Review Articles

pISSN: 1975-5171 eISSN: 2383-7977 Vol. 15/No. 2 Apr. 2020

REVIEW ARTICLES

133 Perioperative management of patients receiving non-vitamin K antagonist oral anticoagulants: up-to-date recommendations

Vol. 15. No. 2. April 2020 143 Viscoelastic coagulation test for liver transplantation

KSNACC KSAP KSOA KSPA KNRS KSCVA KSTA KSPS KSRA http://anesth-pain-med.ohttp://anesth-pain-med.ohttp://anesth-pain-med.orgrg rg http://anesth-pain-med.ohttp://anesth-pain-med.orgrghttp://anesth-pain-med.org

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pISSN: 1975-5171 eISSN: 2383-7977

Aims and Scope Anesthesia 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), and The Korean Spinal Pain Society (KSPS) and Korean Society of Regional Anesthesia (KSRA). 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 foallows : 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 or part of the Journal is indexed/tracked/covered by KoreaMed, KoMCI, Google Scholar, Science Central. Full text is freely available from http://anesth-pain-med.org The circulation number per issue is 400.

Korean Society of Neuroscience in Anesthesiology The Korean Society for Anesthetic Pharmacology

and Critical Care T

E S I K O G R O L E A IO N S E The Korean Society of Obstetric Anesthesiologists The Korean Society of Pediatric Anesthesiologists S O H C ST IE NE TY A OF OBSTETRIC

Korean Society of Cardiothoracic and Vascular Korean Neuromuscular Research Society Anesthesiologists

Korean Society of Transplantation Anesthesiologists The Korean Spinal Pain Society

Korean Society of Regional Anesthesia

Anesth Pain Med i Vol.15 No.2 April 2020

Publisher In-cheol Choi (University of Ulsan) Editor-in-Chief Young-Cheol Woo (Chung-Ang University) Associate Editor Chong Wha Baek (Chung-Ang University) Jung-Won Hwang (Seoul National University) Hyun Kyo Lim (Yonsei University) Editorial Board Yang Hoon Chung (Soonchunhyang University) Young Duck Shin (Chungbuk National University) Hyun Joo Ahn (Sungkyunkwan University) Woo-jong Choi (University of Ulsan) Hyungseok Seo (Kyung Hee University) Byung Gun Lim (Korea University) Seongtae Jeong (Chonnam National University) Wonjin Lee (Inje University) Jae-hun Kim (Konkuk University) Yong Seon Choi (Yonsei University) Jeong Rim Lee (Yonsei University) Young Ju Won (Korea University) Ethic Editor Young Yoo (Korea University) Statistics Editor Junyong In (Dongguk University), Dong-Kyu Lee (Korea University) Illustrated Editor Yong Beom Kim (Gachon University of Medicine and Science) Manuscript Editor Ji Youn Ha (The Korean Society of Anesthesiologists), Se Jueng Kim (MEDrang Inc.)

Contacting the Anesthesia and Pain Medicine All manuscripts must be submitted online through the APM e-Submission system at http://submit-apm.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 Anesthesiologists 101-3503, Lotte Castle President, 109 Mapo-daero, Mapo-gu, Seoul 04146, Korea Tel +82-2-795-5129, Fax +82-2-792-4089, E-mail [email protected]

Printed by M2community Co. 8th FL, DreamTower, 66 Seongsui-ro, Seongdong-gu, Seoul 04784, Korea ii Anesth Pain Med pISSN: 1975-5171 Table of Contents eISSN: 2383-7977

Vol.15 No.2 April 2020

Reviews 133 Perioperative management of patients receiving non-vitamin K antagonist oral anticoagulants: up-to-date recommendations Kwang-Sub Kim, Jong Wook Song, Sarah Soh, Young-Lan Kwak, Jae-Kwang Shim 143 Viscoelastic coagulation test for liver transplantation Sun Young Park

Anesthetic Pharmacology Clinical Research 152 Effect-site concentration of remifentanil for preventing propofol injection pain during induction of balanced anesthesia Joungmin Kim, Daehoon Kim, Hyung Gong Lee 157 Effect of preoperative administration of systemic alpha-2 agonists on postoperative pain: a systematic review and meta-analysis Ji Youn Ju, Kye-Min Kim, Sangseok Lee

Obstetric Anesthesia Clinical Research 167 Hemodynamic effects of carbetocin administered as an intravenous bolus or infusion during cesarean delivery Kihyug Kwon, Dohyung Kim, Hyunmin Jo, Ji Eun Park, Kyung Ok Kim

Pediatric Anesthesia Clinical Research 173 Clinical performance of Ambu AuraGainTM versus i-gelTM in anesthetized children: a prospective, randomized controlled trial Ji-Hyun Lee, Seungpyo Nam, Young-Eun Jang, Eun-Hee Kim, Hee-Soo Kim, Jin-Tae Kim

Cardiothoracic and Vascular Anesthesia Case Report 181 Acute normovolemic hemodilution for a patient with secondary polycythemia undergoing aortic valve replacement due to severe aortic stenosis Ilsang Han, Young Woo Cho, Soon Eun Park, Min Gi An, Ho June Kang, A-ran Lee

Transplantation Anesthesia Clinical Research 187 Systolic anterior motion of mitral chordae tendineae: prevalence and clinical implications in liver transplantation Hye-Mee Kwon, Kyoung-Sun Kim, Gyu-Sam Hwang

Spinal Pain Case Report 193 Carpal tunnel syndrome caused by thrombosed persistent median artery Sang Yoon Jeon, Kwangmin Lee, Weon-Joon Yang 199 Ultrasound-guided treatment of common peroneal neuropathy caused by Baker’s cyst: a clinical note Hana Cho, Dong-Rim Kim, Je Jin Lee, Seung Young Lee, Yong Bum Park, Hee Sung Kim, Hwa-Yong Shin

Anesth Pain Med iii 205 Herpes zoster in the ophthalmic branch of the trigeminal ganglia obscuring cavernous sinus thrombosis due to Streptococcus constellatus subsp. constellatus Ji Hye Lee, Hyun Joo Heo, Ki Man Kim, Han Gyeol Lee, Seung Min Baek, Da Wa Jung

Regional Anesthesia Clinical Research 209 Analgesic effect of ropivacaine with fentanyl in comparison with ropivacaine alone for continuous femoral nerve block after knee replacement arthroplasty: a prospective, randomized, double-blinded study Gunn Hee Kim, Joon Woo Lee, Go Eun Kim, Seong Su Lee, Shill Lee Son, Byung Uk Kim, Ha Na Cho, Mi Young Kwon, Min Seok Koo, Ji Eun Kim, Mi Jung Yun

General Articles Clinical Research 217 The question of preoperative anxiety and depression in older patients and family protectors Sehun Lim, Younmi Oh, Kwangrae Cho, Myoung-hun Kim, Sungho Moon, Seunghee Ki 226 Vocal cord paralysis following general anesthesia with endotracheal intubation: a clinical review on 43 cases Sehun Lim, Dong-chun Kim, Kwangrae Cho, Myoung-hun Kim, Sungho Moon, Hakmoo Cho, Seunghee Ki 233 Risk factors of emergency reoperations Tae Kwan Kim, Jun Rho Yoon, Yu Na Choi, Ui Jin Park, Kyoung Rim Kim, Taehee Kim 241 Correlation between patient health questionnaire-2 and postoperative pain in laparoscopic cholecystectomy Yusom Shin, Tae Woo Park, Huiyoung Kim, Dong-jin Shim, Hochul Lee, Joo-Duck Kim, Donghee Kang Case Report 247 Novel alternative for submental intubation Inyoung Jung, Byung Hoon Yoo, Ji Youn Ju, Sijin Choi, Jun Heum Yon, Kye-Min Kim, Yun-Hee Lim, Woo Yong Lee 251 Abdominal compartment syndrome caused by gastric distension in bulimia nervosa and fatal injury following surgical decompression Byeong Hun Eom, Hyun Kyoung Lim, Nayoung Tae, Helen Ki Shinn

iv Anesth Pain Med KSCVA ------Review Article Review

]. 5 , 4 [ ]. Non-vitamin K antagonist oral anticoagulants anticoagulants oral K antagonist ]. Non-vitamin 3 , 2 Based on cumulating clinical evidence stemming from from evidence stemming clinical Based on cumulating overcome the aforementioned pharmacological limitations limitations pharmacological aforementioned the overcome of warfarin to shown were NOACs trials, randomized multicenter large quires constant dose adjustments and laboratory monitor and laboratory dose adjustments constant quires [ ing (DOACs), anticoagulants oral direct also called (NOACs), to warfarin to in order developed as an alternative were 133 - - - - - eISSN 2383-7977 • Anticoagulants; Blood loss, surgical; Emergency; Non-vitamin K antagonist; Re K antagonist; Non-vitamin loss, Blood Emergency; surgical; Anticoagulants; type of NOAC. Neuraxial anesthesia should be performed 3 days after cessation of NOACs. NOACs. cessation of after 3 days be performed should anesthesia Neuraxial type NOAC. of de 2 days, 1 or an additional for be discontinued to needs instances, dabigatran In both heparin preoperative a require not do NOACs function. renal in decrease the on pending 12 h least at for be delayed preferably should surgeries urgent or Emergent therapy. bridge using consider be delayed, cannot h). If surgery if > 24 (better intake NOAC last the from ri for alfa andexanet and dabigatran for idarucizumab are which agents, reversal specific available, not are agents reversal specific If these edoxaban. and apixaban, varoxaban, concentrates. complex prothrombin using consider Keywords: versal. Indications of non-vitamin K antagonist oral anticoagulants (NOACs), consisting of two two of consisting (NOACs), anticoagulants oral K antagonist non-vitamin of Indications (rivaroxaban, inhibitor Xa factor direct and (dabigatran) inhibitor types: thrombin direct increasing years. Accordingly, few last the over expanded have edoxaban), and apixaban, fact the despite NOACs, to exposed being are surgery for presenting patients of number arti review This risk. bleeding perioperative increased to related inevitably are NOACs that a up set help to recommendations up-to-date evidence-based clinical recent contains cle patients for milieu perioperative a safe provide to strategy management multidisciplinary rec key several evidence, clinical related of paucity the despite In brief, NOACs. receiving expert consensus, evidence, clinical emerging the can be drawn based on ommendations safe it seems surgeries, In elective NOACs. of properties pharmacological predictable and the of regardless NOAC, cessation of after 2 days surgeries risk high-bleeding perform to Perioperative management of patients receiving patients receiving of management Perioperative K antagonist oral anticoagulants: non-vitamin recommendations up-to-date Kwak, Song, Sarah Soh, Young-Lan Jong Wook Kwang-Sub Kim, Shim and Jae-Kwang Research Institute, Medicine, Anesthesia and Pain and Pain Department of Anesthesiology Seoul, Korea University College of Medicine, Hospital, Yonsei Severance Cardiovascular Anesth Pain Med 2020;15:133-142 2020;15:133-142 Med Pain Anesth https://doi.org/10.17085/apm.2020.15.2.133 pISSN 1975-5171 ]. For that purpose, vitamin K an purpose, that ]. For 1 [

INTRODUCTION April 9, 2020 April March 2, 2020 March : March 5, 2020 March Atrial fibrillation, the most frequently encountered ar encountered frequently the most fibrillation, Atrial 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 which (http://creativecommons.org/licenses/by-nc/4.0) License Non-Commercial Attribution Commons Creative the of terms the under Access article is an Open This distributed cited. is properly work original the provided in any medium, reproduction and distribution, use, non-commercial unrestricted 2020 Anesthesiologists, Society of Korean © the Copyright volving rhythm control control rhythm volving been warfarin, long used its incon has despite tagonist, effect re which anticoagulation and unpredictable stant rhythmia, is associated with thromboembolism and stroke and stroke with is associated thromboembolism rhythmia, in other therapies amongst needwhich be to prevented 03722, Korea Korea 03722, 82-2-2228-8500 Tel: 82-2-364-2951 Fax: [email protected] E-mail: Cardiovascular Hospital, Yonsei Yonsei Hospital, Cardiovascular 50-1 Medicine, of College University Seoul Seodaemun-gu, Yonsei-ro, Department of Anesthesiology and and Anesthesiology of Department Pain and Anesthesia Medicine, Pain Severance Institute, Research Corresponding author author Corresponding M.D., Ph.D. Shim, Jae-Kwang Received Received Accepted Revised Revised Anesth Pain Med Vol. 15 No. 2 be non-inferior to warfarin in preventing stroke and throm- types depending on their action mechanisms (Fig. 1): the boembolism with lower risk of serious bleeding events in direct thrombin inhibitor (dabigatran) [19], and the direct patients with non-valvular atrial fibrillation [6–9]. Addi- factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban) tionally, owing to the reliable pharmacokinetic properties which imped the conversion of prothrombin to thrombin of NOACs, they were prescribed in fixed doses without lab- [20]. oratory monitoring. This led to the incorporation of NOACs Compared to warfarin, the pharmacokinetic advantages as valuable therapeutic options for anticoagulation in atrial of NOACs include a more rapid onset (time to peak: 1 to 3 fibrillation patients, by the American Heart Association h), shorter elimination half-life (5 to 15 h), lower predispo- (AHA)/American College of Cardiology (ACC)/Heart sition to food and drug interaction (do not require restric- Rhythm Society (HRS) in 2014 [1]. With the emergence of tion on vitamin K-containing food), and a more predictable newer evidences showing favorable clinical efficacy and anticoagulation effect (Table 1) [18,20]. These features al- safety of NOACs in various subsets of patients [10–12], fo- low fixed-dose administration in the absence of routine cused update of the 2014 guideline by the AHA/ACC/HRS therapeutic laboratory monitoring. Thus, the major studies in 2019 recommended the use of NOACs as first-line agents that compared the efficacy of NOACs with warfarin did not over warfarin in eligible patients with non-valvular atrial carry out dose adjustments or perform routine laboratory fibrillation (i.e., except those with moderate-to-severe mi- testing to detect the therapeutic level of NOACs [6–9]. tral stenosis or a mechanical heart valve) [13]. A similar NOACs undergo hepatic metabolism and plasma hydro- preference of NOACs over warfarin was also advocated by lysis, and are substrates for the multidrug transporter the European Heart Rhythm Association in 2018 [14]. Fur- P-glycoprotein and CYP 3A4 metabolism, while edoxaban thermore, current indications of NOACs include treatment exists mostly in an unchanged form in plasma, being mini- or prevention of deep vein thrombosis and pulmonary embolism, promoting its widespread use [15–17]. Accordingly, increasing number of patients presenting for surgery are exposed to NOACs, despite the fact that NO- Intrinsic pathway Extrinsic Pathway

ACs can inevitably increase risk of bleeding as other anti- XII XIIa VIIa VII Warfarin coagulants. This review aimed to provide essential knowledge on NOACs, and evidence-based up-to-date recom- XI XIa mendations regarding the perioperative management of NOACs. Warfarin IX IXa Common Pathway

Rivaroxaban Warfarin X Xa Apixaban PHARMACOLOGICAL ASPECTS OF Edoxaban NOACS Warfarin II (Prothrombin) IIa (Thrombin) Dabigatran Unlike warfarin which affects multiple vitamin K-dependent coagulation factors II, VII, IX, and X, NOACs were designed to directly act on a single target factor to yield a Fibrinogen Fibrin more predictable anticoagulant response [18]. Currently, Fig. 1. Comparison of action mechanisms between warfarin and there are 4 approved NOACs which can be divided in 2 non-vitamin K antagonists.

