM

-ICU,

M

MSE

Trai

ned

lay

in

terv

iew

ers

Dex

med

etom

idin

eIn

trao

p14

774

49/5

1

Cont

rol

157

7449

/51

Dja

iani

et a

l. [3

3 ]20

16Ca

nada

Card

iac

surg

ery

G/A

CAM

, CAM

-ICU

Test

erD

exm

edet

omid

ine

Post

op91

72.7

75/2

5

Prop

ofol

9272

.476

/24

Sush

eela

et a

l. [7

0 ]20

17U

SACa

rdia

c su

rger

yG

/ACA

M, M

MSE

Res

earc

h m

embe

rsD

exm

edet

omid

ine

Intr

aop

&

Post

op3

No

desc

ribed

(>

60 )

No

desc

ribed

Dex

med

etom

idin

e +

AAP

3

Prop

ofol

3

Prop

ofol

+ A

AP3

Li e

t al.

[35 ]

2017

Chin

aCa

rdia

c su

rger

yG

/ACA

M, C

AM-IC

UR

esea

rch

mem

bers

Dex

med

etom

idin

ePe

riop

142

6667

/30

Cont

rol

143

6871

/29

Mal

dona

do e

t al.

[4]

2009

USA

Card

iac

surg

ery

G/A

CAM

, CAM

-ICU,

D

RS

Neu

rops

ychi

a-tr

ist

Dex

med

etom

idin

ePo

stop

4055

65/3

5

Prop

ofol

3858

58/4

2

Mid

azol

am40

6068

/32

Park

et a

l. [6

2 ]20

14So

uth

Kor

eaCa

rdia

c su

rger

yG

/ACA

M-IC

UM

edic

al s

taff

and

non-

psy-

chia

tris

ts

Dex

med

etom

idin

ePo

stop

6751

60/4

0

Rem

ifent

anil

7554

55/4

5

Sheh

abi e

t al.

[31 ]

2009

Aust

ralia

Card

iac

surg

ery

G/A

CAM

-ICU

Nur

se a

nd th

e re

sear

ch

team

Dex

med

etom

idin

eN

o de

scrib

ed15

271

75/2

5

Mor

phin

e14

771

75/2

5

Su e

t al.

[36 ]

2016

Chin

aN

onca

rdia

c su

rger

yG

/A,

CAM

-ICU

Res

earc

h m

embe

rsD

exm

edet

omid

ine

Perio

p35

0N

o de

scrib

ed

(> 6

5 )N

o de

scrib

ed

R/A

Cont

rol

350

Wu

et a

l. [6

5 ]20

18Ta

iwan

Thor

acos

copi

c su

rger

yG

/AN

o de

scrib

edN

o de

scrib

edD

exm

edet

omid

ine

Intr

aop

3059

50/5

0

Cont

rol

359

51/4

9

Clem

mes

en e

t al.

[48 ]

2018

Den

mar

kH

ip fr

actu

re

surg

ery

G/A

,R

/ACA

MR

esea

rch

mem

bers

Met

hylp

redn

isol

one

Preo

p59

7937

/63

Cont

rol

5881

37/6

3

de J

ongh

e et

al.

[58 ]

2014

Net

herla

ndH

ip fr

actu

re

surg

ery

No

de

scrib

edD

SM-IV

Med

ical

and

nu

rsin

g

reco

rds

Mel

aton

inPe

riop

186

8428

/72

Cont

rol

192

8332

/68

Die

lem

an e

t al.

[59 ]

2012

Net

herla

ndCa

rdia

c su

rger

yG

/AN

o de

scrib

edN

o de

scrib

edD

exam

etha

sone

Intr

aop

2 ,23

566

73/2

7

Cont

rol

2 ,24

766

72/2

8

Fuka

ta e

t al.

[54 ]

2014

Japa

nAb

dom

inal

, or

thop

edic

su

rger

y

G/A

,N

EECH

AMR

esea

rch

mem

bers

Hal

oper

idol

Post

op59

8150

/50

R/A

Cont

rol

6080

50/5

0

Gam

berin

i et a

l. [6

4 ]20

09Sw

itzer

land

Card

iac

surg

ery

G/A

CAM

, MM

SE,

CDT

Res

earc

h m

embe

rsR

ivas

tigm

ine

Perio

p56

7466

/34

Cont

rol

5774

70/3

0

Hud

etz

et a

l. [7

1 ]20

09U

SACa

rdia

c su

rger

yG

/AIC

DSC

Anes

thes

iolo

-gi

stK

etam

ine

Intr

aop

2968

No

desc

ribed

Cont

rol

2960

(Con

tinue

d to

the

next

pag

e)

www.anesth-pain-med.org 33

Pharmacological strategies for POD

Page 42

Kal

isva

art e

t al.

[60 ]

2005

Net

herla

ndH

ip fr

actu

re

surg

ery

No

de

scrib

edCA

M, D

SM-IV

, M

MSE

, D

RS-

R-9

8

Trea

ting

su

rgeo

nsH

alop

erid

olPe

riop

212

7919

/81

Cont

rol

218

8021

/79

Kan

eko

et a

l. [5

5 ]19

99Ja

pan

Gas

troi

ntes

ti-na

l sur

gery

G/A

DSM

Med

ical

and

nu

rsin

g re

-co

rds

Hal

oper

idol

Post

op38

7260

/40

Cont

rol

4073

65/3

5

Lars

en e

t al.

[72 ]

2010

USA

Join

t rep

lace

-m

ent s

urge

ryG

/A,

CAM

, DSM

-IV,

MM

SE,

DR

S-R

-98

Trai

ned

nurs

eO

lanz

apin

ePe

riop

196

7352

/48

R/A

Cont

rol

204

7440

/60

Lee

et a

l. [6

3 ]20

18So

uth

Kor

eaLa

paro

scop

ic

maj

or s

urge

ryG

/ACA

MPs

ychi

atris

tD

exm

edet

omid

ine

Intr

a23

673

45/5

5

Cont

rol

118

7443

/57

Leun

g et

al.

[73 ]

2017

USA

Spin

e, jo

int r

e-pl

acem

ent

surg

ery

G/A

,CA

MR

esea

rch

as-

sist

ants

Gab

apen

tinPe

riop

350

7345

/55

R/A

Cont

rol

347

7355

/45

Li e

t al.

[1]

2017

Chin

aSp

ine

surg

ery

G/A

Nu-

DES

CN

urse

Nim

odip

ine

Perio

p30

6937

/63

Cont

rol

3070

43/5

7

Liu

et a

l. [2

]20

16Ch

ina

Join

t rep

lace

-m

ent s

urge

ryG

/ACA

MN

o de

scrib

edD

exm

edet

omid

ine

Intr

aop

6071

43/5

7

Cont

rol

5873

50/5

0

Mar

dani

and

Big

de-

lian

[52 ]

2013

Iran

Card

iac

surg

ery

G/A

MM

SE, D

SM-IV

No

desc

ribed

Dex

amet

haso

nePe

riop

4365

84/1

6

Cont

rol

5060

88/1

2

Moh

amm

adi e

t al.

[53 ]

2016

Iran

Non

card

iac

surg

ery

No

de

scrib

edCA

M-IC

UAn

esth

esio

lo-

gist

Cypr

ohep

tadi

nePo

stop

2060

60/4

0

Cont

rol

2060

70/3

0

Papa

dopo

ulos

et a

l. [4

9 ]20

14G

reec

eFe

mor

al, f

emur

fr

actu

re s

ur-

gery

G/A

CAM

, MM

SER

esea

rch

mem

bers

Ond

anse

tron

Post

op51

72N

o de

scrib

ed

Cont

rol

5571

Prak

anra

ttan

a an

d Pr

apai

trak

ool [

67]

2007

Thai

land

Card

iac

surg

ery

G/A

CAM

, CAM

-ICU

Anes

thes

iolo

-gi

stR

ispe

ridon

ePo

stop

6361

57/4

3

Cont

rol

6361

60/4

0

Priy

e et

al.

[50 ]

2015

Indi

aCa

rdia

c su

rger

yG

/AN

o de

scrib

edN

o de

scrib

edD

exm

edet

omid

ine

Post

op32

4551

/49

Cont

rol

3241

50/5

0

Rob

inso

n et

al.

[74 ]

2014

USA

Vasc

ular

,uro

-lo

gic,

thor

acic

su

rger

y

G/A

,CA

M-IC

UR

esea

rch

mem

bers

L-tr

ypto

phan

Post

op15

269

99/1

R/A

Cont

rol

149

6997

/3

Roy

se e

t al.

[32 ]

2017

Aust

ralia

Card

iac

surg

ery

G/A

CAM

-ICU

No

desc

ribed

Met

hylp

redn

isol

one

Intr

aop

250

7363

/37

Cana

daCo

ntro

l24

874

66/3

4

Sam

pson

et a

l. [6

8 ]20

07U

KTH

RN

o

desc

ribed

DSI

No

desc

ribed

Don

epez

ilPo

stop

1970

58/4

2

Cont

rol

1465

43/5

7

Shei

kh e

t al.