Table 1. Pharmacological Properties of Non-vitamin K Antagonists Non-vitamin K antagonists Dabigatran Rivaroxaban Apixaban Edoxaban Inhibitory target Thrombin Factor Xa Factor Xa Factor Xa Time to peak 1–2 h 2–4 h 1–4 h 1–2 h Half-life 12–17 h 5–9 h 8–15 h 10–14 h Renal elimination 80% 33% 20% 50% Dialyzable Yes No No No Reversal agent Idarucizumab Andexanet Andexanet Andexanet

134 www.anesth-pain-med.org KSCVA ------135 ]. Although ]. Although ]. Shortly af ]. Shortly 27 [ 13 [ ]. Thus, theoretical ]. Thus, ]. Thus, despite the the despite ]. Thus, 30 [ 27 [ ]. 26 [ ]. Yet, administration of a second administration ]. Yet, 29 [ ]. 13 [ ]. Thus, it frees thrombin from dabigatran inhibition inhibition dabigatran from thrombin it frees ]. Thus, ]. The recommended administration protocol suggests suggests protocol administration recommended The ]. Andexanet is an inactive variant of human recombinant recombinant of human variant Andexanet is an inactive agent, Considering the importance of a specific reversal While relevant clinical evidence is limited, overall, idaru evidence is limited, overall, clinical While relevant 28 29 aban- or apixaban-induced life-threatening or uncon life-threatening or apixaban-induced aban- based bleeding, on the limited evidence from trolled been incorporated newly has this and volunteers, healthy IIa (class guidelines of AHA/ACC/HRS in the 2019 update of evidence B-NR) level recommendation, of rele of andexanet and the publication the approval ter in 2019, full the AHA/ACC/HRS focused by update vant dence of thromboembolic events at 30 days after idaruci after 30 days at events dence of thromboembolic 4.8% was administration zumab ap has FDA the U.S. evidence, clinical of related paucity dab receiving for patients the use of idarucizumab proved bleeding or require exhibit who life-threatening igatran of surgery 2019 update in the emergent as incorporated level recommendation, I (class guidelines AHA/ACC/HRS of evidence B-NR) Andexanet alfa by Xafactor replaced is serine-residue the active in which the prevent activity and to its catalytic eliminate to alanine complex of prothrombin formation effect of all the anticoagulant reverse andexanet can ly, An dabigatran. except Xa factor inhibitors, are that NOACs Xa affinity factor to binding is similar inhibitors dexanet’s Xa factor of the native that to (accelerated-approval approved recently has FDA the U.S. of rivarox the use of andexanet alfa for reversal pathway) fold higher binding affinity to dabigatran than thrombin thrombin than affinity dabigatran to binding fold higher [ effect in a the anticoagulation reverses and immediately administration intravenous after manner dose-dependent [ in 50 boluses given of 5 g), each (total two 2.5 g intravenous 99% of the es reverse to 5–10 min in order over ml infusion effect anticoagulation dabigatran’s timated 45 min, doses of 2 is approximately half-life its elimination been and sus exert shown to a complete have g or more 72 h tained effect over if necessary. be considered, dose of 5 g may dabig been be shown to effective in reversing has cizumab efficacy also been has Its bleeding. major atran-induced emergency surgery,requiring nor and patients in shown with hemostasis its use be the sur confirmedmal could by while the inci 93% of the patients, geons in approximately ------], 23 , NOAC and surgery and NOAC 9 , 7 , ]. 6 4 ]. [ ]. 24 [ ]. Therefore, ]. Therefore, 26 ]. Additional ]. In contrast, contrast, ]. In 20 22 13 , [ [ 18 [ ]. Although there is limit there ]. Although 27 – 25 [ ]. NOACs are mostly excreted via via excreted mostly are ]. NOACs 21 ], all anticoagulants have the innate the innate have ], all anticoagulants [ 22 ]. Nonetheless, bleeding complications happen, happen, bleeding complications ]. Nonetheless, 22 [ NOACS AND REVERSAL AGENTS REVERSAL AGENTS NOACS AND BLEEDING RISK ASSOCIATED WITH ASSOCIATED BLEEDING RISK Idarucizumab is a humanized monoclonal antibody antibody monoclonal is a humanized Idarucizumab Unlike warfarin which can be readily reversed by vitamin by reversed warfarin be readily can Unlike which Although NOACs were shown to be associated with lower with be to associated shown lower were NOACs Although www.anesth-pain-med.org fragment (antigen-binding fragment; Fab) which has a 350- a has which fragment; (antigen-binding Fab) fragment ing studied, and the results are being awaited [ awaited being are and the results studied, ing Idarucizumab ly, another reversal agent, ciraparantag, which can theoreti can which ciraparantag, agent, another reversal ly, is be effects of all NOACs the anticoagulation reverse cally were approved by the U.S. Food and Drug Administration Drug and Administration Food U.S. the by approved were and andexanet reversal for dabigatran idarucizumab (FDA): reversal apixaban and alfa for rivaroxaban ping major bleeding events bleeding events major ping unexpectedthe due to evidencetheseon agents ed clinical agents two reversal bleeding events, of spontaneous nature whether spontaneous in nature or associated with or associated an inva in nature whether spontaneous agents reversal the surgery. Accordingly, procedure/ sive be in stop to effective shown were developed for NOACs bleeding was similar or even less than that of patients on on of patients that than less or even similar bleeding was warfarin zen plasma (FFP), there were no available reversal agents agents reversal no available were (FFP), there plasma zen the Still, trials. III clinical phase during the major for NOACs who exhibited major on NOACs of patients rate fatality with an overall 3.3% incidence of major bleeding 3.3% incidence of major with an overall (PCC), fro or fresh concentrates complex K, prothrombin bleeding, which accounted for approximately 90% of the ma for approximately accounted which bleeding, warfarin to [ compared bleeding, jor extracranial lar atrial fibrillation treated with NOACs, the estimated pooled the estimated with NOACs, treated fibrillation atrial lar 0.4% was stroke incidence of hemorrhagic risk of gastrointestinal a 1.5-fold increased conferred NOACs rates of intracranial and life-threatening bleeding when com and life-threatening of intracranial rates with warfarinpared [ with non-valvu patients bleeding risk. In increase to potential dabigatran, rivaroxaban, apixaban, and edoxaban, respec edoxaban, and apixaban, rivaroxaban, dabigatran, mandating elimination, renal unchanged undergo tively, function monitoring of renal the need for regular verapamil, may increase the active drug the active of the NO levels increase may verapamil, edoxaban except ACs, of 50% and 27%, 33%, 80%, approximately and kidney, the mally metabolized through CYP 3A4 through metabolized mally inhibit strongly drugs of that administration concomitant and amiodarone, as dronedarone, such these pathways, Anesth Pain Med Vol. 15 No. 2 study results of a prospective multicenter trial addressing taining the balance between bleeding and thromboembol- the efficacy of andexanet alfa for bleeding associated with ic risk. factor Xa inhibitors (ANNEXA-4 trial) were published [25]. To provide the patients with a safe perioperative milieu, In that study, treatment with andexanet resulted in imme- two major questions arise: 1) when to discontinue NOACs diate reduction of anti-factor Xa activity (92% reduction in before surgery, and 2) the need for bridge-anticoagulation both apixaban and rivaroxaban), yielding good hemostatic therapy. First, NOACs have a relatively short half-life, rang- efficacy in 82% of the patients at 12 h, with a thromboem- ing from 5 to 15 h in patients with normal renal function bolic event rate of 10% at 30 days. [20]. Thus, discontinuing NOACs for 2 days before surgery Current dosing recommendations are intravenous bolus with high bleeding risk would allow negligible residual over 15–30 min, followed by 2 h of continuous infusion: 1) drug concentration (usually < 10% corresponding to dis- 400 mg bolus, 480 mg infusion in patients who received ri- continuation for 3 to 4 half-lives), whereas discontinuation varoxaban (last intake > 7 h) or apixaban, and 2) 800 mg for 1 day would suffice for surgeries or procedures with low bolus, 960 mg infusion in patients who received rivarox- bleeding risk (15 to 25% residual activity) [38]. Notably, the aban within 7 h (or unknown timing) or edoxaban [14,25]. elimination of NOACs depends on the renal function to Notably, andexanet also binds to heparin-antithrombin various degrees which must be assessed and properly tak- III complex, reversing the actions of low molecular-weight en into consideration before surgery. Based on creatinine heparin and unfractionated heparin [31]. clearance (CrCl), dabigatran needs to be discontinued for 3 days and 4 days with CrCl of 50 to 79 ml/min and 30 to 49 Ciraparantag ml/min, respectively [14]. In case of rivaroxaban, apixaban, and edoxaban, 2 days would suffice in most of the patients, Ciraparantag is a synthetic cationic molecule that was de- regardless of the renal function. In all patients, further con- veloped to reverse the anticoagulation effect of unfractionated sideration should be given when receiving concomitant or low molecular-weight heparin via non-covalent hydrogen dronedarone, amiodarone, or verapamil, such as discon- linkage and charge-charge interaction [32]. Also, it directly tinuation for an additional 1 day when the thromboembol- binds to Xa inhibitors and thrombin inhibitors in a similar ic risk is not high [14,21]. manner [20]. Thus, it would be able to reverse the anticoagu- Second, preoperative bridge therapy with heparin is usu- lation effect of all NOACs, irrespective of their action mecha- ally recommended for patients at high-risk of thromboem- nism. Available data which show its promising results in re- bolic complication, such as those with mechanical heart versing the anticoagulation effect of all NOACs are limited to valve [13]. However, as NOACs are currently not indicated animal studies or healthy volunteers [33]. Currently, ci- in patients with mechanical heart valve, this recommenda- raparantag is not approved for clinical use. tion does not apply to patients receiving NOACs. Also, the short elimination half-lives of NOACs require a short duration ELECTIVE SURGERY AND NOACS of cessation before surgery as opposed to the 5 days required in warfarin [20,39]. Moreover, discontinuation of NOACs has Approximately 10% of patients who require oral antico- not been shown to result in rebound hypercoagulability [7–9]. agulants undergo surgery or invasive procedures yearly Indeed, sub-analysis of major NOAC trials showed a low inci- [34,35]. For patients’ safety, it is unarguable that NOACs dence of thromboembolic events ranging from 0.2 to 0.6% should be appropriately discontinued in patients undergo- without bridging, whereas bridging with heparin resulted in ing intermediate/ high bleeding risk procedures. So far, increased bleeding complications without any benefit in clinical evidence is not enough to support a uniform guide- terms of thromboembolic risk [24,40,41]. Thus, bridging ther- line, and current recommendations by responsible societ- apy for NOACs in the preoperative period is currently not rec- ies including the AHA, European Heart Rhythm Associa- ommended, but it should be restarted after surgery as soon as tion, and the European Society of Anaesthesiologists pub- possible [14]. lished in 2017, 2018, and 2017, respectively, are largely So far, clinical evidence adhering to the above-men- based on limited clinical studies and expert consensus tioned recommendations for interruption of NOACs before [14,20,36–38]. Nonetheless, NOACs’ reliable pharmacolog- surgery resulted in a similar rate of postoperative bleeding ic profiles would permit safe surgery and recovery by main- events when compared to patients receiving warfarin [38].

136 www.anesth-pain-med.org KSCVA . - - - - - 137 Fig. 2 Fig.

]. Dabiga 44 [ ]. ≥ 72 h ≥ 72 h ≥ 72 h 14 Neuroaxial Anesthesia Not advised High ≥ 48 h ≥ 48 h ≥ 48 h ≥ 48 h NOACS Rivaroxban, apixban, edoxaban cent clinical evidences are displayed in displayed evidences are clinical cent Surgical bleeding risk Low ≥ 24 h ≥ 24 h ≥ 24 h ≥ 36 h EMERGENT/URGENT SURGERY AND EMERGENT/URGENT In life-threatening or salvage emergencies such as cardi such emergencies salvage or life-threatening In A summary of the current recommendations incorporat recommendations summary A current the of be immediately should NOACs situation, an emergent In NOACs on a more conservative considering the even basis on a more NOACs regard evidence in that limited clinical more for 3, 4, and 5 be to discontinued recommended was tran with CrCl of in patients days > and 79, 80, 50 to <50 ml/ and edoxaban apixaban, Rivaroxaban, min, respectively. before for 3 days be to discontinued recommended were anesthesia. Neuraxial re the most ing possibly chromogenic anti-factor Xa or diluted throm anti-factor assay, chromogenic possibly [ECA]) assays bin time [dTT]/ecarin-based [ stopped, and the following detailed knowledge should be ac should detailedstopped,knowledge and the following 3) renal used, of intake, time 1) type2) last of NOAC quired: (prothrombin tests of coagulation function, and 4) full panel time [aPTT],time [PT], partial thromboplastin activated and ------≥ 72 h ≥ 96 h ≥ 120 h Neuroaxial Anesthesia Not advised NOAC and surgery and NOAC Additional considerations Duration of non-vitamin K antagonists interruption ]. Recently, full full ]. Recently, High ≥ 96 h ≥ 48 h ≥ 72 h 42 , Dabigatran 24 [ Not enough evidence Surgical bleeding risk Low ≥ 48 h ≥ 24 h ≥ 36 h Dabigatran is usually not indicated in patients with creatinine clearance < 30 ml/min Consider adding an extra 24 h in patients taking dronedarone, amiodarone, or verapamil longer than 4 days of interruption, while related evidence ensuring the safety of this protocal is lacking longer than 4 days of interruption, while related evidence ensuring the safety of this protocal No preoperative bridge theray with heparin is indicated during the interruption of non-vitamin K antagonists No preoperative bridge theray with heparin is indicated during the interruption of non-vitamin ]. In that study, NOACs were discontinued for 1 for 1 discontinued were NOACs study, that ]. In Neuraxial anesthesia is not advised at creatinine clearance < 30 ml/min regardless of the type of non-vitamin K antagonist Neuraxial anesthesia is not advised at creatinine clearance < 30 ml/min regardless of the However, patients on dabigatran may present at the time of surgery with creatinine clearance < 30 ml/min and may require patients on dabigatran may present at the time of surgery with creatinine clearance < 30 ml/min However, clearance Creatinine 43 ≥ 80 ml/min < 30 ml/min 50-79 ml/min 30-49 ml/min [ Perioperative management of non-vitamin K antagonists for elective surgery. elective for K antagonists non-vitamin of management Perioperative Neuraxial anesthesia, such as spinal or epidural, is con or epidural, as spinal such anesthesia, Neuraxial www.anesth-pain-med.org Fig. 2. Fig. esthesia and Pain Medicine published in 2018 approaches in 2018 approaches published Medicine and Pain esthesia sidered a high-bleeding risk procedure. The most recent recent most The risk a high-bleeding procedure. sidered the American An Society of Regional by recommendations less than 1%, showing similar efficacies as with efficacies similar warfarin 1%, showing than less man usefulness of the simple and confirming the clinical strategy. agement sumed 1 day and 2 to 3 days after low- and high-bleeding and high-bleeding low- after days 3 and 2 to sumed 1 day bleeding rates major Overall, respectively. risk surgeries, were of thromboembolism 2%, and the rates than less were respectively. In patients receiving dabigatran, longer inter longer dabigatran, receiving patients In respectively. re were CrCl. NOACs for accounting applied ruptionwas more insights regarding the perioperative NOACs manage NOACs the perioperative regarding insights more ment risk and high-bleeding procedures, for low- and 2 days day data from the perioperative anticoagulation use for surgery anticoagulation the perioperative from data cohort trial and so published, far, was (PAUSE) evaluation provided trial that multicenter prospective it is the largest Data from pivotal NOACs studies including the German the German including studies NOACs pivotal from Data bleedingincidences registry, major reported and Canadian surgery 3% after 0.6 to from ranging Anesth Pain Med Vol. 15 No. 2 ac, vascular, or neurosurgical surgeries that cannot be de- able in all institutions, and clinical evidence on targeting layed even for a few hours, consideration should be given therapies according to the specific test results is lacking, to administer specific reversal agents: idarucizumab for leaving the clinical judgment at the discretion of the at- dabigatran and andexanet for rivaroxaban, apixaban, and tending physician. edoxaban [14]. Yet, in case of surgeries requiring systemic In case of dabigatran, hemodialysis may be considered, heparinization, such as cardiac or vascular, the use of an- as it has been shown that approximately 50 to 60% of the dexanet may be deferred until heparin reversal with prota- drug was removed after 4 h of hemodialysis administration mine, as it may inhibit the anticoagulant effect of heparin [55]. But, the practicability of hemodialysis remains ques- [31] which is an absolute necessity for surgery. It should be tionable considering that it requires anticoagulation. Other noted that the incidence of thromboembolic events NOACs are unlikely to be removed by hemodialysis due to showed a dramatic increase to 18% after administration of their high-protein binding properties [56]. the reversal agents [45,46], whereas it was less than 1% in Other non-specific measures to decrease its absorption is case of planned interruption of NOACs [43]. Thus, apart the use of activated charcoal (30 to 50 g), which has been from their high cost, the use of specific reversal agents shown to effectively reduce the absorption of recently over- should be carefully decided. dosed NOACs [36]. Thus, it may be considered in patients If these specific reversal agents are not accessible, PCC who ingested NOAC within 2 to 4 h before urgent surgery. may be given, although the supporting clinical evidence is However, its efficacy in patients who received a prescribed limited and controversial [47–49]. Suggested regimens of dose of NOAC, and not accidental overdosed, remains ques- PCC include 2 doses of 4-factor PCC or an initial bolus of tionable considering the side effects of charcoal including 50 IU/kg followed by an additional 25 IU/kg if necessary nausea/vomiting and aspiration [57]. [14]. FFP is not likely to effectively reverse NOACs, unless A summary of the current recommendations incorpo- used in large volumes (at least 8–16 units of FFP would rating the most recent clinical evidences are displayed in equal the dose of 25–50 IU/kg of 4-factor PCC), and thus, it Table 2 and Fig. 3. is not recommended for that purpose [50]. Also, without related clinical evidence, other therapies aimed at reducing CONCLUSIONS perioperative blood loss, such as tranexamic acid, which is an antifibrinolytic agent that may be considered due to its Emerging evidence advocates the use of NOACs over war- proven efficacy and relative safety in major surgeries [36]. farin in patients with non-valvular atrial fibrillation, with in- In urgent cases that need to be done within hours, con- dications expanding to patients at increased risk of deep sideration should be given to delaying the surgery for at vein thrombosis or pulmonary embolism [13,14,16,58]. As least 12 h (preferably 24 h) after the last NOAC administra- the field of anesthesiology has expanded to perioperative tion, as a considerable amount of the given NOAC would medicine, critical care, and pain medicine, patients receiv- be eliminated within this timespan. After delay, the coagu- ing NOACs will be encountered more frequently in our daily lation tests should be performed again. Routine coagula- practice. Practice guidelines regarding the management of tion tests, such as PT and aPTT, cannot quantify or deter- NOACs should be available in every institution incorporat- mine the activity of any given NOAC. Yet, a normal dTT or ing the recent evidence regarding the interruption strategy aPTT would most likely exclude high therapeutic levels of and specific reversal agents to provide optimal care in pa- dabigatran, whereas normal PT would rule out high levels tients requiring surgeries. of rivaroxaban as well as edoxaban (to a lesser extent) [51]. Despite these associations, it should be noted that none of CONFLICTS OF INTEREST the routine coagulation tests ensure the absence of clinically significant levels of NOACs even when the test results No potential conflict of interest relevant to this article are normal [51]. Preferably, specific tests to measure the was reported. activity of NOACs should be performed to guide the need for reversal agents. These include ECA for dabigatran and AUTHOR CONTRIBUTIONS anti-factor Xa assays for rivaroxaban, apixaban, or edoxaban [52–54]. However, these tests may not be readily avail- Conceptualization: Kwang-Sub Kim, Jae-Kwang Shim.

138 www.anesth-pain-med.org KSCVA - 139 Rivaroxaban, apixaban, edoxaban apixaban, Rivaroxaban, Repeat full coagulation tests antagonist (preferably > 24 h) 1) Idarucizumab for dabigatran > apixaban) 7 h or tive factor Xa factor tive edoxaban) or unknown] within 7 h [or Andexanet alfa Andexanet Xa factor recombinant human of variant Inactive na affinity with similar to inhibitors Xa factor to Binds complex III heparin-antithrombin to Also binds infusion: continuous min + 2 h of 15–30 over bolus IV intake (rivaroxaban infusion 480 mg bolus, 1) 400 mg intake (rivaroxaban infusion 960 mg bolus, 2) 800 mg applicable not Hemodialysis Urgency (requires surgery within hours) Consider using specific reversal agents: if specific reversal agents are not available prothrombin complex concentrates, if necessary Consider using prothrombin complex concentrates, Repeat administration of specific reversal agents or Delay surgery for > 12 h from the last non-vitamin K Delay surgery for > 12 h from the last non-vitamin 2) Andexanet for rivaroxaban, apixaban, or edoxban Andexanet for rivaroxaban, apixaban, 2) NOAC and surgery and NOAC Full coagulation tests Additional considerations Dabigatran PCC, 2 doses of 4-factor PCC or bolus of 50 IU/kg of (+ 25 IU/kg bolus PCC or as necessary) 4-factor PCC, 2 doses of A normal aPTT or dTT may rule out high levels of dabigatran or dTT normal aPTT A Tranexamic acid, bolus 10–30 mg/kg (10–20 min) + continuous infusion 3–5 mg/kg/h infusion + continuous min) mg/kg (10–20 10–30 bolus acid, Tranexamic A normal PT may rule out high levels of revaroxaban, apixban, edoxaban may rule out high levels normal PT A thrombin Idarucizumab fragment antibody monoclonal Humanized affinity than higher with 350-fold dabigatran to Binds min 5–10 5 g (2.5 g over of bolus IV × 2) 4 h for Hemodialysis Risk of thromboembolic events may rise considerably after using specific reversal agents the reversal of heparin as it may interfere with necessary action heparin-antithrombin III complex Repeat full coagulation tests 1) Idarucizumab for dabigatran Consider using specific reversal agents: Emergency (requires immediate surgery) if specfic reversal agents are not available None of routine coagulation tests can ensure the absence of clinically signficant levels of non-vitamin K antagonists prothrombin complex concentrates, if necessary In case of cardiac or vascular surgeries requiring systemic heparinization, use of andexanet should be dalayed until after Consider using prothrombin complex concentrates, Consider using prothrombin complex concentrates, Repeat administration of specific reversal agents or 2) Andexanet for rivaroxaban, apixaban, or edoxban Andexanet for rivaroxaban, apixaban, 2) (PT, aPTT, and possibly dTT and/or ECT for dabigatran and anti-factor Xa assay for rivaroxaban, apixban, or edoxaban) for dabigatran and and/or ECT and possibly dTT aPTT, (PT, Reversal Agents and Alternative Options for Patients on Non-vitamin K Antagonist Requiring Emergent/Urgent Surgery Emergent/Urgent Requiring K Antagonist Non-vitamin on Patients for Options Alternative and Agents Reversal Perioperative management of non-vitamin K antagonists for emergent/urgent surgery. PT: prothrombin time, aPTT: activated partial aPTT: time, activated PT: prothrombin surgery. emergent/urgent for K antagonists non-vitamin of management Perioperative Mode of action of Mode Non-vitamin K antagonists K Non-vitamin options Alternative Dosage

Reversal agents Reversal www.anesth-pain-med.org Fig. 3. Fig. assay. ecarin-based ECT: time, dTT: thrombin time, diluted thromboplastin IV: intravenous, PCC: prothrombin complex concentrates. complex PCC: prothrombin intravenous, IV: Table 2. Table Anesth Pain Med Vol. 15 No. 2

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142 www.anesth-pain-med.org KSTA ------]. Furthermore, CCT has CCT has ]. Furthermore, 6 , 5 Review Article Review ]. This test was developed in 1948 and and 1948 in developed was test This ]. 7 [ ] and that CCT is insufficient to distinguish whether a whether a distinguish to insufficient is CCT ] and that 4 – 2 perioperative applications have been reported. Viscoelastic been Viscoelastic reported. have applications perioperative in is a method determine to test coagulation coagulation while the the thromboelastrography obtaining by real-time this test that is reported It is in process. blood coagulation (aPTT), and fibrinogen. time (TT), count, thrombin platelet predict to it is difficult that reported have studies However, with CCT of bleedingthe possibility or blood transfusion [ [ occurred has coagulopathy it and hence, time-consuming, of being the disadvantage judgment rapid require that be in situations applied cannot has test viscoelastic coagulation Recently, and treatment. overcome can as a method that attention been garnering theselimitations distin by treatment targeted use enabling for in approved with co in patients factors coagulation deficient guishing of cases the 1960s, Since deficiencies. factor agulation 143 ------eISSN 2383-7977 • Blood coagulation disorders; Blood coagulation tests; Liver transplantation; transplantation; Liver tests; coagulation Blood disorders; coagulation Blood Keywords: Keywords: Thromboelastography. challenging. Proper perioperative monitoring of hemostasis is essential to predict the risk risk the predict to is essential hemostasis of monitoring perioperative Proper challenging. guide to and in time, hemorrhage of causes potential detect to surgery, during bleeding of in the is questionable test coagulation conventional of value The therapy. hemostatic adequate to inability the and time turnaround long their to due setting perioperative acute Viscoelastic disease. with liver in patients in hemostasis changes complex the reflect ly whole-blood of aspects multiple of measurement simultaneous provide tests coagulation re that inhibitors and factors fibrinolytic and coagulation plasmatic including coagulation fi and stability, clot mechanical initiation, Coagulation hemostasis. of aspects most flect visco Therefore, techniques. point-of-care using immediately can be estimated brinolysis blood patient guide to be useful would & TEG ROTEM including tests coagulation elastic transplantation. liver during strategy management Viscoelastic coagulation test for liver test coagulation Viscoelastic transplantation Park Sun Young University Seoul Medicine, Soonchunhyang and Pain Department of Anesthesiology Hospital, Seoul, Korea is transplantation liver undergoing patients in management transfusion and Coagulation Anesth Pain Med 2020;15:143-151 Med Pain Anesth https://doi.org/10.17085/apm.2020.15.2.143 pISSN 1975-5171 INTRODUCTION ], it is important to rapidly perceive and manage manage and perceive rapidly to ], it is important March 2, 2020 March March 5, 2020 March 1 [ As the liver plays an important role in the blood coagula role an important plays As the liver 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 permits which (http://creativecommons.org/licenses/by-nc/4.0) License Non-Commercial Attribution Commons Creative the of terms the under Access article is an Open This distributed cited. is properly work original the provided in any medium, reproduction and distribution, use, non-commercial unrestricted 2020 Anesthesiologists, Society of Korean © the Copyright gery. Conventional coagulation test (CCT) test diagnose to co coagulation gery. Conventional (BT), time bleeding for tests includes disorders agulation time time (PT), partial prothrombin activated prothrombin the changes of the blood coagulation status to prevent ex prevent to status of the blood coagulation the changes during sur blood transfusion bleeding reduce and cessive excessive bleeding and blood transfusion during liver during liver bleeding and blood transfusion excessive poor out risk for patients’ factors are transplantations comes not stable. Most patients undergoing liver transplantation transplantation liver undergoing patients Most not stable. status in blood coagulation changes experience severe tendency. bleeding in Because results surgeryduring that tion system, hepatic dysfunction could lead to coagulopa to lead could dysfunction hepatic tion system, system the coagulation failure, during hepatic Even thy. it is but mechanisms, various via a balance maintain can 04401, Korea Korea 04401, 82-2-709-9291 Tel: 82-2-790-0394 Fax: [email protected] E-mail: Pain Medicine, Soonchunhyang Soonchunhyang Medicine, Pain 59 Hospital, Seoul University Seoul Yongsan-gu, Daesagwan-ro, Corresponding author author Corresponding M.D., Ph.D. Park, Sun Young and Anesthesiology of Department Accepted Received Received Anesth Pain Med Vol. 15 No. 2 can provide a more comprehensive and accurate informa- time (clotting time or CT in ROTEM; reaction time or R in tion about coagulation function than conventional tests [8]. TEG) which is the time it takes until the graph amplitude Other than the platelet count, most CCTs are plasma-based reaches 2 mm. This can be considered an index of the co- tests and can only reflect the initial stages of the coagula- agulation factor function. Delay in this parameter can sig- tion. In contrast, viscoelastic coagulation tests are plasma nal coagulation factor deficiency or dysfunction. The next and cell-based tests using the whole blood and can provide parameter is the amount of time it takes for the amplitude information from coagulation initiation to fibrinolysis, the to increase from 2 mm to 20 mm which is referred to as the strength and stability of the clot. Therefore, it provides a clot formation time (clot formation time or CFT in RO- real time accurate biological representation of coagulation TEM; k in TEG), and this reflects fibrin formation. Platelet [6] and can be used as a point-of-care testing. The visco- response is considered to start at this time, and the slope elastic coagulation test is often applied to patients under- of the graph until this point is represented as the a angle. going surgery for trauma in which bleeding can be prob- Then, the amplitude gradually increases and reaches max- lematic, and various studies on its utility has been con- imum. This maximum amplitude (maximum clot firmness ducted. And there are many studies have been conducted or MCF in ROTEM; maximum amplitude or MA in TEG) is on its use during liver transplantation recently. Therefore, an index that reflects the strength of the clot. To quickly this review article aims to examine the usefulness of the assess the strength of the clot, estimates can be made from viscoelastic coagulation test and its application in liver the amplitudes measured at the 5, 10, and 20 min after the transplantation. clotting time. The final parameter represents the fibrinolysis. The amplitude 30 min or 60 min after clotting time is VISCOELASTIC COAGULATION TEST calculated as a percentage of the maximum amplitude (LI30, LI60 in ROTEM; LY30, LY60 in TEG) to represent the Viscoelastic coagulation test is a method that measures, stability of the clot (Fig. 1). Because the activators used in digitalizes, and graphically plots the viscoelasticity gener- the two equipment are slightly different, the reference ated between the fibrin strands and the platelets in the ranges are different. process of blood coagulation. There are currently two The types of tests that can be performed with TEG in- types of equipment that can be used for viscoelastic coag- clude Native and Kaolin TEG as the basic tests, Rapid TEG ulation test: classical thrombelastography (TEG, Haemon- which enables quick response by inducing responses with etics, USA) and rotational thromboelastometry (ROTEM, the tissue factors, heparinase method that shows results by Tem International GmbH, Germany). The parameter that removing the effects of heparin, and Heparinase method can be obtained first through these tests is the clotting that shows results by removing the effects of heparin, and

Coagulation Fibrinolysis MCF CFT

CT ROTEM 30 min LI30

30 min LY30 TEG R

K Enzymatic Fibrin MA Lysis Platelets

Clot initiation Clot kinetics Clot strength Clot stability

Fig. 1. Viscoelastic coagulation test using whole blood. CT: clotting time, R: reaction time, CFT: clot formation time, MCF: maximum clot firmness, MA: maximum amplitude.