[51 ]

2018

Indi

aCa

rdia

c su

rger

yG

/AN

o de

scrib

edN

o de

scrib

edD

exm

edet

omid

ine

Intr

aop

3034

No

desc

ribed

Prop

ofol

3036

Tabl

e 1

. Con

tinue

d

Stud

yYe

arCo

untr

ySu

rger

yAn

esth

esia

Asse

ssm

ent

tool

Asse

ssor

Man

agem

ent

Adm

inis

trat

ion

time

No.

of

patie

nts

Age

(yr)

Sex,

M/F

(%)

(Con

tinue

d to

the

next

pag

e)

34 www.anesth-pain-med.org

Anesth Pain Med Vol. 16 No.1

Page 43

KS

NAC

C

Suga

no e

t al.

[56 ]

2017

Japa

nG

I, lu

ng c

ance

r su

rger

yG

/AD

SM-IV

Phys

icia

nsTJ

-54

Perio

p93

7665

/35

Cont

rol

9377

65/3

5

Wan

g et

al.

[37 ]

2012

Chin

aN

onca

rdia

c su

rger

yG

/A,

CAM

-ICU

Res

earc

h m

embe

rsH

alop

erid

olPo

stop

229

7463

/37

R/A

Cont

rol

228

7463

/37

Whi

tlock

et a

l. [3

4 ]20

15Ca

nada

Card

iac

surg

ery

G/A

CAM

Out

com

e

adju

dica

tors

Met

hylp

redn

isol

one

Intr

aop

3 ,75

568

60/4

0

Cont

rol

3 ,75

267

61/3

9

Yang

et a

l. [3

8 ]20

15Ch

ina

Free

flap

sur

-ge

ryG

/ACA

M-IC

UIn

vest

igat

orD

exm

edet

omid

ine

Perio

p39

5050

/50

Cont

rol

4050

50/5

0

He

et a

l. [6

]20

18Ch

ina

Vert

ebra

l ost

e-ot

omy

G/A

CAM

No

desc

ribed

Dex

med

etom

idin

ePe

riop

3083

53/4

7

Mid

azol

am30

8263

/37

Cont

rol

3083

56/4

4

Ma

et a

l. [3

9 ]20

13Ch

ina

Ort

hope

dic

surg

ery

G/A

CAM

Res

earc

h m

embe

rsK

etam

ine

Perio

p30

6653

/47

Dex

med

etom

idin

e30

6934

/66

Keta

min

e +

Dex

emet

omid

ine

3066

40/6

0

Cont

rol

3068

60/4

0

Xuan

et a

l. [4

0 ]20

18Ch

ina

Join

t rep

lace

-m

ent s

urge

ryN

o

desc

ribed

CAM

, CAM

-ICU

Res

earc

h m

embe

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exm

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ine

Post

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767

42/5

8

Cont

rol

226

6745

/55

Sauë

r et a

l. [6

1 ]20

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ethe

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Card

iac

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ery

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Res

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h nu

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Dex

amet

haso

neIn

trao

p36

767

70/3

0

Cont

rol

370

6669

/31

Huy

an e

t al.

[41 ]

2019

Chin

aRa

dica

l pul

mo-

nary

rese

ctio

nG

/AIC

DSC

No

desc

ribed

Dex

med

etom

idin

ePe

riop

173

7151

/49

Cont

rol

173

7254

/46

Shi e

t al.

[42 ]

2019

Chin

aCa

rdia

c su

rger

yG

/ACA

MR

esea

rch

mem

bers

Dex

med

etom

idin

eIn

trao

p84

7575

/25

Prop

ofol

8074

70/3

0

Liu

et a

l. [4

3 ]20

16Ch

ina

Card

iac

surg

ery

G/A

CAM

No

desc

ribed

Dex

med

etom

idin

ePo

stop

4453

52/4

8

Prop

ofol

4457

68/3

2

Mei

et a

l. [4

4 ]20

18Ch

ina

Hip

art

hrop

last

yR

/ACA

MR

esea

rch

mem

bers

Dex

med

etom

idin

eIn

trao

p14

876

43/5

7

Prop

ofol

148

7448

/52

Guo

et a

l. [4

5 ]20

15Ch

ina

Ora

l can

cer

surg

ery

G/A

CAM

-ICU

No

desc

ribed

Dex

med

etom

idin

ePo

stop

7872

53/4

7

Cont

rol

7871

50/5

0

Aiza

wa

et a

l. [5

7 ]20

02Ja

pan

GI s

urge

ryG

/AD

SM-IV

Psyc

hiat

rist

Dia

zepa

m +

Flu

nitr

azep

am

+ Pe

thid

ine

(DFP

)Po

stop

2076

75/2

5

Cont

rol

20

7655

/45

Mu

et a

l. [4

6 ]20

17Ch

ina

Join

t rep

lace

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ent s

urge

ryR

/ACA

M, C

AM-IC

UR

esea

rch

mem

bers

Pare

coxi

bN

o de

scrib

ed31

070

26/7

4

Cont

rol

310

7127

/73

Tabl

e 1

. Con

tinue

d

Stud

yYe

arCo

untr

ySu

rger

yAn

esth

esia

Asse

ssm

ent

tool

Asse

ssor

Man

agem

ent

Adm

inis

trat

ion

time

No.

of

patie

nts

Age

(yr)

Sex,

M/F

(%)

(Con

tinue

d to

the

next

pag

e)

www.anesth-pain-med.org 35

Pharmacological strategies for POD

Page 44

Tabl

e 2.

Ris

k of

Bia

s As

sess

men

t

Stud

yB

ias

aris

ing

from

the

ra

ndom

izat

ion

proc

ess

Bia

s du

e to

dev

iatio

ns fr

om

inte

nded

inte

rven

tions

Bia

s du

e to

mis

sing

ou

tcom

e da

taB

ias

in m

easu

rem

ent

of th

e ou

tcom

eB

ias

in s

elec

tion

of

the

repo

rted

resu

ltO

vera

ll ris

k of

bia

s ju

dgem

ent

Dei

ner e

t al.,

201

7 [6

9 ]Lo

w ri

skSo

me

conc

erns

Low

risk

Low

risk

Low

risk

Som

e co

ncer

ns

Dja

iani

et a

l., 2

016

[33 ]

Low

risk

Low

risk

Low

risk

Low

risk

Low

risk

Low

risk

Sush

eela

et a

l., 2

017

[70 ]

Som

e co

ncer

nsSo

me

conc

erns

Low

risk

Low

risk

Low

risk

Hig

h ris

k

Li e

t al.,

201

7 [3

5 ]Lo

w ri

skLo

w ri

skLo

w ri

skLo

w ri

skLo

w ri

skLo

w ri

sk

Mal

dona

do e

t al.,

200

9 [4

]So

me

conc

erns

Som

e co

ncer

nsLo

w ri

skLo

w ri

skLo

w ri

skH

igh

risk

Park

et a

l., 2

014

[62 ]

Som

e co

ncer

nsSo

me

conc

erns

Low

risk

Low

risk

Low

risk

Hig

h ris

k

Sheh

abi e

t al.,

200

9 [3

1 ]So

me

conc

erns

Low

risk

Low

risk

Low

risk

Low

risk

Som

e co

ncer

ns

Su e

t al.,

201

6 [3

6 ]Lo

w ri

skLo

w ri

skLo

w ri

skLo

w ri

skLo

w ri

skLo

w ri

sk

Wu

et a

l., 2

018

[65 ]

Som

e co

ncer

nsLo

w ri

skLo

w ri

skLo

w ri

skLo

w ri

skSo

me

conc

erns

Clem

mes

en e

t al.,

201

8 [4

8 ]Lo

w ri

skLo

w ri

skLo

w ri

skLo

w ri

skLo

w ri

skLo

w ri

sk

de J

ongh

e et

al.,

201

4 [5

8 ]So

me

conc

erns

Low

risk

Low

risk

Low

risk

Low

risk

Som

e co

ncer

ns

Die

lem

an e

t al.,

201

2 [5

9 ]Lo

w ri

skLo

w ri

skLo

w ri

skLo

w ri

skLo

w ri

skLo

w ri

sk

Fuka

ta e

t al.,

201

4 [5

4 ]So

me

conc

erns

Som

e co

ncer

nsLo

w ri

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[71 ]

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36 www.anesth-pain-med.org

Anesth Pain Med Vol. 16 No.1

Page 45

KS

NAC

C

Kal

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200

5 [6

0 ]Lo

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eko

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999

[55 ]

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risk

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erns

Lars

en e

t al.,

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Lee

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018

[63 ]

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t al.,

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]So

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risk

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risk

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[49 ]