144 www.anesth-pain-med.org KSTA ------145 LIVER TRANSPLANTATION LIVER TRANSPLANTATION Description NECESSITY AND ADVANTAGES OF NECESSITY AND ADVANTAGES Because patients undergoing liver transplantation have have transplantation liver undergoing patients Because VISCOELASTIC COAGULATION TEST FOR VISCOELASTIC COAGULATION severely reduced liver functions, they are unable to gener to unable they are functions, liver reduced severely procoagu of vitamin K-dependent amounts sufficient ate roles important play which S, C, and protein protein lants, factor deficiencyfactor be assessed generally within can 5 min. be assessed can within 25 min if strength clot Abnormal used are time clotting after min 20 or 10, 5, at values the observed. is amplitude Additionally, maximum the before to or FF of FIBTEM results the amplitude interpreting by between fibrin the plate and discriminate we could gether, take it can Although problems. let function or quantity of fibri assess the state completely to one hour than more within be 35 min if the abnor made can prediction nolysis, 30 at the values referencing by fibrinolysis is severe mal the visco using other words, In time. the clotting min after of the ur the assessment enables test coagulation elastic within 5 min, the need plasma frozen needgent for fresh coagulation the than other supplement fibrin for platelet or and the riskfactors of bleeding within 25 min. ------). A test ). A test Table 1 Table Viscoelastic coagulation test for liver transplantation liver for test coagulation Viscoelastic overall clot strength. clot overall strength aPTT the of that to similar tion assess effect to analysis ITEM heparin to compared and TEM reagent thrombosis or ing heparin systemic of presence properties sess coagulation to that of the PT the of that to EXTEM assess to analysis fibrinolysis When compared to EXTEM analysis, allows qualitative analysis of the fibrinogen contribution to clot clot to contribution fibrinogen the of analysis EXTEM qualitative to allows analysis, compared When informa provides and as activators acid ellagic and phospholipid contains Reagent activation: Contact with IN used in conjunction heparin; unfractionated neutralizing for heparinase lyophilized Contains bleed of risk and characteristics hemostatic underlying identifies assay activated pathway An intrinsic assess with Kaolin the conjunction used in and sample, test in the heparin of effect the Eliminates as rapidly more process to coagulation the speeds assay activated pathway extrinsic and An intrinsic to fibrin and platelets of contribution assess TEG relative Rapid or with Kaolin Used in conjunction Native whole blood sample analyzed following only recalcification only following analyzed sample blood whole Native CFT long time use given clinical for Impractical similar information provides and as an activator tissue factor contains reagent activation: Tissue factor to compared and with EXTEM used in conjunction reagent fibrinolysis; inhibiting for aprotinin Contains contribution platelet the exclude to inhibitor polymerization an actin D, cytochalasin Utilizes TEG Assays TEG & HEPTEM APTEM FIBTEM - TM Test Description of ROTEM ROTEM of Description Although the reference ranges of clotting time variestime be of clotting ranges the reference Although Functional fibrinogen Functional Kaolin with hepari Kaolin nase TEG Rapid TEG Kaolin INTEM EXTEM ROTEM NATEM www.anesth-pain-med.org CFT: clot formation time, PT: prothrombin time, aPTT: activated partial prothrombin time. partial aPTT: prothrombin time, activated PT: prothrombin time, CFT: formation clot Table 1. Table tween testing equipment and method, plasma coagulation coagulation and method, plasma tween equipment testing creased presently with the introduction of the cartridge-type with the introduction presently creased models. to be commercialized. Both TEG and ROTEM were previ Both were TEG and ROTEM beto commercialized. and at cup the blood in the testing putting used by ously in has testing of convenience the machine, the it to taching ellagic acid. HEPTEMellagic be performed can hepari adding by the effect of heparin ( and neutralizing nase is soon coagulation the platelet assess separately can that iting platelet functions, FIBTEM can be performed. The be performed. can The FIBTEM functions, platelet iting path the intrinsic which is INTEM of tests other family by adding by be identified can of the blood coagulation way adding aprotinin to this test and inhibiting fibrinolysis, AP fibrinolysis, and inhibiting this test to aprotinin adding cytochalasin adding be D and inhib obtained. By TEM can ing the response speed faster by activating the coagulation the coagulation activating speed by faster the response ing method,the this Through factors. tissue the using process By be identified. can of the coagulation extrinsic pathway which is a basic test that adds calcium to the citrated blood. the citrated to adds calcium that test is a basic which two types: into be classified can tests EX remaining The EXTEM is a method of mak INTEM and group. TEM group Functional Fibrinogen (FF) Fibrinogen the fibrin shows which func Functional is added. test function The the platelet addition, In tions. be performed can NATEM include with that tests ROTEM Anesth Pain Med Vol. 15 No. 2 in coagulation. Furthermore, they simultaneously show fibrin concentration, a quick assessment of the clot decreased alpha-2-antiplasmin, thrombin activatable fibri- strength is possible [16]. Additionally, the viscoelastic test nolysis inhibitor (TAFI), and plasminogen and increased showed better results than CCT in predicting bleeding after tissue plasminogen activator (tPA) and plasminogen acti- the liver transplantation due to pathologic coagulopathy vator inhibitor-1 (PAI-1) which must be removed by the liv- [17]. Thus, viscoelastic test is often used to test the coagu- er. Besides deficiency in liver functions, decrease in platelet lation function of the patients undergoing liver transplan- count and its functions can be observed due to spleen en- tation. It was reported in the 1980s by the University of largement and bone marrow suppression in patients with Pittsburgh that blood transfusion can be decreased by ap- liver diseases. In addition, decrease in fibrinogen and its plying TEG during liver transplantation [18]. A decrease in functions are common. These changes in the coagula- the transfusion of fresh frozen plasma by applying the tion-related substances maintain an equilibrium but are transfusion strategy using this viscoelastic coagulation test unstable. Therefore, coagulopathy disorders and the result- for liver transplantation was also reported recently [19]. ing worsening of bleeding during liver transplantation is Because this test enables the immediate assessment of the common. Because pre-operative CCT only reflects the state of fibrinolysis which cannot be obtained through pro-coagulant aspects of the plasma, it cannot provide ac- CCT, it is suggested that transfusion may be decreased if curate information, and the results are not related to the the viscoelastic coagulation test is applied for liver trans- volume of bleeding or the transfusion of blood products plantation where hyperfibrinolysis commonly occurs [20]. during liver transplantation. Thus, it is difficult to predict Depending on the type of the liver diseases that caused bleeding or the need for blood transfusion [9,10]. Further- the hepatic failure, the state of coagulopathy may differ more, because there are severe changes in the state of co- among patients undergoing liver transplantation. For ex- agulation among the stages of surgery during liver trans- ample, patients with hepatocellular carcinoma, cholestatic plantation, perioperative real-time monitoring is more im- hepatitis, and non-alcoholic steatohepatitis (NASH) show portant than the results from pre-operative tests. CCT re- a relative hypercoagulation. In these patients, thrombosis quires the process of obtaining blood and sending it to a is as important as bleeding. Although the prevalence of diagnostic lab, and generally 45–90 min are required to ob- thrombosis is not high in Korea, liver disease and liver tain the results. Therefore, CCT is not suitable for point-of- transplantation are clear risk factors for thromboembolism. care testing during liver transplantation. In contrast, the Even if there is a bleeding tendency due to a coagulopathy, viscoelastic coagulation test enables point-of-care testing. the risk of thrombosis does not decrease [21]. Furthermore, It can lessen the burden of sending the blood to the lab, as patients undergoing organ transplantation have a risk of fi- long as the testing equipment is available, and generally brinolytic shutdown [22], and this is reported to increase 15–25 min are sufficient to obtain the main results for treat- the risk of thrombosis and bleeding during surgery. Krzan- ment. Therefore, it enables real-time monitoring and icki et al. [23] showed that many patients suffer from hyper- goal-directed therapy [11]. Although it can take 60–90 min coagulation during liver transplantation. Data on the re- to obtain all results, only few minutes are necessary to pre- sulting pulmonary embolism in liver transplantation dict an immediate coagulopathy and clinically assess the showed that although the incidence was not high, the mor- need for treatment and the type of treatment. Many studies tality rate was high, and it was particularly common just suggest that the viscoelastic coagulation test is more sensi- before or after graft reperfusion [24]. Therefore, diagnosing tive to coagulation disorders than CCT [12,13]. Moreover, hypercoagulation state during liver transplantation is an in vivo studies on liver transplantation showed that pre-op- important issue. According to the prospective study by Mc- erative ROTEM test results are good predictors of the need Crath et al. [25], the increase in MA is an independent pre- for blood transfusion, particularly the need for fresh frozen dictive factor for post-operative acute myocardial infarc- plasma blood transfusion [14]. A retrospective analysis of tion. Another research using ROTEM by Hincker et al. [26] patients undergoing liver transplantation reported that the showed that the increase in MCF can predict thrombosis. MCF was strongly correlated with platelet count and fibrin This emphasizes the need for viscoelastic coagulation test concentration, and thus, can replace conventional tests in liver transplantation. [15]. In particular, because the amplitude obtained 5 or 10 However, some studies reported that there were no dif- min after the clotting time reflect the decrease in platelet or ferences in bleeding or blood transfusion before and after

146 www.anesth-pain-med.org KSTA ------147 ). Defi). Fig. 2 Fig. ( ]. Although coagulopa Although ]. 35 ]. – 14 33 [ [ Severe fluctuations in the coagulation status appear at at appear status in the coagulation fluctuations Severe sion, due to the increase in tPA and PAI-1, decrease in al decrease and PAI-1, in tPA the increase due to sion, and the influx of heparin-like sub pha-2-antiplasmin, liver donated the in stances in the changes is observed referencing thy in combination, func fibrinogen platelet of and results the and value each as in help be much of can test viscoelastic the from tions the neohe In needed treatment. urgently the most sessing ciency or functional decline in blood coagulation factor factor ciency decline blood in coagulation or functional There phase. for the preanhepatic is typical and platelet of values with CT R and and low extended thin graphs fore, the reflects it better common. Because MA and MCF are be seen can on results stable state, balanced coagulation coagulop with severe in patients even the viscoelastic test CCT in the beginning of the surgery. the to according athy of the surgery, the On with other hand, the progression the beobserved can in re worsening of the coagulopathy unnecessary while Therefore, viscoelastic test. al-time by the pallia only using when is possible transfusion plasma beginning of the surgery, in the results test coagulation tive viscoelastic the coagula applying by beprevented can this be performed can when it is really and a treatment tion test mentioned the previously phase, the anhepatic needed. In and thus, is not eliminated, worsens and tPA coagulopathy and LI30, LI60, LY30, Thus, occur. hyperfibrinolysis can administra an appropriate or worsen. Here, increase LY60 acid) (tranexamic medication tion of an anti-fibrinolysis all particular, In the worsening of bleeding. prevent can the worsen at disorders discussed coagulation previously reperfu after immediately and phase anhepatic the of end studies vary, it is difficult to conclude which method was vary,studies method which was conclude to it is difficult viscoelastic of values reference the Additionally, best. the subjects. healthy of values average just are test coagulation does neces not of this range outside are that values Thus, out values Because disorder. a coagulation sarily suggest it bleeding, to linked directly not is range reference the side In based values. test on the a protocol make to is difficult in transplantations as liver such in situations particular, ap not is it rapidly, changes coagulation of state the which based results, on test only perform to propriate treatment Re situation. clinical the consider to and it is essential transplantation liver undergoing patients on search of risk bleeding for values cut-off the predicted that showed which range within the reference were or blood transfusion decisions based on only treatment that further emphasized inappropriate are results test surgery transplantation liver of phase each ------angle angle a ] state that CCT is that ] state 30 Viscoelastic coagulation test for liver transplantation liver for test coagulation Viscoelastic [ ]. It can be defi to difficult can ]. It ] consider the blood] consider trans ] recommended the transfu ] recommended 27 [ 29 [ 18 [ ] and the guideline by the American the American by ] and the guideline 28 ]. Moreover, since protocols applied in the in the applied protocols since ]. Moreover, 32 [ LIVER TRANSPLANTATION LIVER TRANSPLANTATION ]. Because there are large variances in the indicators variances the indicators in large are there ]. Because 31 [ To date, there is no protocol that applies viscoelastic co applies that is no protocol there date, To VISCOELASTIC COAGULATION TEST FOR VISCOELASTIC COAGULATION BLOOD TRANSFUSION STRATEGY USING USING BLOOD TRANSFUSION STRATEGY www.anesth-pain-med.org of the coagulation test during liver transplantation, the the transplantation, during liver test of the coagulation not highly but related significantly are of the tests protocols consistent showed that using higher TEG threshold for blood transfu TEG threshold higher using showed that bleed did not increase in this protocol suggested than sion ing fusions do not improve blood coagulation or if the or blood coagulation improve do not fusions 2012 in research from Findings 40 degrees. than is less more; transfusion of 1 unit/10 kg of platelet if MA, of platelet of 1 unit/10 kg transfusion which more; 40 mm; is thinner than and trans strength, the clot reflects theseif blood cryoprecipitate units of 6–12 of trans fusion protocol published in 1993 published protocol re which if R time, plasma frozen of 2–4 units of fresh sion or 15 minutes by is delayed flects the start of coagulation, agulation test, which was found to be clearly superior as superior be to clearly as found was which test, agulation A transplantation. for liver strategies blood transfusion tion test can improve prognosis by reducing blood transfu reducing by prognosis improve can tion test hy identify and can management targeted facilitate sion, perfibrinolysis. agulation disorders. Although further is necessary, Although study disorders. agulation viscoelastic coagula based on that, this recommendation European Society Anaesthesiology of European with disease liver and for surgeries in patients not suitable co diagnose to perioperative TEG or ROTEM recommend for not only liver transplantation but also perioperative also perioperative but transplantation liver only not for for manage the guidelines Moreover, blood management. the bleeding by published perioperative of severe ment blood transfusion [ blood transfusion Society of Anesthesiologists be to important TEG ROTEM and using strategies fusion transplantation can reduce bleeding and blood transfu reduce can transplantation for perioperative guideline the Korean Therefore, sion. sis, and it can more sensitively and accurately diagnose co accurately and sensitively more can and it sis, this reason, during CCT the surgery. than For agulopathy for liver test of viscoelastic coagulation the application transplantation can really improve patient prognosis. How prognosis. patient improve really can transplantation the over of reflecting advantage the clear has this test ever, fibrinoly to formation clot from of coagulation, all process using this coagulation testing testing this coagulation using viscoelastic the coagula applying whether conclude nitely during liver strategy the blood to transfusion tion test Anesth Pain Med Vol. 15 No. 2

Sample data: Normal range: A R 15.2 min 4–8 K 5.8 min 0–4 Angle 32.3 deg 47–74 MA 39.4 mm 54–72 PMA 1.0 G 3.2 K d/sc 6.0 K–13.2 K EPL 0.0 % 0–15 A 41.6 mm CI –12.6 –3–3 LY30 0.0 % 0–8 A30 39.4 mm CL30 100.0 % 92–100 A60 38.7 mm CL60 100.0 % 85–100 LY60 0.0 % 0–15 CLT 33.7 min TPI 5.6 /sec 32–527 R K Angle MA PMA TMA 42.4 min min min deg mm 15.2 5.8 32.3 39.4 1.0 E 65.0 d/sc 120–264 4–8 0–4 47–74 54–72 SP 13.1 min LTE > 3 h min

Sample data: Normal range: B R 4.5 min 4–8 K 3.8 min 0–4 Angle 52.6 deg 47–74 MA 37.4 mm 54–72 PMA 1.0 G 3.0 K d/sc 6.0 K–13.2 K EPL 34.1 % 0–15 A 6.3 mm CI –3.6 –3–3 LY30 34.1 % 0–8 A30 6.6 mm CL30 17.6 % 92–100 A60 6.3 mm CL60 16.8 % 85–100 LY60 34.2 % 0–15 CLT 31.1 min TPI 7.8 /sec 32–527 R K Angle MA PMA TMA 20.2 min min min deg mm E 59.7 d/sc 120–264 4.5 3.8 52.6 37.4 1.0 4–8 0–4 47–74 54–72 SP 4.0 min LTE 33.6 min

Fig. 2. Examples of thromboelastography during liver transplantation. (A) Preanhepatic phase. (B) Anhepatic phase. (C) Five minutes after reperfusion. (D) Neohepatic phase. R: reaction time, MA: maximum amplitude (Continued to the next page).

148 www.anesth-pain-med.org KSTA 149 4–8 0–4 0–8 4–8 0–4 0–8 0–15 –3–3 0–15 0–15 –3–3 0–15 47–74 54–72 47–74 54–72 92–100 85–100 92–100 85–100 32–527 32–527 120–264 120–264 6.0 K–13.2 K 6.0 K–13.2 K Normal range: Normal range: % % % % % % % % % % deg deg min min min min min min min min min min min min /sec /sec mm mm mm mm mm mm mm mm d/sc d/sc d/sc d/sc 0.0 0.6 2.9 9.3 8.9 9.8 1.7 0.0 0.0 0.0 1.0 0.6 0.6 2.9 0.9 57.1 30.8 62.3 10.7 20.2 66.1 57.1 60.1 57.1 39.9 34.4 13.5 23.0 20.4 65.7 65.7 20.2 24.7 25.6 –2.8 > 3 h 100.0 6.6 K 1.3 K 100.0 133.0 –15.6 E E R R K K G A G A CI CI SP SP LTE TPI TPI CLT LTE CLT MA EPL MA EPL A60 A60 A30 A30 LY60 LY60 CL60 CL60 TMA TMA PMA PMA LY30 LY30 CL30 CL30 Angle Angle Sample data: Sample data: 0.0 1.0 PMA PMA MA MA mm mm 57.1 20.4 54–72 54–72 Viscoelastic coagulation test for liver transplantation liver for test coagulation Viscoelastic deg deg 66.1 23.0 Angle Angle 47–74 47–74 K K 1.7 min min 0–4 0–4 13.5 R R 9.8 min min 4–8 4–8 10.7 (Continued from the previous page). previous the from (Continued D C www.anesth-pain-med.org Fig. 2. Fig. Anesth Pain Med Vol. 15 No. 2 patic phase, the coagulopathy can improve due to the 1279-85. functions of the transplanted liver, and this is reflected in 3. Chowdary P, Saayman AG, Paulus U, Findlay GP, Collins PW. the viscoelastic coagulation test results. If the coagulopathy Efficacy of standard dose and 30 ml/kg fresh frozen plasma in appears unchanged or worsened according to the visco- correcting laboratory parameters of haemostasis in critically ill elastic coagulation test in this phase, the possibility of ex- patients. Br J Haematol 2004; 125: 69-73. cessive bleeding must be considered even if this is a gener- 4. Plotkin AJ, Wade CE, Jenkins DH, Smith KA, Noe JC, Park MS, ally stable period; in addition, the possibility that the trans- et al. A reduction in clot formation rate and strength assessed planted liver is dysfunctional must be considered as well. by thrombelastography is indicative of transfusion requirements in patients with penetrating injuries. J Trauma 2008; 64(2 Suppl): S64-8. CONCLUSION 5. Fries D, Innerhofer P, Schobersberger W. Time for changing coagulation management in trauma-related massive bleeding. Viscoelastic coagulation test is a point-of-care testing Curr Opin Anaesthesiol 2009; 22: 267-74. that can show not only the beginning of the coagulation 6. Johansson PI, Stissing T, Bochsen L, Ostrowski SR. Thrombe- but also the clot strength and stability. It enables faster lastography and tromboelastometry in assessing coagulopathy judgment and treatment than CCT. As its utility has already in trauma. Scand J Trauma Resusc Emerg Med 2009; 17: 45. been shown in clinical situations with coagulation disor- 7. Kim GS. Thromboelastography. Korean J Anesthesiol 2004; 47: ders and severe bleeding such as trauma using both clini- 297-304. cal and academic studies, this method can be used effec- 8. Mallett SV. Clinical utility of viscoelastic tests of coagulation tively for liver transplantation which has a high risk of (TEG/ROTEM) in patients with liver disease and during liver bleeding. Through further research, it is anticipated that transplantation. Semin Thromb Hemost 2015; 41: 527-37. this test can be used as one of the standardized patient 9. Findlay JY, Rettke SR. Poor prediction of blood transfusion re- blood management strategies for liver transplantation. quirements in adult liver transplantations from preoperative variables. J Clin Anesth 2000; 12: 319-23. SUPPLEMENTARY MATERIALS 10. Massicotte L, Beaulieu D, Roy JD, Marleau D, Vandenbroucke F, Dagenais M, et al. MELD score and blood product require- Supplementary data containing Korean version of this ments during liver transplantation: no link. Transplantation article is available at https://doi.org/10.17085/apm.2020. 2009; 87: 1689-94. 15.2.143. 11. Watson GA, Sperry JL, Rosengart MR, Minei JP, Harbrecht BG, Moore EE, et al. Inflammation and Host Response to Injury In- CONFLICTS OF INTEREST vestigators. Fresh frozen plasma is independently associated with a higher risk of multiple organ failure and acute respirato- No potential conflict of interest relevant to this article ry distress syndrome. J Trauma 2009; 67: 221-7. 12. Davenport R, Manson J, De’Ath H, Platton S, Coates A, Allard S, was reported. et al. Functional definition and characterization of acute traumatic coagulopathy. Crit Care Med 2011; 39: 2652-8. ORCID 13. Woolley T, Midwinter M, Spencer P, Watts S, Doran C, Kirkman E. Utility of interim ROTEM® values of clot strength, A5 and Sun Young Park, https://orcid.org/0000-0003-2588-3324 A10, in predicting final assessment of coagulation status in severely injured battle patients. Injury 2013; 44: 593-9. REFERENCES 14. Fayed N, Mourad W, Yassen K, Görlinger K. Preoperative thromboelastometry as a predictor of transfusion require- 1. 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Effect-site concentration of remifentanil for preventing propofol injection pain during induction of balanced anesthesia