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inso

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risk

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risk

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risk

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ncer

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pson

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kh e

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erns

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Mu

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www.anesth-pain-med.org 37

Pharmacological strategies for POD

Page 46

Fig. 2. Network plot of included studies comparing different pharmacological interventions. The nodes show a comparison of pharmacological interventions to prevent postoperative delirium, and the edges show the available direct comparisons among the pharmacological interventions. The nodes and edges are weighed on the basis of the weights applied in the network meta-analysis and the inverse of the standard error of effect. (A) All types of anesthesia, (B) general anesthesia, (C) cardiac surgery.

inconsistencies were observed between the direct and in-

direct point estimates in the Cont-Mela-Clon (02-11-25)

and Cont-Mida-Mela (02-06-11) loops (Fig. 3A).

Dexm showed a lower incidence of POD than Cont only

in terms of 95% CI. Olan showed marginal significance

compared with Cont in terms of 95% CI (Fig. 4A). Insignifi-

cance in the 95% PrIs suggests that any future RCT could

change the significance of the effectiveness of these com-

parisons.

The rankograms showed that Prop+AAP and Keta+Dexm

had the lowest incidence of POD (Fig. 5A). The cumulative

ranking plot was drawn, and the SUCRA probabilities of the

different pharmacological agents for POD were calculated

(Fig. 6A). The expected mean rankings and SUCRA values of

each pharmacological intervention are presented in Fig. 7A.

According to the SUCRA value, the incidence of POD was

lower in the order of the Prop + AAP (86.1%), followed by

Keta + Dexm (86.0%), Diaz + Flun + Pethi (84.8%), and Olan

(75.6%). The comparison-adjusted funnel plots showed that

the funnel plots were symmetrical around the zero line,

which suggested a less likely publication bias (Fig. 8A).

General anesthesia

A total of 35 studies (17,241 patients) were analyzed. The

pooled overall incidence of POD after general anesthesia

was 16.5% (95% CI: 14.2% to 19.2%, Pchi2 < 0.001, I2 =

89.3%).

The network plot of all eligible comparisons for this end-

point is depicted in Fig. 2B. Although all 20 management

modalities (nodes) were connected to the network, two

comparisons (Cont, Dexm) were directly compared to the

other 18 nodes.

The evaluation of the network inconsistency using the

design-by-treatment interaction model suggested no sig-

nificant inconsistency (χ2 [6] = 11.50, P = 0.074). Of the 10

closed loops in the network for the comparison of postop-

erative delirium, three loops (Dexm-Dexm + AAP-Prop +

AAP [01-04-05] [70], Pro-Dexm + AAP-Prop + AAP [01-09-

19] [70], Dexm-Keta-Dexm + Keta [03-04-05] [39]) were

formed only by multi-arm trials. Thus, local inconsistency

was evaluated in seven loops. There was no significance in

the local inconsistency between the direct and indirect

point estimates (Fig. 3B).

Dexm showed a lower incidence of POD than Cont only

in terms of 95% CI (Fig. 4B). Insignificance in the 95% PrIs

suggests that any future RCT could change the significance

Keta Morp Remi

B

A

C

38 www.anesth-pain-med.org

Anesth Pain Med Vol. 16 No.1

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Fig. 4. Predictive interval plots between each management modality and placebo group. Diamond shape represents the mean summary effects. Black line represents the 95% confidence interval (CI), and red line represents the predictive interval (PrI). PrIs provide an interval that is expected to encompass the estimate of a future study. (A) All type of anesthesia, (B) general anesthesia, (C) cardiac surgery.

Fig. 3. Inconsistency plot between the direct and indirect effect estimates for the same comparison. Inconsistency factor (IF) as the absolute difference with 95% confidence interval (CI) between the direct and indirect estimates for each paired comparison is presented. IF values close to 0 indicate that the two sources are in agreement. (A) All type of anesthesia, (B) general anesthesia, (C) cardiac surgery.

B

A

C

B

A

C

www.anesth-pain-med.org 39

Pharmacological strategies for POD

Page 48

Fig. 5. Rankogram. Profiles indicate the probabilities for treatments to assume any of the possible ranks. It is the probability that a given treatment ranks first, second, third, and so on, among all of the treatments evaluated in the NMA. (A) All type of anesthesia, (B) general anesthesia, (C) cardiac surgery. NMA: network meta-analysis.

Fig. 6. Cumulative ranking curve plot. The profile indicates the sum of the probabilities from those ranked first, second, third, and so on. A higher cumulative ranking curve (surface of under cumulative ranking curve [SUCRA]) value is regarded as an improved result for an individual’s intervention. When ranking treatments, the closer the SUCRA value is to 100%, the higher the treatment ranking is relative to all other treatments. (A) All type of anesthesia, (B) general anesthesia, (C) cardiac surgery.

B

A

C

B

A

C

40 www.anesth-pain-med.org

Anesth Pain Med Vol. 16 No.1

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SUC

RA

SUC

RA

SUC

RA

Mean ranking

Mean ranking

Mean ranking

5 10 15 20 25 2

2

4

4

6

6

8

8

10

10

12

12

14 16 18

100

80

60

40

20

0

100

80

60

40

20

0

90

80

70

60

50

40

30

20

10

BA

C

Fig. 7. Expected mean ranking and surface of under cumulative ranking curve (SUCRA) values. X-axis corresponds to expected mean ranking based on SUCRA value, and Y-axis corresponds to SUCRA value. (A) All type of anesthesia, (B) general anesthesia, (C) cardiac surgery.

of the effectiveness of these comparisons.

The rankogram showed that Prop + AAP, Keta + Dexm,

and Gaba had the lowest incidence of POD (Fig. 5B). The

cumulative ranking plot was drawn, and the SUCRA proba-

bilities of the different pharmacological agents for the POD

were calculated (Fig. 6B). The expected mean rankings and

SUCRA values of each pharmacological agent are present-

ed in Fig. 7B. According to the SUCRA value, the incidence

of POD was lower in the order of the Prop + AAP (85.9%),

followed by Keta + Dexm (83.2%), Gaba (82.2%), and Diaz

+ Flun + Pethi (79.7%).

Cardiac surgery

A total of 19 studies (15,090 patients) were analyzed. The

pooled overall incidence of POD after cardiac surgery was

15.4% (95% CI: 12.8% to 18.4%, Pchi2 < 0.001, I2 = 89.8%).

The network plot of all eligible comparisons for this end-

point is depicted in Fig. 2C.

Although all 13 management modalities (nodes) were

connected to the network, three comparisons (Cont, Dexm,

Prop) were compared directly to the other 10 nodes.

The evaluation of the network inconsistency using the

design-by-treatment interaction model suggested no sig-

nificant inconsistency (χ2 [2] = 4.12, P = 0.128). Of the five

closed loops in the network of the comparison of postoper-

ative delirium, two loops (Dexm-Dexm + AAP-Prop + AAP

[01-04-05] [70] and Pro-Dexm + AAP-Prop + AAP [03-04-05]

[70]) were formed only by multi-arm trials. Thus, local in-

consistency was evaluated in three loops. There was no

significance in the local inconsistency between the direct

and indirect point estimates (Fig. 3C).

None of the regimens showed a lower incidence of POD

than Cont only in terms of both 95% CI and 95% PrIs (Fig.

4C). The rankogram showed that Prop + AAP and Keta had

the lowest incidence of POD (Fig. 5C). The cumulative

ranking plot was drawn, and the SUCRA probabilities of

the different pharmacological interventions for the POD

were calculated (Fig. 6C). The expected mean rankings and

SUCRA values of each pharmacological intervention are

www.anesth-pain-med.org 41

Pharmacological strategies for POD

Page 50

Fig. 8. Comparison-adjusted funnel plot.

presented in Fig. 7C. According to the SUCRA value, the in-

cidence of POD was lower in the order of Keta (87.1%),

Prop + AAP (86.0%), followed by Dexm + AAP (66.3%). The

comparison-adjusted funnel plots showed that the funnel

plots were symmetrical around the zero line, which sug-

gested a less likely publication bias (Fig. 8C).

Quality of evidence

Three outcomes were evaluated using the GRADE sys-

tem. For each outcome, the qualities of inconsistency, in-

directness, imprecision and publication bias were assessed

as not serious, but qualities of risk of bias were assessed as

serious. Thus, the overall quality of evidence for each out-

come was downgraded and rated as moderate (Table 3).

DISCUSSION

There are various pharmacological interventions to pre-

vent POD. We performed a network meta-analysis to com-

pare the effectiveness of reported pharmacological inter-

ventions. In our study, the incidence of POD was decreased

in the following order: Prop + AAP, Keta + Dexm, Gaba, and

Diaz + Flun + Pethi after all types of anesthesia; Prop + AAP,

Keta +Dexm, Gaba, and Diaz + Flun + Pethi after general

anesthesia; and Keta, Prop + AAP, and Dexm + AAP after

cardiac surgery. However, only the Dexm group showed a

statistically lower incidence of POD compared with the

control group after all types of anesthesia and after general

anesthesia.