Joungmin Kim1,2, Daehoon Kim2, and Hyung Gong Lee1,2 Received August 21, 2019 1 Revised September 26, 2019 Department of Anesthesiology and Pain Medicine, Chonnam National University Medical 2 Accepted September 27, 2019 School, Chonnam National University Hospital, Gwangju, Korea

Background: Despite various strategies designed for preventing pain from propofol injection, it is still common and distressing to the patients. The purpose of the present study was to investigate the adequate effect-site concentration (Ce) of remifentanil to prevent pain due to propofol injection. Methods: A total of 160 adults scheduled for elective surgery were randomly assigned to one of four groups receiving normal saline (group S) or remifentanil at a Ce of 2 (group R2), 3 (group R3), or 4 ng/ml (group R4), administered via target-controlled infusion, followed by the injection of 2 mg/kg of propofol (delivered with 1% lipid propofol). The severity and incidence of injection pain were assessed on a four-point scale. Corresponding author Results: The incidence of propofol injection pain was significantly lower in group R2, R3, Hyung Gong Lee, M.D., Ph.D. or R4 than in group S (30%, 5%, or 2.5% vs. 70%, respectively). Moreover, the intensity of Department of Anesthesiology and the pain was lesser in group R2, R3, or R4 than in group S. However, the incidence or se- Pain Medicine, Chonnam National verity of injection was not different between groups R3 and R4. University Hospital, Chonnam National Conclusions: During the induction of balanced anesthesia using propofol injection, pre- University Medical School, 42 Jebong- ro, Dong-gu, Gwangju 61469, Korea treatment with remifentanil at a target Ce of 3 ng/ml effectively reduced propofol injection Tel: 82-62-220-6893 pain in adults. Fax: 82-62-232-6294 E-mail: [email protected] Keywords: Injection; Pain; Propofol; Remifentanil; Target-controlled infusion.

INTRODUCTION ful site throughout the perioperative period. Therefore, numerous techniques have been use to re- Propofol is widely used as the induction agent of anesthe- duce propofol injection pain. In a recent systematic review, sia owing to its pharmacological advantages, including rapid Jalota et al. [5] recommended the routine use of opioids in onset time, short duration of action, easy titration, and a fa- all patients before propofol injection for general anesthe- vorable side-effect profile [1]. Recently, its use has gradually sia, unless contraindicated. There have been several stud- expanded to sedation for outpatient procedures [2,3]. ies on the preventive effect of remifentanil on pain from a Despite these advantages, pain during vascular injection single injection or continuous infusion of propofol in is a major drawback of propofol use. Without other treat- adults [6–8]. Compared to other opioids, remifentanil has ments, pain is experienced after propofol injection by ap- faster onset, shorter duration of action, and shorter con- proximately 70% of the patients [4]. A few patients com- text-sensitive half-life [9]. plained that the propofol injection site was the most pain- Lee et al. [10] showed that effect-site concentrations (Ce)

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, 2020

152 KSAP ------153 , Hana Pharm. Pharm. Hana , ® ]. After the patients the patients ]. After 12 [ ], the sample size of 160 sub 160 of size sample the ], 4 ] in a TCI device (Orchestra, Fresenius-Vial, France). France). Fresenius-Vial, device (Orchestra, ] in a TCI Based on previous studies [ studies previous on Based The patients were not medicated before the surgery, before and not medicated were patients The 11 USA). The one-way analysis of variance test was used for used was for of variance test analysis one-way USA). The height, age, (e.g., variables distributed continuous normally used was for discrete test and the chi-squared and weight), and the Kruskal– exact test sex). Fisher’s (e.g., variables the in differences used detectany to were test rank Wallis injection inten pain and mean pain incidence of propofol 0.05 than less P values respectively. groups, among sity pain), the patient complained of pain, and there was facial facial was and there of pain, complained the patient pain), of the arm or withdrawal grimacing performed was intubation fol tracheal unconscious, were and bal of rocuronium, an injectionlowing of 0.8 mg/kg and with sevoflurane maintained anced was anesthesia Heart pump. the TCI via infusion remifentanil continuous com were (MAPs) arterial (HRs) and mean pressures rates target the remifentanil and after the infusion before pared (>hypotension Remifentanil-related reached. was Ce 20% (HR in MAP) and bradycardia decrease < 45 beats/min) minor and rigidity, assessed. desaturation, wall Chest were also as were cough, and dizziness as such complications, assessed for 24 postoperative were sessed. patients The re flare and edema, pain, as such effects, for adverse hours injection site. the propofol sponse at of 5%) rate (with dropout assumed an jects groups in four detect of 85% to a power a linearly have to calculated was with z-test continuity a one-sided using trend decreasing 0.05 (PASS least of at level withcorrection, a significance per were analyses LCC, USA).13.0.05, NCSS, All statistical (SPSS Inc., 15.0 version formed with SPSS software, the were administered using a Minto pharmacokinetic model model pharmacokinetic a Minto using administered were [ anes the patients, blind to covered was pump infusion The and investigators. thesiologists, cephalic their in placed was cannula venous 20-gauge a performed were monitoring and assessment Standard vein. pulse included which electrocardiography, continuously, monitoringoximetry, of arterial pressure. and non-invasive was of remifentanil Ce target When the predetermined Anepol (1% mg/kg 2 propofol achieved, 30 s. over intravenously administered was Korea) Ltd., Co., injection, severity the pain as was the propofol During no pain), 1 (no scale: four-point sessed the following using the injection; to 2 (mild pain), reaction verbal/facial/motor the injection; to 3 reaction a minor verbal/facial/motor there but of pain, complained the patient pain), (moderate 4 (severe or withdrawal; grimacing no accompanied was ------). Fig. 1 Fig. ( Ce of 4 ng/ml (n = 40) Group R4 Ce of remifentanil for propofol injection pain injection propofol for remifentanil Ce of Excluded (n = 31) · Patient refusal (n = 22) · Sedative medication (n = 9) Ce of 3 ng/ml (n = 40) Group R3 , GlaxoSmithKline, Belgium) Belgium) , GlaxoSmithKline, ® Screening (n = 191) Enrollment (n = 160) Ce of 2 ng/ml (n = 40) Group R2 MATERIALS AND METHODS MATERIALS CONSORT flow diagram of participants through the study. study. the participants of through diagram flow CONSORT Using a computer-generated randomization table, each each table, randomization computer-generated a Using This study was approved by the Institutional Review Board Board Review the Institutional by approved was study This The aim of this study was to determine to of was Ce the effective aim of this study The Normal saline (n = 40) Group S www.anesth-pain-med.org Fig. 1.Fig. concentration. Ce: effect-site was diluted with 20 ml of normal saline. Normal saline was was saline Normal diluted withwas saline. of normal 20 ml drugs All study with a 20-ml syringe controls. to delivered remifentanil at a Ce of 2, 3, or 4 ng/ml, respectively respectively of 2, 3, or 4 ng/ml, a Ce at remifentanil (Ultiva 1 mg Remifentanil patient was randomly allocated to group S, R2, R3, or R4 R4 or R3, R2, S, group to allocated randomly was patient n (each = with or normal saline 40) and administered known allergies to opioids and propofol, (2) neurological (2) neurological opioids and propofol, to allergies known use med of pain (3) current disorders, deficits or psychiatric and (4) a history of drug or sedatives, abuse. ication gists physical status I or II), undergoing elective surgery I or II), undergoing un status physical gists (1) criteria were: exclusion The anesthesia. general der formed consent was obtained from all study participants. participants. all study formed obtained from was consent performed prospectively of 160 pa on a total this study We (American Society aged 20–65 years of Anesthesiolo tients, (2015–2019) (IRB No: CNUHH-2015-019), and written in CNUHH-2015-019), (2015–2019) (IRB No: fol, which is used to induce anesthesia in adults. is usedfol, which adults. in anesthesia induce to remifentanil to reduce pain from the injection of 1% propo from pain reduce to remifentanil the 2% propofol solution elicits more intense pain than the than pain intense solution elicits more the 2% propofol pre to required solution, of remifentanil Ce 1% propofol be different. injection may pain propofol vent fol solution usedcommonly is in total for the induction of solution propofol 1% the but (TIVA), anesthesia travenous As usedis usually for the induction of balanced anesthesia. of remifentanil of 4 and 6 ng/ml reduced the injection the pain reduced 6 ng/ml and 4 of remifentanil of during infusions of anes the induction 2% propofol from 2% propo The (TCI). infusion withthesia target-controlled Anesth Pain Med Vol. 15 No. 2 were considered statistically significant. Results are ex- or saline infusion were significant in all groups compared pressed as mean ± SD or absolute numbers (%). to baseline, reductions in HR and MAP were of no clinical importance, and no patients required treatment for hypo- RESULTS tension or bradycardia (Table 3). Participants did not experience major adverse events, such as desaturation or chest The study enrolled 160 people, none of whom dropped wall rigidity during the study period (Table 4). Minor com- out. There were no differences in demographic characters, plications, including dizziness and cough, occurred more such as age, gender, weight, or height, among the groups frequently in groups R2, R3, and R4 than in group S (P < (Table 1). 0.05). However, the incidence of complications did not dif- The incidence of propofol-induced pain was significantly fer significantly among the three groups receiving remifen- lower in groups R2, R3, and R4 (30%, 5%, and 2.5%, respec- tanil (Table 4). No side effects at the injection site were tively) than in group S (70%, P < 0.05, Table 2). In addition, the seen in any patient. severity of propofol-induced pain was significantly lower in groups R2, R3, and R4 compared to group S (P < 0.05, Table 2). DISCUSSION However, there were no significant differences in pain incidence or severity between groups R3 and R4. This study showed that the administration of remifent- Although the changes in HR and MAP after remifentanil anil at target Ce of 2, 3, or 4 ng/ml significantly reduced the

Table 1. Demographic Characteristic Group S (n = 40) Group R2 (n = 40) Group R3 (n = 40) Group R4 (n = 40) Target Ce of remifentanil (ng/ml) 0 2 3 4 Sex (M/F) 15/25 15/25 14/26 15/25 Age (yr) 49.0 ± 9.5 48.0 ± 7.7 50.0 ± 9.3 48.0 ± 9.6 Weight (kg) 63.6 ± 10.7 62.6 ± 9.2 63.5 ± 11.6 65.1 ± 11.0 Height (cm) 159.9 ± 10.2 164.0 ± 6.5 162.2 ± 9.0 161.7 ± 10.0 Values are presented as number of patients or mean ± SD. There were no significant differences among the four groups. Ce: effect-site concentration.

Table 2. Incidence and Severity of Pain with Propofol Injection Group S (n = 40) Group R2* (n = 40) Group R3*,† (n = 40) Group R4*,† (n = 40) Incidence of pain 28 12 2 1 Severity of pain 1 (no pain) 12 28 38 39 2 (mild pain) 16 12 2 1 3 (moderate pain) 11 0 0 0 4 (severe pain) 1 0 0 0 Values are presented as number of patients (%). *P < 0.05 for comparison of the incidence and severity of pain with the control. †P < 0.05 for comparison of the incidence and severity of pain with Group R2. However, there was no significant difference in the incidence or severity of pain between groups R3 and R4.

Table 3. Hemodynamic Changes during the Induction of General Anesthesia Heart rate Mean arterial pressure Baseline Before intubation Baseline Before intubation Group S (n = 40) 78.4 ± 9.7 68.6 ± 8.9* 99.6 ± 10.3 80.0 ± 8.3* Group R2 (n = 40) 75.2 ± 11.4 64.4 ± 9.5* 100.9 ± 9.9 76.4 ± 7.3* Group R3 (n = 40) 79.9 ± 13.7 65.4 ± 10.6* 101.0 ± 10.4 72.6 ± 8.4* Group R4 (n = 40) 81.5 ± 13.6 64.4 ± 8.1* 99.2 ± 13.5 70.6 ± 9.2* Values are presented as mean ± SD. Although changes in the heart rate (HR) and mean arterial pressure (MAP) after remifentanil or saline infusion were significant compare to baseline (*P < 0.05) in all groups, reductions in HR or MAP were of no clinical importance, and no patients required treatment for hypotension or bradycardia.