In our study, there was a synergistic effect when Prop

was added to AAP. Although Prop + AAP failed to show sta-

tistical significance, Prop + AAP was ranked the most effec-

tive pharmacological intervention with a low incidence of

POD after all types of anesthesia and after general anesthe-

sia. Prop is a short-acting, intravenous sedative-hypnotic

agent commonly used for general anesthesia and sedation.

It has also been used to control other conditions such as

chemotherapy-induced emesis, as an antipruritic in pa-

tients with intractable pruritus due to liver disease, as an

adjuvant in alcohol withdrawal syndrome, and to treat sta-

tus epilepticus and severe refractory delirium. Prop has

been recently shown to have a long-term neuroprotective

effect and CNS inhibition effect [78–80]. AAP is commonly

used as an adjuvant analgesic. Some prior studies have in-

dicated that AAP reduces opioid consumption and inflam-

mation. Recently, AAP has been shown to confer central

B

A

C

42 www.anesth-pain-med.org

Anesth Pain Med Vol. 16 No.1

Page 51

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analgesic properties. This makes it likely that AAP would

reduce delirium. Despite these properties, IV AAP has not

been studied in the context of delirium prevention [81,82].

In our study, a synergistic effect occurred as the neuropro-

tective effect of Prop was added to the POD prevention ef-

fect of AAP.

Dexm, a selective α2-adrenergic agonist, has a strong

modulating effect on the activity of the sympathetic system

and is increasingly used as a sedative and an adjuvant an-

esthetic during surgery. Dexm binds to α2-receptors pres-

ent in both the central and peripheral nervous systems

[83–86]. Meanwhile, Dexm inhibits the release of norepi-

nephrine and sympathetic activity. In our study, Dexm re-

duced POD after all types of anesthesia and after general

anesthesia compared with the control group. These results

are in close agreement with a previous report by Al Tmimi

et al. [13] and Shen et al. [14] in which the risks of POD

were decreased in elderly patients after non-cardiac sur-

gery.

Several mechanisms have been suggested to explain how

Dexm reduces the incidence of POD after surgery and an-

esthesia. First, because of its highly selective and specific

α2-adrenergic agonistic characteristics, Dexm reduces the

amount of other sedatives and opioids used during sur-

gery, which may cause POD development and prolonga-

tion [40,51]. Second, Dexm attenuates the immune cascade

and inflammatory mediators, consequently relieving in-

flammatory response [87], which is associated with POD.

Third, Dexm induces a near-natural sleep-like sedative

pattern, which might help to reduce the risk of delirium

significantly. In addition, Dexm has been suggested as a

neuroprotectant during mechanical ventilation by reduc-

ing cerebral blood and cerebral perfusion pressure [88–90].

Keta, which is ineffective with monotherapy, when com-

bined with Dexm becomes the most effective modality.

Several reports in the past few years have evaluated Keta

for the treatment of hyperactive delirium. Keta offers a po-

tential option for treating difficult to manage hyperactive

delirium [91]. Moreover, Keta is an NMDA receptor antago-

nist, which reduces post-ischemic neuronal cell loss in the

cortex and improves neurological outcome after cerebral

ischemia [92,93]. Thus, Keta may produce a prolonged ef-

fect on postoperative neurocognitive function by causing a

“preconditioning-like” effect through the temporary inacti-

vation of NMDA receptors, thereby rendering these recep-

tors less susceptible to subsequent activation by ischemia

and reperfusion injury. However, this intriguing hypothesis

has not been formally tested. Keta may also confer neuro-

protection by suppressing the inflammatory response after

surgery [71,94].

For quality of life, which has recently attracted attention,

postoperative complications of surgical patients should be

prevented and treated appropriately. Among complica-

tions, POD can directly or indirectly increase postoperative

morbidity and mortality in elderly patients. Delirium is not

always a transient disorder; in some cases, it may be ac-

companied by subtle structural brain damage, leading to

permanent cognitive impairment. Therefore, there is grow-

ing interest in proper preventive methods [62,68].

In our study, we focused on the incidence of POD, pre-

ventive effect of interventions, and collected pharmacolog-

ical intervention data. There have been a number of pre-

ventative methods introduced in other studies, but their ef-

ficacy has not been properly compared. To compensate for

this, our NMA including various pharmacological inter-

ventions. Throughout this study, we attempted to identify

the most effective prevention of POD.

There are several limitations in this study. First, as with

all meta-analyses, there were clinical and methodological

heterogeneities regarding administration timing (for exam-

ple, preoperative or intraoperative or postoperative), meth-

od (for example, bolus or continuous infusion) and dose

spectrum of pharmacological interventions, and assessor

of POD and assessment tool of POD. Second, in our study,

Table 3. The GRADE Evidence Quality for Post-operative Delirium

Type No. of studiesQuality assessment

QualityRisk of bias Inconsistency Indirectness Imprecision Publication bias

All type of anesthesia 51 Serious Not serious Not serious Serious None ⨁⨁⨁○

Moderate

General Anesthesia 35 Serious Not serious Not serious Serious None ⨁⨁⨁○

Moderate

Cardiac surgery 19 Serious Not serious Not serious Serious None ⨁⨁⨁○

Moderate

GRADE: grading of recommendations, assessment, development, and evaluation.

www.anesth-pain-med.org 43

Pharmacological strategies for POD

Page 52

incidence of POD was used as an indicator of prevention.

However, to reduce morbidity and mortality associated

with POD, it is also important to reduce the severity and

duration of POD. Therefore, further studies should be con-

ducted to evaluate the effects on the severity and duration

of POD. Third, the most efficacious modalities determined

in the current NMA were documented to be effective in a

limited number of clinical trials. Further, as our NMA was

based on various single-center small-scale trials, a risk of

overestimation or underestimation of true treatment ef-

fects or lack of power to discriminate the effectiveness of

pharmacological interventions may be present. Therefore,

further large-scale RCTs with the qualified protocol should

be conducted in the future to encompass different phar-

macological interventions and substantiate our findings.

Despite these limitations, the current NMA has several

strengths compared to previous NMAs. First, a rigorous

methodology based on a published, pre-planned protocol

to provide evidence of pharmacological interventions to

prevent POD was used. Second, inconsistencies among the

enrolled studies were not significant, and publication bias

of the enrolled studies was minimal. Third, most enrolled

studies exhibited a low risk of bias, except for bias from the

randomization process and bias due to deviations from in-

tended intervention domains.

In conclusion, the NMA performed in this study has

strength and meaning for comparing pharmacological in-

terventions in the clinical efficacy of preventing POD.

Dexm showed a significant decrease in the incidence of

POD compared with the control group. The combination of

Prop and AAP and the combination of Keta and Dexm

seemed to be effective in preventing POD. However, fur-

ther studies are needed to determine the optimal pharma-

cological intervention to prevent POD.

SUPPLEMENTARY MATERIALS

Supplementary data including search terms used for

MEDLINE and EMBASE can be found online at https://doi.

org/10.17085/apm.20079

ACKNOWLEDGEMENTS

This research was supported by the Basic Science Re-

search Program through the National Research Foundation

of Korea (NRF) funded by the Ministry of Education, Sci-

ence and Technology (2018R1A2A2A05021467).

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article

was reported.

AUTHOR CONTRIBUTIONS

Conceptualization: Jun Mo Lee, Eun Jin Ahn, Geun Joo

Choi, Hyun Kang. Data curation: Jun Mo Lee, Hyun Kang.

Formal analysis: Ye Jin Cho, Hyun Kang. Funding acquisi-

tion: Hyun Kang. Methodology: Geun Joo Choi, Hyun

Kang. Project administration: Jun Mo Lee, Ye Jin Cho, Hyun

Kang. Visualization: Ye Jin Cho, Geun Joo Choi, Hyun Kang.

Writing - original draft: Jun Mo Lee, Ye Jin Cho, Geun Joo

Choi, Hyun Kang. Writing - review & editing: Jun Mo Lee,

Eun Jin Ahn, Hyun Kang. Investigation: Jun Mo Lee, Ye Jin

Cho, Eun Jin Ahn, Hyun Kang. Resources: Jun Mo Lee,

Hyun Kang. Software: Hyun Kang. Supervision: Eun Jin

Ahn, Geun Joo Choi, Hyun Kang. Validation: Jun Mo Lee,

Ye Jin Cho, Eun Jin Ahn, Hyun Kang.

ORCID

Jun Mo Lee, https://orcid.org/0000-0001-5607-7232

Ye Jin Cho, https://orcid.org/0000-0002-9138-6126

Eun Jin Ahn, https://orcid.org/0000-0001-6321-5285

Geun Joo Choi, https://orcid.org/0000-0002-4653-4193

Hyun Kang, https://orcid.org/0000-0003-2844-5880

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