154 www.anesth-pain-med.org KSAP ] ------10 [ 155 to pre to 50 0 0 2 20* ]. Lee et al. 15 [ ) and 95% for mini Group R4 (n R4 (n Group = 40) 50 0 0 1 18* ]. In this study, we used the 1% propofol solu we used this study, the 1% propofol ]. In Group R3 (n R3 (n Group = 40) 10 [ Previous studies examining remifentanil at EC at remifentanil examining studies Previous In this study, the incidence of propofol injection in pain propofol of incidence the study, this In The 2% propofol solution, containing more aqueous aqueous more solution, containing 2% propofol The tanil to cause inhibitions by 50% (EC inhibitions by cause tanil to duringof TIVA induction pain the infusion propofol mizing respectively 3.09 and 3.78 ng/ml, were technique was not used for the injection of remifentanil, usednot injectionremifentanil, the for of was technique injected of remifent was Ce when the target and propofol reached. anil was intu endotracheal following changes hemodynamic vent did of 2.0–5.0 ng/ml Ce at remifentanil showed that bation chest or bradycardia, hypotension, significant cause not propofol, might cause more infusion pain than the 1% propo than pain infusion more cause might propofol, fol solution usedtion as it is commonly for the induction of balanced an intense solution elicits more As the 2% propofol esthesia. the test solution, this study, in the 1% propofol than pain 4 ng/ml. than lower were doses of remifentanil Ce of target was R2, R3, or R4 (30%, 5%, and 2.5%, respectively) group (70%). group the control in that than lower significantly also injection was significant severity pain The of propofol group. control in the R2, R3, or R4 than in group lower ly R2, R3, in group reported was pain moderate-to-severe No pa the of 30% experienced by was it whereas (0%) R4 or incidence or severity The of group. in the control tients R3 and between groups different not significantly was pain not signifi was of complications R4, and the occurrence finding R3 and R4. This between groups different cantly be the might of 3 ng/ml a Ce at remifentanil that suggests injection pain propofol reduce to concentration optimal The in adults. for the induction of balanced anesthesia be mediated might effect of remifentanil pain-relieving tourniquet a because receptors opioid central through reported that pretreatment with remifentanil at a target Ce Ce a target at with remifentanil pretreatment that reported the frequency and intensity reduced effectively of 4 ng/ml during infusions the induction of propofol from of pain complications. without significant TIVA, 0 0 0 17* ------Group R2 (n R2 (n Group = 40) Ce of remifentanil for propofol injection pain injection propofol for remifentanil Ce of ]. Another study ]. Another study 6 [ 0 0 0 0 ]. Therefore, previous data data previous ]. Therefore, 8 [ Group S (n S (n Group = 40) ]. Moreover, previous studies studies previous ]. Moreover, 5 [ ]. TCI of remifentanil is suitable for use as is suitable of remifentanil ]. TCI ]. A previous study reported that pretreat that reported study ]. A previous 10 8 [ – 6 ]. [ 14 , Incidence of Complications in Patients Who Received Normal Saline (Group S) or Remifentanil at Target Effect-site Concentrations of 2, of Concentrations Effect-site Target at Remifentanil S) or (Group Saline Normal Received Who in Patients Complications of Incidence 13 [ In adult women, the effective concentrations of remifen adult women, concentrations the effective In As opioids, including remifentanil, are commonly used used commonly are remifentanil, including As opioids, During the induction of anesthesia, the propofol injec the propofol the induction of anesthesia, During ]. Although the mechanism underlying propofol injection propofol underlying the mechanism ]. Although 4 Desaturation rigidity wall Chest Dizziness Cough www.anesth-pain-med.org showed that 0.25 μg/kg/min of remifentanil started 1 min started min 1 remifentanil of μg/kg/min 0.25 that showed immedi administered that than effective more was earlier injection propofol before ately ment with remifentanil was effective in reducing propofol propofol effective in reducing was withment remifentanil remifentan of mg 0.02 least injectiondosea and pain, at of be usedil should for this purpose incidence and severity of propofol injection with pain incidence and severity vary of propofol results ing seems reasonable because opioids have half the risk of the risk of half opioids have because seems reasonable injection pain propofol the reduced with remifentanil pretreatment that showed tively tively the use of opioids for induction for balanced anesthesia, pain seem to be involved with the immediate stimulation with stimulation seempain the immediate be to involved respec mediators, of pain of nociceptors and activation line-only control group, consistent with previous reports reports with previous consistent group, control line-only [ delayed and initial been not understood, fully has pain tion often causes pain, which might be distressing to the the to be distressing might which pain, causes tion often injection oc pain propofol study, the present In patients. the sa was which S, in group in 26 (70%) patients curred the induction of balanced anesthesia in adults. There were were There adults. in balancedanesthesia of induction the between of 3 and 4 ng/ml. Ce target no differences incidence and severity of propofol injection pain during injectionincidence and severity during pain of propofol Table 4. Table 4 ng/ml 3, or Ce could be a good method to prevent propofol injection injection propofol be a good could Ce method prevent to for the induction of balanced anesthesia. pain ic property allows the desired targeted blood plasma con blood targeted plasma the desired allows ic property There achieved. bequickly to remifentanil of centration target an efficacious at with remifentanil pretreatment fore, a part of an anesthesia regimen owing to its pharmacologic its pharmacologic to owing a part regimen of an anesthesia pharmacolog This onset. rapid include which advantages, indicate that both dose and time intervals are fundamental fundamental both dose intervalstime and are that indicate on propofol effect of remifentanil for the maximal factors injection pain Values are presented as number of patients. There were no significant differences in the incidence of desaturation or chest wall rigidity rigidity wall chest or desaturation of incidence in the differences significant no were There patients. of as number presented are Values although group, control the to < 0.05) compared R4 (*P R2, R3, and in groups frequent more significantly was Dizziness groups. the among groups. study three the among different significantly not was complications of incidence the Anesth Pain Med Vol. 15 No. 2 tightness [16]. Although in the present study, reductions in nonbenzodiazepine sedatives in the intensive care unit. Crit HR and MAP following the administration of remifentanil Care Clin 2001; 17: 863-80. were significant, no adult patients with American Society 3. Külling D, Rothenbühler R, Inauen W. Safety of nonanesthetist of Anesthesiologists physical status I or II required treat- sedation with propofol for outpatient colonoscopy and esoph- ment for hypotension or bradycardia, consistent with pre- agogastroduodenoscopy. Endoscopy 2003; 35: 679-82. vious reports [10,16]. 4. Picard P, Tramèr MR. Prevention of pain on injection with This study had two limitations, and the findings of this propofol: a quantitative systematic review. Anesth Analg 2000; study should be considered within the context of these lim- 90: 963-9. 5. Jalota L, Kalira V, George E, Shi YY, Hornuss C, Radke O, et al. itations. Prevention of pain on injection of propofol: systematic review First, the study population was limited to relatively young and meta-analysis. BMJ 2011; 342: d1110. patients. As older patients are more sensitive to opioids, 6. Iyilikci L, Balkan BK, Gökel E, Günerli A, Ellidokuz H. The ef- age-related variations in the effects should be considered. fects of alfentanil or remifentanil pretreatment on propofol in- Second, the prevalence of propofol injection pain could be jection pain. J Clin Anesth 2004; 16: 499-502. influenced by the patient’s sex. Remifentanil at EC used 50 7. Roehm KD, Piper SN, Maleck WH, Boldt J. Prevention of propo- to reduce propofol injection pain was lower in women than fol-induced injection pain by remifentanil: a placebo-con- in men [15]. trolled comparison with lidocaine. Anaesthesia 2003; 58: 165- In conclusion, we showed that remifentanil infusion at a 70. target Ce of 3 ng/ml for the induction of balanced anesthe- 8. Basaranoglu G, Erden V, Delatioglu H, Saitoglu L. Reduction of sia using a single propofol injection was a useful strategy to pain on injection of propofol using meperidine and remifent- minimize propofol injection pain in adults, without caus- anil. Eur J Anaesthesiol 2005; 22: 890-2. ing significant complications. 9. Egan TD, Kern SE, Muir KT, White J. Remifentanil by bolus injection: a safety, pharmacokinetic, pharmacodynamic, and age CONFLICTS OF INTEREST effect investigation in human volunteers. Br J Anaesth 2004; 92: 335-43. No potential conflict of interest relevant to this article 10. Lee JR, Jung CW, Lee YH. Reduction of pain during induction was reported. with target-controlled propofol and remifentanil. Br J Anaesth 2007; 99: 876-80. AUTHOR CONTRIBUTIONS 11. Minto CF, Schnider TW, Egan TD, Youngs E, Lemmens HJ, Gam- bus PL, et al. Influence of age and gender on the pharmacoki- Conceptualization: Joungmin Kim, Hyung Gon Lee. Data netics and pharmacodynamics of remifentanil. I. Model devel- acquisition: Hyung Gon Lee. Formal analysis: Hyung Gon opment. Anesthesiology 1997; 86: 10-23. Lee, Daehoon Kim. Supervision: Hyung Gon Lee. Writing— 12. King SY, Davis FM, Wells JE, Murchison DJ, Pryor PJ. Lidocaine for the prevention of pain due to injection of propofol. Anesth original draft: Joungmin Kim, Daehoon Kim. Writing—re- Analg 1992; 74: 246-9. view & editing: Joungmin Kim, Hyung Gon Lee. 13. Briggs LP, Clarke RS, Dundee JW, Moore J, Bahar M, Wright PJ. Use of di-isopropyl phenol as main agent for short procedures. ORCID Br J Anaesth 1981; 53: 1197-202. 14. Scott RP, Saunders DA, Norman J. Propofol: clinical strategies for Joungmin Kim, https://orcid.org/0000-0003-1135-1968 preventing the pain of injection. Anaesthesia 1988; 43: 492-4. Daehoon Kim, https://orcid.org/0000-0001-6275-2433 15. Lee JY, Yang H, Choi SH, Shin DW, Hong SK, Chun DH. The op- Hyung Gong Lee, https://orcid.org/0000-0003-4898-4355 timal effect-site concentration of remifentanil to attenuate the pain caused by propofol. Korean J Anesthesiol 2012; 63: 108-12. REFERENCES 16. Yon JH, Jo JK, Kwon YS, Park HG, Lee S. Effect-site concentration of remifentanil for blunting hemodynamic responses to trache-

1. Marik PE. Propofol: therapeutic indications and side-effects. al intubation using light wand during target controlled infu- Curr Pharm Des 2004; 10: 3639-49. sion-total intravenous anesthesia. Korean J Anesthesiol 2011; 2. Angelini G, Ketzler JT, Coursin DB. Use of propofol and other 60: 398-402.

156 www.anesth-pain-med.org KSAP ------]. 2 , 1 [ Clinical Research Clinical Recently, multimodal analgesia with reduced doses with of opi reduced analgesia multimodal Recently, doses of opioids increased since been emphasized oids has sedation, hyper as excessive such adverse to events, lead respiratory and vomiting, nausea, sensitivity,postoperative during regional anesthesia. Because of their analgesic of their analgesic Because anesthesia. during regional use of alpha-2 or postoperative intraoperative properties, for use in postoperative be good adjuvants may agonists of analgesics consumption reduce and may analgesia 157 eISSN 2383-7977 • In this meta-analysis, high degree of heterogeneity limits the preoperative preoperative limits the heterogeneity of degree high In this meta-analysis, Alpha-2 agonists have sedative, analgesic, and opioid-sparing effects. More effects. opioid-sparing and analgesic, sedative, have agonists Alpha-2 drenergic alpha-2 receptor agonists; Anesthesia; Clonidine; Dexmedetomi Clonidine; Anesthesia; agonists; receptor alpha-2 drenergic A We searched the MEDLINE, EMBASE, Cochrane Library (CENTRAL), KoreaMed, (CENTRAL), KoreaMed, Library Cochrane EMBASE, MEDLINE, the searched We Eleven RCTs involving 748 participants were included in this meta-analysis. Pre in this meta-analysis. included participants were 748 involving RCTs Eleven opioid consumption up to 6 h (SMD, –0.52; 95% confidence interval [– 0.90 to –0.14]) –0.14]) [– 0.90 to interval –0.52; 95% confidence 6 h (SMD, to up consumption opioid adminis preoperative Moreover, surgery. –0.09]) after to –0.68 [–1.27 h (SMD, 24 and 6 h (SMD, at pain intensity postoperative reduced significantly agonists alpha-2 of tration –0.03]). – 0.44 [–0.86 to h (SMD, 24 and –0.21]) –0.50 [–0.78 to Conclusions: pain and consumption opioid postoperative in reducing agonists alpha-2 of administration on certainty the evidence of increase to required are RCTs large powered Future intensity. pain intensity. and consumption opioid postoperative in reducing effect the Keywords: review. pain; Systematic Postoperative opioid; Analgesics, Meta-analysis; dine; Background: ago adrenergic alpha-2 of administration systemic postoperative or intraoperative over, meta-analysis This consumption. opioid pain and postoperative reduce to nists is known postoper can affect agonists alpha-2 of administration preoperative whether investigated consumption. opioid and pain ative Methods: controlled randomized relevant identify to 2019 March through KMbase databases and on agonists alpha-2 of administration systemic preoperative of effect the on (RCTs) trials to according meta-analysis a conducted We consumption. opioid pain and postoperative guidelines. Collaboration Cochrane the Results: cumulative reduced significantly agonists alpha-2 systemic of administration operative Effect of preoperative administration of systemic of administration of preoperative Effect pain: a on postoperative alpha-2 agonists and meta-analysis systematic review Sangseok Lee Ju, Kye-Min Kim, and Ji Youn Hospital, Inje University Medicine, Sanggye Paik and Pain Department of Anesthesiology Seoul, Korea College of Medicine, Anesth Pain Med 2020;15:157-166 2020;15:157-166 Med Pain Anesth https://doi.org/10.17085/apm.2020.15.2.157 pISSN 1975-5171

INTRODUCTION October 25, 2019 October September 2, 2019 September

October 20, 2019 October Alpha-2 adrenergic agonists, which are widely used for widely used for are which agonists, adrenergic Alpha-2 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 which (http://creativecommons.org/licenses/by-nc/4.0) License Non-Commercial Attribution Commons Creative the of terms the under Access article is an Open This distributed cited. is properly work original the provided in any medium, reproduction and distribution, use, non-commercial unrestricted 2020 Anesthesiologists, Society of Korean © the Copyright of keeping hemodynamic index stable and reducing the the reducing and stable index hemodynamic keeping of intraoperative during of anesthetics surgery.amount Also, perform to sedation administered is often agonists alpha-2 various purposes. As an anesthetic premedication, alpha-2 alpha-2 premedication, As an anesthetic purposes. various the effect anxiolytic effects and have have mainly agonists E-mail: [email protected] [email protected] E-mail: 01757, Korea Korea 01757, 82-2-950-1171 Tel: 82-2-950-1323 Fax: Pain Medicine, Sanggye Paik Hospital, Hospital, Paik Sanggye Medicine, Pain Medicine, of College University Inje Seoul Nowon-gu, Dongil-ro, 1342 Corresponding author author Corresponding M.D. Lee, Sangseok and Anesthesiology of Department Revised Revised Accepted Received Received Anesth Pain Med Vol. 15 No. 2 depression [1,3]. restriction on the year of publication. Additionally, we A previous meta-analysis demonstrated that intraopera- manually searched the reference lists of included studies to tive or postoperative systemic administration of alpha-2 ad- identify other relevant trials in the Korean databases (Ko- renergic agonists reduced postoperative pain and opioid reaMed [https://koreamed.org] and KMbase [http://km- consumption [4]. That meta-analysis, which included 30 base.medric.or.kr]). The search terms included variants of studies, provided evidence of postoperative morphine-spar- alpha-2 adrenergic receptor stimulating agents and posting at 24 h and showed that the weighted mean difference operative pain, as well as Medical Subject Heading (MeSH) was 4.1 mg (95% confidence interval [CI], 6.0 to 2.2) with or EMBASE Subject Heading (EMTREE) terms. A primary clonidine and 14.5 mg (22.1 to 6.8) with dexmedetomidine. investigation was performed to confirm the search key- This meta-analysis also provided evidence of a decrease in words and strategy (Appendix 1). The language of the arti- pain intensity at 24 h and showed that the weighted mean cles was limited to Korean and English. The last search was difference on a 10-cm visual analog scale (VAS) was 0.7 cm conducted on March 26, 2019. (1.2 to 0.1) with clonidine and 0.6 cm (0.9 to 0.2) with dexmedetomidine. Study selection and eligibility criteria Nevertheless, controversy exists regarding whether preoperative use of alpha-2 agonists as sedatives has an effect The draft search of the electronic databases for identify- on reducing postoperative pain. Shariffuddin et al. [5] con- ing potentially relevant research was completed by two au- cluded that a single dose of dexmedetomidine was a useful thors (JJ and KMK). Thereafter, they independently select- adjuvant in reducing postoperative pain, and Sung et al. [6] ed or excluded the studies. Primary selection was based on demonstrated that oral clonidine premedication reduced an article’s title and abstract. Secondary selection was per- the requirement of postoperative analgesia in patients un- formed after full-text review of an article. Studies for final dergoing laparoscopic cholecystectomy. However, Lee et assessment were selected in consensus by the two investi- al. [7] found that pre-anesthetic administration of a single gators. If necessary, a third investigator (SL) participated in loading dose of dexmedetomidine given 10 min before in- study selection, and the final decision was made on the ba- duction did not reduce patient-controlled anesthesia con- sis of a majority. sumption of postoperative fentanyl or the pain score. Studies were included in the meta-analysis if they satis- The aim of this study was to evaluate the effect of alpha-2 fied the following criteria: (1) patients underwent non-car- agonists administered before general anesthesia and surgery diac surgery or neurosurgery under general anesthesia; (2) on postoperative pain and opioid consumption for postop- intravenous or oral administration of an alpha-2 agonist erative analgesia. was used prior to surgery as an intervention; (3) results of the control group were reported; and (4) postoperative MATERIALS AND METHODS pain scores or opioid consumption was reported as a primary outcome. Study design Studies were excluded for the following reasons: (1) in- tranasal, rectal, local, or topical administration of an al- This systematic review and meta-analysis was performed pha-2 agonist; (2) did not report appropriate outcomes or according to recent methodological guidelines [8]. The outcome measurements as mentioned; (3) patients under- protocol was registered on PROSPERO (https://www.crd. went epidural anesthesia combined with general anesthe- york.ac.uk/PROSPERO, no. CRD42016051454). The study sia; (4) non-randomized controlled trials (RCTs) or studies was approved by the Institutional Review Board of the Inje Uni- without a control group; (5) non-human studies; and (6) versity Sanggye Paik Hospital (no. 2017-08-013). articles not in Korean or English.

Information sources and search strategy Risk of bias in individual studies

Three researchers (JJ, KMK, and SL) systematically Two authors (JJ and KMK) reviewed the articles inde- searched electronic databases such as the PubMed/MED- pendently to assess the risk of bias by using the “risk of bias LINE, EMBASE, and Cochrane Library (CENTRAL) without (ROB)” tool provided in the Review Manager software ver-

158 www.anesth-pain-med.org KSAP ------as a as 159 2 I > signifi represent to considered 50% was 2 I Publication bias was not evaluated because only few few only because not evaluated was bias Publication performed the sta evaluate to a sensitivity analysis We Synthesis of results as postoperative such outcomes, in continuous Changes performed pos were analyses where subgroup Post-hoc The VAS scores were extracted for analyzing postopera analyzing for extracted were scores VAS The Summary measures and mean as extracted were data consumption Opioid (per oral) and dexmedetomidine (intravenous). Chi- and dexmedetomidine (intravenous). (per oral) performed were identify to for heterogeneity tests squared between subgroups. the differences included in this meta-analysis. 10 were than less studies included in the meta-analy study Each bility of the results. SD of the cumulative morphine consumption in the early in the early morphine consumption of the cumulative SD we extracted intensity, pain measure To periods. and late late and early the of scores pain the of SD and mean the periods. pooled were or dose of opioid consumption, intensity pain differ because (SMDs), differences mean as standardized expected were measurements of outcome scaling ent for all esti the 95% CIs also calculated We trials. across used model was pool to the study A random-effect mates. in effect siz variations possible account into taking results, Q and Cochrane statistic heterogeneity The trials. es across (df) corresponding its wellas Higgins’ as value P and P calculated. were of heterogeneity measure < 0.05 was hetero significant of statistically representative considered geneity, and heterogeneity. cant based on heterogeneity explore to outcome for each sible between clonidine of administration route the different the cumulative opioid consumption up to 24 h after surgery.24 h after up to consumption opioid the cumulative included and stan mean scores Pain intensity. pain tive in We the time of measurement. at (SD) deviation dard from only data opioid consumption cluded postoperative of performed administration IV oral or that thosestudies the mode to applied of ad was no restriction but opioids, the reported that also studies excluded We ministration. or the number for opioid analgesics request first the time to used When studies required. was of times opioid analgesics the doses were morphine, other than opioid analgesics cumulative the and equivalents, morphine into converted recorded. was time of measurement the at consumption Statistical analysis ------Effect of preoperative alpha-2 agonists alpha-2 preoperative of Effect ]. 9 Before we selectively extracted data from various studies, studies, various from data we selectively extracted Before Regarding preoperative administration of alpha-2 ago of alpha-2 administration preoperative Regarding Three authors (JJ, KMK, and HK) extracted information KMK, information and HK) extracted (JJ, authors Three The agreement between the two reviewers independent agreement The www.anesth-pain-med.org sumption were not available at postoperative 6 h, supersed h, 6 postoperative at not available were sumption with those pain of way same the collected in were eddata defined period as was “Late opioid consumption” scores. as “late period pain scores.” Cumulative opioid consump Cumulative periodas “late scores.” pain period surgery 6 h after tion up to defined as “early were opioid con for cumulative If the data opioid consumption.” case of lack of data at postoperative 24 h, the latest pain pain the latest 24 h, postoperative at of data of lack case considered 6 and 24 h were betweenscores postoperative nearest time point within postoperative 6 h were defined as h were 6 within time point postoperative nearest postop at measured scores The period scores.” pain “early In period defined as “late scores.” pain 24 h were erative surgery excluded. was the 6 h or at postoperative at measured scores the pain was included, but the mode of administration (bolus or (bolus or the mode of administration included, but was A study not restricted. and dose infusion) were continuous of intervention infusion drugs during continuous using nists, only intravenous (IV) method administration or oral intravenous only nists, analgesic method and usage. If the data were insufficient insufficient were If the data method and usage. analgesic or tables, the text, from extracted were the data or unclear, graphs. data were included in the data extraction form: patient form: extraction included in the data were patient data sex, age, intervention dose and method, characteristics, and postoperative tool score, and pain pain-measurement from the original articles, and another author (SL) inde (SL) and another author articles, the original from following The data. confirmedpendently all the extracted Data collection process and extracted items Data collection process and extracted for the level of risk of bias regarding the seven domains was was the seven domains of riskfor the level regarding of bias [ kappa assessed Cohen’s using reflect a high risk of bias, low risk of bias, or uncertainty of risk of bias, low risk a high of bias, reflect respectively. bias, estimation of sample size calculation. The methodology methodology The calculation. size of sample estimation or “unclear” to “low,” as “high,” trialfor each graded was blinding of outcome assessment, incomplete outcome outcome incomplete assessment, of outcome blinding specifiedthe We bias. other and selectivereporting, data, the adequate for assessing bias” “other domain seventh lowing seven domains to assess the risk of bias were used riskthe assess to were bias of seven domains lowing allocation sequence generation, trial:each in random personnel, and participants of blinding concealment, sion 5.3 (The Cochrane Collaboration, UK) based on Co Collaboration, 5.3 (Thesion Cochrane If necessary, re risk of of bias. assessment a third chrane’s fol The includedviewer sort to was (SL) disagreements. Anesth Pain Med Vol. 15 No. 2 sis was deleted each time to reflect the influence of an indi- Records identified through vidual data set on the pooled effect estimate. We performed database searching all analyses using R 3.51 (R Foundation for Statistical Com- PubMed (n = 960) Additional records identified EMBASE (n = 651) through sources puting, Austria) and Review Manager (RevMan, version 5.3, Cochrane Library (n = 704) Korea DB (n = 162) The Cochrane Collaboration).

Records after duplicates removed (n = 1,845) RESULTS

Study selection and characteristics Records screened Records excluded (n = 632) (n = 550) We retrieved 2,477 articles after the initial database search: PubMed/MEDLINE (n = 960), EMBASE (n = 651), Full-text articles Full-text articles excluded, with CENTRAL (n = 704), and Korean databases (n = 162). assessed for reasons (n = 71) After removing 1,845 duplicate articles, primary selec- eligibility (n = 82) · Not general anesthesia (n = 7) · Cardiac surgery (n = 1) tion was performed on 632 articles. First, we excluded 550 · Neurosurgery (n = 1) unrelated articles by analyzing their titles and abstracts. · Not administered only preoperatively (n = 18) Thereafter, full-text reviews were conducted on 82 articles. Studies included in · Administered other route except IV Of these 82 full-text articles, 71 were excluded for the fol- qualitative synthesis or PO (n = 7) (meta-analysis) · Associated with other compounds lowing reasons: general anesthesia not performed or com- (n = 11) (n = 3) bined with regional anesthesia (n = 7), cardiac surgery (n · Not appropriate pain score or opioid consumption date (n = 13) = 1), neurosurgery wherein neurological symptoms could · Not controlled with placebo (n = 9) occur (n = 1), continuous infusion during or after surgery · Not in Korea or English (n = 4) · Unable to obtain full text (n = 5) or unclear injection time (n = 18), administration via · Duplicated study (n = 3) routes other than the IV or oral route (n = 7), used in combination with other drugs (i.e., ketamine, gabapentin, or Fig. 1. Flow diagram of search strategy and study selection. DB: remifentanil) (n = 3), did not report appropriate outcomes database, IV: intravenous, PO: postoperative. such as pain score or opioid consumption (n = 13), no placebo group or study protocol without results (n = 9), articles not in Korean or English (n = 4), duplicated study Quality assessment of the included studies (risk (n = 3), and full text unavailable (n = 5). Finally, ROB of bias within studies) evaluation and data extraction were performed on 11 studies [5–7,10–17]. Three studies [7,11,14] that did not re- The ROB evaluation revealed an overall low risk of bias port SD values were excluded from the meta-analysis of (Figs. 2, 3).The proportion of studies assessed as “unclear” pain intensity (Fig. 1). was 18.2% in random sequence generation, 27.3% in allo- In all studies, alpha-2 agonists were administered via the cation concealment, 27.3% in blinding of participants and oral [6,13,16] or IV route [5,7,10–12,14,15,17], but the doses personnel, 9.1% in incomplete outcome data, and 18.2% in and timing of injection differed among the studies (in most other bias. Random sequence generation was unclear in studies, the timing was between 2 h and right before anes- two studies [6,10] that did not specify a randomization thesia induction; in study of Pawlik et al. [13], the timing method. Allocation concealment was unclear in three was the evening before and 2 h before anesthesia induc- studies [6,10,11] that did not mention the specific allocation). Moreover, the type of opioids used differed across tion concealment method. Three studies that did not de- studies (morphine [14,17], fentanyl [7,11,15], and pethidine scribe the blinding method for placebos were also rated as [6]). The frequency and interval of measurement of the “unclear” [6,13,16]. The risk of incomplete outcome data pain score also varied across studies (ranging from every was unclear in the study by Lee et al. [7], because the drop- 30 min to once daily) (Table 1). out rate was 5 to 20%. Among the risk assessments of other biases mentioned in the Materials and Methods section, a

160 www.anesth-pain-med.org

KSAP

ENT: ear, nose, and throat, IV: intravenous, N/S: normal saline, PO: postoperative, VAS: visual analogue scale, PACU: post-anesthesia care unit. care post-anesthesia PACU: scale, analogue visual VAS: postoperative, PO: saline, normal N/S: intravenous, IV: throat, and nose, ear, ENT:

10 ml (21) ml 10

161

Placebo (21), IV dexmedetomidine 1 μg/kg + N/S N/S + μg/kg 1 dexmedetomidine IV (21), Placebo surgery Gynecological ] 12 [ 2013 al. et Shin VAS (1–10) at PACU at (1–10) VAS -

Transabdominal hysterectomy Transabdominal ] 7 [ 2017 al. et Lee VAS (1–10) at 6th, 24th hour 24th 6th, at (1–10) VAS h 24 6, at consumption fentanyl Cumulative (16) μg/kg 1 dexmedetomidine IV (18), Placebo

50 ml (30) ml 50

Laparoscopic cholecystectomy Laparoscopic ] 11 [ 2019 al. et Park Placebo (30), IV dexmedetomidine 0.5 μg/kg + N/S N/S + μg/kg 0.5 dexmedetomidine IV (30), Placebo VAS (1–10) at 30 min, 24 h 24 min, 30 at (1–10) VAS PACU at consumption Fentanyl

20 ml (30) ml 20 stenting

Ambulatory ureteroscopy, ureteric ureteric ureteroscopy, Ambulatory ] 5 [ 2018 al. et Shariffuddin Placebo (30), IV dexmedetomidine 0.5 μg/kg + N/S N/S + μg/kg 0.5 dexmedetomidine IV (30), Placebo VAS (1–10) at PACU, 24th hour 24th PACU, at (1–10) VAS -

Laparoscopic cholecystectomy Laparoscopic ] 6 [ 2000 al. et Sung Placebo (65), PO clonidine 150 μg (43) μg 150 clonidine PO (65), Placebo VAS (1–10) at 2nd hour 2nd at (1–10) VAS h 24 consumption pethidine Cumulative

Laparoscopy ] 10 [ 1992 al. et Carabine Placebo (12), IV clonidine 100 μg + N/S 5 ml (12) ml 5 N/S + μg 100 clonidine IV (12), Placebo - PACU at consumption morphine Cumulative

10 ml (30) ml 10 biopsy breast tectomy,

Inguinal hernia, laparoscopic cholecys laparoscopic hernia, Inguinal ] 14 [ 2010 al. et Mizrak Placebo (30)/IV dexmedetomidine 0.5 μg/kg + N/S N/S + μg/kg 0.5 dexmedetomidine (30)/IV Placebo - VAS (1–10) at 30 min 30 at (1–10) VAS -

ENT surgery ENT ] 13 [ 2005 al. et Pawlik Placebo (15)/PO clonidine 2 μg/kg (15) μg/kg 2 clonidine (15)/PO Placebo VAS (1–10) at PACU, 8th hour 8th PACU, at (1–10) VAS -

incisional hernia repair hernia incisional

100 ml (30) ml 100 umbilical, inguinal, and splenectomy h

Mini-laparotomy, cholecystectomy, cholecystectomy, Mini-laparotomy, ] 17 [ 2005 al. et Unlugenc Placebo (30)/IV dexmedetomidine 100 μg + N/S N/S + μg 100 dexmedetomidine (30)/IV Placebo VRS (1–10) at 6th, 24th hour 24th 6th, at (1–10) VRS 24 6, at consumption morphine Cumulative

Transabdominal hysterectomy Transabdominal ] 16 [ 2013 al. et Behdad Placebo PO (30)/PO clonidine 100 μg (30) μg 100 clonidine (30)/PO PO Placebo VAS (1–10) at 6th, 24th hour 24th 6th, at (1–10) VAS -

] 15 [

Thoracic surgery Thoracic 2012 al. et Samantaray Placebo (30)/IV clonidine 3 μg/kg + N/S 50 ml (30) ml 50 N/S + μg/kg 3 clonidine (30)/IV Placebo VAS (1–100) at 6th, 24th hour 24th 6th, at (1–100) VAS h 6 at consumption fentanyl Cumulative

Pain score Pain consumption Opioid

Study Intervention (number of patients) of (number Intervention Surgery

Reported outcomes Reported

Characteristics of the Included Studies Included the of Characteristics Table 1. Table

] ------= = 13 2 [ I Effect of preoperative alpha-2 agonists alpha-2 preoperative of Effect ], leading to a high risk a high to of ], leading 14 [ ] (n = 236; 118 in the experi 17 , ] were data collected from the the collected from data ] were 15 , 11 , 11 ] (n (n ] = experimental the in 89 202; , 10 10 17 [ , , 7 7 [ , 6 ]. Most studies did not provide information information did not provide studies ]. Most [ ] were data collected from the PACU instead instead the PACU collected from data ] were 16 , ). 13 , ] analyzed pain score data measured at the 2nd the 2nd at measured data score pain ] analyzed 15 , 6 ]. [ 12 [ 11 16 , [ Fig. 4A Fig.

10 , 7 after surgery) from data performed synthesizing a meta-analysis We Opioid consumption for late postoperative pain (24 h The test for subgroup differences indicated that there is is there that indicated differences for subgroup test The after surgery) effect five sizes from data synthesizing A meta-analysis Opioid consumption for early postoperative pain (6 h Opioid consumption for early postoperative The early period opioid consumption data extracted extracted period data early The opioid consumption , 6 www.anesth-pain-med.org group and 113 in the control group), which suggested that that suggested which group), and 113 in the control group signifi was pain postoperative for late opioid consumption group agonist alpha-2 preoperative in the reduced cantly three studies studies three tion does not modify the effect of alpha-2 agonist in com tion does agonist not modify the effect of alpha-2 drug for ear on the opioid consumption parison control to pain. postoperative ly no statistically significant subgroup effect (P subgroup significant no statistically = 0.63, analy of administra the route that suggesting not presented), sis nificantly reduced in the preoperative alpha-2 agonist agonist alpha-2 in the preoperative reduced nificantly P –0.14]; to [–0.90 CI 95% –0.52; (SMD, group =0.093; 50%; mental group and 118 in the control group) suggested that that suggested group) and 118 in the control group mental sig was pain postoperative for early opioid consumption from five studies studies five from instead of those collectedinstead surgery. 24 h after up to hour. For the late period pain score analysis, data collected data analysis, period the late score pain For hour. one study from surgery 8 h after up to extracted were studies studies anoth of those collected surgery. 6 h after up to Moreover, er study from two studies from those collected of instead (PACU) unit care post-anesthesia two other from data period early The score pain 6 h. up to tion Effects on postoperative pain and opioid consump Effects on postoperative [ for one except sites, registration study Web-based about study 54.5% in blinding of outcome assessment and 90.9% in se assessment of outcome 54.5% in blinding described wheth inaccurately studies Six lective reporting. implemented was assessment of outcome er blinding power analysis to calculate the required sample size was was size sample the required calculate to analysis power et al. not performed Mizrak by assessed “unclear” as of studies proportion was The bias. Anesth Pain Med Vol. 15 No. 2

Random sequence generation (selection bias) Allocation concealment (selection bias) Blinding participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Selective reporting (reporting bias) Other bias

0% 25% 50% 75% 100% Low risk of bias Unclear risk of bias High risk of bias

Fig. 2. Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

(SMD, –0.68; 95% CI [–1.27 to –0.09]; P = 0.025; I2 = 73%; Fig. 4B). A subgroup analysis comparing the effect in postoperative opioid consumption in late period (24 h) was not possible due to there being too few trials in this category.

Pain score for early postoperative pain (6 h after surgery) A meta-analysis synthesizing data from seven studies [5,6,12,13,15–17] (n = 418; 199 in the experimental group and 219 in the control group) suggested that the pain score for early postoperative pain was significantly reduced in the preoperative alpha-2 agonist group (SMD, –0.50; 95% Random sequence generation (selection bias) Allocation concealment (selection bias) Blinding participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Selective reporting (reporting bias) Other bias CI [–0.78 to –0.21]; P = 0.058; I2 = 51%; Fig. 4C). Behedad 2013 The test for subgroup differences indicated that there is

Carabine 1992 no statistically significant subgroup effect (P = 0.86, analysis not presented), suggesting that the route of administra- Lee 2017 tion does not modify the effect of alpha-2 agonist in com-

Mizrak 2010 parison to control drug on the early postoperative pain.

Park 2019 Pain score for late postoperative pain (24 h after

Pawlik 2005 surgery) Five studies [5,13,15–17] (n = 268; 135 in the experimental Samantaray 2012 group and 133 in the control group) reported data on the pain score for late postoperative pain. Preoperative alpha-2 ago- Shariffuddin 2018 nists significantly reduced the postoperative pain score (SMD, Shin 2013 – 0.44; 95% CI [–0.86 to –0.03]; P = 0.026; I2 = 64%; Fig. 4D). The test for subgroup differences indicated that there is Sung 2000 no statistically significant subgroup effect (P = 0.53, analy- Unlugenc 2005 sis not presented), suggesting that the route of administration does not modify the effect of alpha-2 agonist in com- Fig. 3. Risk of bias summary: review authors' judgements about parison to control drug on the late postoperative pain. each risk of bias item for each included study.

162 www.anesth-pain-med.org KSAP - - - 163 ], which had a great influence on het influence a great had ], which DISCUSSION 17 , 16 [ In this meta-analysis, we evaluated the effectpreoper of we evaluated this meta-analysis, In ative administration of alpha-2 agonists on total opioid opioid on total agonists of alpha-2 administration ative and postopera analgesia for postoperative consumption and opioid consumption that found We score. pain tive riods were not statistically significantly different between different significantly not statistically riods were omitting after group and control group agonist the alpha-2 one trial each not shown). (results erogeneity - Effect of preoperative alpha-2 agonists alpha-2 preoperative of Effect Forest plot diagram showing the effect of alpha-2 agonist on postoperative pain intensity and opioid consumption. (A) Early period period (A) Early consumption. opioid and pain intensity postoperative on agonist alpha-2 of effect the showing diagram plot Forest ]. Opioid consumption in the late postoperative period postoperative in the late ]. Opioid consumption ]. The pain scores in the early and late postoperative pe postoperative and late in the early scores pain ]. The Opioid consumption in the early postoperative period period postoperative in the early Opioid consumption B D C A 17 17 www.anesth-pain-med.org 0.010) than the pooled estimate effect size (SMD, –0.68; –0.68; (SMD, effect size the pooled estimate 0.010) than –0.09]; P 95% CI [–1.27 to = one trial omitting 0.025) after [ 95% CI [–0.90 to –0.14]; P 95% CI [–0.90 to = one trial omitting 0.007) after [ –0.10]; P –0.44; 95% CI [–0.78 to (SMD, 35% lower was = was 38% lower (SMD, –0.32; 95% CI [–0.62 to –0.02]; P –0.32; 95% CI [–0.62 to (SMD, 38% lower was = –0.52; (SMD, effect size the pooled estimate 0.036) than Sensitivity analysis opioid consumption. (B) Late period opioid consumption. (C) Early period pain score. (D) Late period pain score. Std. Mean difference: difference: Mean Std. pain score. period (D) Late pain score. period (C) Early consumption. opioid period (B) Late consumption. opioid deviation. SD: standard interval, CI: confidence intravenous, IV: difference, mean standardized Fig. 4. Fig. Anesth Pain Med Vol. 15 No. 2 pain score were significantly lower in both the early and Furthermore, we did not distinguish between dexmede- late periods. This may be due to a preemptive analgesic ef- tomidine and clonidine when analyzing alpha-2 agonists. fect, anxiolytic effect, analgesic-sparing effect, or a residual Because these two drugs have different selectivity for al- additive effect of alpha-2 agonists [5,17]. pha-2 adrenal receptors, their effects may be different. Recently, intraoperative administration of alpha-2 ago- In summary, we demonstrated that preoperative IV or nists has mainly been used for multimodal analgesia [1]. oral administration of alpha-2 agonists, such as clonidine According to the results of a meta-analysis conducted by and dexmedetomidine, may reduce postoperative opioid Schnabel et al. [18], intraoperative use of dexmedetomi- consumption and pain intensity until 24 h. However, high dine leads to lower postoperative pain intensity and re- degree of heterogeneity due to variations in the study duced opioid consumption. Therefore, in our analysis, why method and small sized studies, limits the recommenda- did the analgesic effect continue after surgery when al- tions in the preoperative administration of alpha-2 ago- pha-2 agonists were administered before surgery? This was nists. Future powered large RCTs are required to increase the reason why we aimed to investigate whether preopera- the certainty of evidence on the effect in reducing postop- tive administration of alpha-2 agonists affects postopera- erative opioid consumption and pain intensity. tive pain as does intraoperative administration of alpha-2 agonists. Intraoperative or postoperative administration of CONFLICTS OF INTEREST alpha-2 agonists is likely more beneficial when considering only the duration of drug administration for postoperative No potential conflict of interest relevant to this article pain management. However, this was difficult to analyze was reported. because each included study used different types of anesthetics, analgesics, and surgeries, as well as different dura- AUTHOR CONTRIBUTIONS tions of surgery. First, this could be considered a result of reducing preoperative anxiety in patients. Preoperative al- Conceptualization: Sangseok Lee. Study design: Ji Youn pha-2 agonists are frequently used to reduce a patient’s Ju, Kye-Min Kim, Sangseok Lee. Data acquision: Ji Youn Ju, anxiety, which is also associated with a patient’s preopera- Kye-Min Kim. Data analysis: Ji Youn Ju, Sangseok Lee. tive well-being and decreased levels of postoperative pain Writing—original draft: Ji Youn Ju, Kye-Min Kim, Sangseok [19]. Moreover, the preemptive effects could already have Lee. Writing—review & editing: Ji Youn Ju, Kye-Min Kim, occurred as a result of the administration of alpha-2 ago- Sangseok Lee. nists before surgical stimulation [19,20]. This meta-analysis has several limitations. The number ORCID of studies included was quite small. To maintain good quality, only complete RCTs and studies published in En- Ji Youn Ju, https://orcid.org/0000-0001-9069-4189 glish and Korean were included in this meta-analysis, Kye-Min Kim, https://orcid.org/0000-0003-1298-7642 thereby resulting in the small number of studies. Moreover, Sangseok Lee, https://orcid.org/0000-0001-7023-3668 most studies had small sample sizes and some studies did not report postoperative pain and opioid consumption as REFERENCES primary endpoints. Since the types of anesthetics and analgesics used in each study were different, they could pos- 1. 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. 3. : recovery after after recovery eview and me Effect of preoperative alpha-2 agonists alpha-2 preoperative of Effect . . 0. 2 agonists on postoperative morphine on postoperative 2 agonists Waldhauser D, Selig C, Kuehnel TS. TS. Selig C, Kuehnel D, Waldhauser α . Blaudszun G, Lysakowski C, Elia N, Tramèr MR. Effect of MR. of Effect C, Tramèr Elia N, Lysakowski G, Blaudszun Shariffuddin II, Teoh WH, Wahab S, Wang CY. Effect of sin Effect CY. Wang S, WH, Wahab II, Teoh Shariffuddin Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. DG; Altman Group. PRISMA J, A, Liberati Tetzlaff D, Moher Sung CS, Lin SH, Chan KH, Chang WK, Chow LH, Lee TY. Ef WK, Chang KH, LH, LeeLin Chan SH, Chow TY. CS, Sung al. Pretreatment with decreas dexmedetomidine thiopental or Pretreatment al. Clonidine premedication in patients with syn sleep apnea in patients Clonidine premedication placebo-controlled double-blind, a randomized, drome: 2005; 101: 1374-8 Analg Anesth study. Anesthesiol 2013; 65: 114-20. Anesthesiol thetic dexmedetomidine 1 µg/kg single infusion is a simple, is a simple, infusion thetic dexmedetomidine single 1 µg/kg J Korean anesthesia. for general and economiceasy, adjuvant dine on the remifentanil and propofol requirement during during requirement and propofol dine on the remifentanil 2019; 14: 29- Med cholecystectomy. Pain Anesth laparoscopic 34. thesiol 1992; 9: 325-9 thesiol of dexmedetomi administration single fects of preanesthetic pressor response to endotracheal intubation. A comparisonof intubation. endotracheal to response pressor J Anaes Eur and fentanyl. clonidine the effects of intravenous ta-analyses: the PRISMA statement. BMJ 2009; 339: b2535 2009; 339: BMJ ta-analyses: statement. PRISMA the 2005; 37: 360-3 Med Fam statistic. the kappa Preferred reporting items for systematic reviews and me reviews for systematic items reporting Preferred fect of pre-anesthetic administration of dexmedetomidine on administration fect of pre-anesthetic gynecologic pa of opioids in postoperative the consumption 2017; 12: 37-41 Med Pain Anesth tients. for patients undergoing laparoscopic cholecystectomy. Acta cholecystectomy. Acta laparoscopic undergoing for patients 2000; 38: 23-9. Sin Anaesthesiol fect of oral clonidine premedication on perioperative hemo on perioperative premedication clonidine fect of oral requirement analgesic and postoperative response dynamic gle-dose dexmedetomidine on postoperative gle-dose dexmedetomidine on postoperative blind a double stenting: ureteric and ambulatory ureteroscopy 2018; 18 Anesthesiol BMC study. controlled randomized ta-analysis of randomized controlled trials. Anesthesiolog trials. controlled of randomized ta-analysis 2012; 116: 1312-22. perioperative systemic systemic perioperative r systematic intensity: and pain consumption Viera AJ, Garrett JM. Understanding interobserver agreement: interobserver Understanding JM. Garrett AJ, Viera Lee KY, Lee WY, Kim KM, Yoo BH, Lee S, Lim ef YH, et al. The Lee BH, S, KM, Yoo Kim Lee WY, Lee KY, Pawlik MT, Hansen E, Hansen MT, Pawlik Carabine UA, Allen RW, Moore J. Partial attenuation of the the of attenuation Partial J. RW, Moore Allen UA, Carabine Park H, Kim HS, Kim JW, Lee GG, Park DH, Jeong CY, et al. Ef CY, DH, Jeong JW, Lee Kim Park GG, HS, H, Kim Park Shin HW, Yoo HN, Kim DH, Lee H, Shin HJ, Lee HW. Preanes Lee DH, Kim HJ, H, Shin HN, HW, Yoo Shin Mizrak A, Koruk S, Bilgi M, Kocamer B, Erkutlu I, Ganidagli S, et S, I, Ganidagli B, Erkutlu M, Kocamer Bilgi A, S, Mizrak Koruk . . . . 9 8 7 6. 5. 4. www.anesth-pain-med.org 14. 13. 12. 11. 10 Anesth Pain Med Vol. 15 No. 2

Appendix 1. Example of electronic database searching strategy for MEDLINE

#16. #14 AND #15

#15. random*

#14. #13 AND [english]/lim

#13. #5 AND #11 AND #12

#12. postop* OR postane* OR 'post op*' OR 'post ane*' OR postanae* OR 'post anae*'

#11. #6 OR #7 OR #8 OR #9 OR #10

#10. pca OR 'patient controlled analgesia'

#9. analgesic*

#8. fentanyl

#7. morphine

#6. opioid*

#5. #1 OR #2 OR #3 OR #4

#4. (alpha AND 2 OR 'alpha-2' OR a2 OR 'a 2') AND agonist*

#3. precedex

#2. dexmedetomidine

#1. clonidine

166 www.anesth-pain-med.org KSOA ------

. ]. 2 [ Clinical Research Clinical ] compared hemodynamic change be change hemodynamic ] compared ]. Other reported side effects include effects side ]. Other reported include 8 5 [ ]. However, it is associated with it is associated dose-re ]. However, [ 4 [ ]. Thomas et al. ]. Thomas 7 Oxytocin being the most popular uterotonic agent, has has agent, Oxytocin uterotonic popular the most being , 6 sea and vomiting sea and vomiting effect of oxytocin pulmonary the antidiuretic due to edema [ bolus in by oxytocin administered was that tween a group delivery section cesarean and delivery both after vaginal and administered been routinely section cesarean nau tachycardia, hypotension, including effects, side lated 167 - ) was attached to the patient’s finger soon after the induction of spinal an spinal of induction the after soon finger patient’s the to attached ) was eISSN 2383-7977

® • The method of administration of carbetocin does not influence its hemody influence does not carbetocin of administration of method The

Postpartum hemorrhage is the leading cause of maternal mortality. Oxytocin maternal of cause leading is the Postpartum hemorrhage

Carbetocin; Cesarean section; Hypotension; Tachycardia Hypotension; Cesarean section; Carbetocin; We recruited 34 women undergoing elective cesarean section under spinal an spinal under section cesarean elective undergoing 34 women recruited We The demographic data showed no significant difference between the two groups. groups. two the between difference significant no showed data demographic The every 15 s, starting from 15 s before the administration of carbetocin to 5 min after. After After after. 5 min to carbetocin of administration the s before 15 s, starting 15 from every injection bolus intravenous administered was group bolus the placenta, the of removal the μg diluted 100 carbetocin administered was group infusion the and μg 100 carbetocin of pump. an infusion 5 min using over saline, in 50 ml normal Results: groups. two the between differences hemodynamic significant no were there Furthermore, Conclusions: effects. namic Keywords: Background: vagi both after administered routinely been has agent, uterotonic popular most the being the provides and agent uterotonic is a newer Carbetocin section. cesarean and delivery nal post-delivery. administration additional without action of duration a longer of benefit Methods: 8–10 Marcaine 0.5% hyperbaric using anesthesia spinal received was All patient esthesia. Hartmann’s position. decubitus lateral left the in μg 20 fentanyl with conjugation in mg started as soon operation The carbetocin. before ml/kg administered was 10–15 solution monitoring hemodynamic A non-invasive confirmed. T4–T6 was level at block as sensory cuff (Finometer at pressure arterial mean and heartthe rate recorded we Finometer, the Using esthesia. Hemodynamic effects of carbetocin administered administered of carbetocin effects Hemodynamic during cesarean bolus or infusion as an intravenous delivery Eun Park, Dohyung Kim, Hyunmin Jo, Ji Kihyug Kwon, Kim and Kyung Ok Medicine, Dongguk University Ilsan Hospital, and Pain Department of Anesthesiology Goyang, Korea Anesth Pain Med 2020;15:167-172 2020;15:167-172 Med Pain Anesth https://doi.org/10.17085/apm.2020.15.2.167 pISSN 1975-5171

INTRODUCTION ]. Uterine atony is the most common cause of common cause is the most atony ]. Uterine 2 , 1 [ January 31, 2020 31, January August 7, 2019 7, August

January 28, 2020 January ]. The World Health Organization (WHO) recom Organization Health World ]. The 3 [ Postpartum hemorrhage (PPH) is associated with is associated (PPH) nearly hemorrhage Postpartum 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 which (http://creativecommons.org/licenses/by-nc/4.0) License Non-Commercial Attribution Commons Creative the of terms the under Access article is an Open This distributed cited. is properly work original the provided in any medium, reproduction and distribution, use, non-commercial unrestricted 2020 Anesthesiologists, Society of Korean © the Copyright PPH and of labor stage of the third management mends active during of PPH vaginal for the prevention use of uterotonics leading cause of maternal mortality in most low-income low-income mortality most in maternal of cause leading countries one quarter of all maternal deaths globally. It is also the is also the It globally. deaths one quarter of all maternal Tel: 82-31-961-7868 Tel: 82-31-961-7869 Fax: [email protected] E-mail: Department of Anesthesiology and and Anesthesiology of Department University Dongguk Medicine, Pain Dongguk-ro, 27 Hospital, Ilsan Korea 10326, Goyang Ilsandong-gu, Corresponding author author Corresponding M.D. Kwon, Kihyug Received Received Accepted Revised Revised Anesth Pain Med Vol. 15 No. 2 jection and another group that was administered oxytocin 8–10 mg and fentanyl 20 μg in the left lateral decubitus posi- by infusion. They concluded that the infusion group had tion. Hartmann’s solution 10–15 ml/kg was administered lesser hemodynamic changes than the bolus group. before administration of carbetocin. The operation started Carbetocin is a newer uterotonic agent and a long-acting as soon as the sensory block at level T4–T6 was confirmed. synthetic octapeptide analogue of oxytocin with oxytocin A non-invasive hemodynamic monitoring cuff (Finome- receptor agonist properties. Because carbetocin has a 4–10 ter®, Finapres medical system, Netherlands) was attached to fold longer elimination half-life than that of oxytocin, it the patient’s finger soon after the induction of spinal anes- provides the benefit of longer duration of oxytocic action thesia. Using the Finometer, heart rate (HR) and mean arte- without additional administration in post-delivery [4]. Al- rial pressure (MAP) was recorded at every 15 s starting from though the difference between carbetocin and oxytocin in 15 s before the administration of carbetocin to 5 min after. terms of hemodynamic changes, postpartum blood loss After the removal of placenta, the bolus group received and incidence of side effects is not statistically significant an intravenous bolus injection of carbetocin 100 μg and the [4,9], carbetocin is superior to oxytocin in terms of addi- infusion group received 100 μg carbetocin diluted in 50 ml tional dosing and cost-effectiveness [10]. normal saline, over 5 min using an infusion pump (Orches- There is no definite consensus about how to administer tra® Module DPS, Fresenius Kabi, France). We defined hy- carbetocin. We compared the hemodynamic effects of car- potension as less than 20% of the preoperative value or be- betocin when administered as an intravenous bolus and as low 80 mmHg systolic blood pressure. Hypotension was an infusion over 5 minutes using a non-invasive hemody- treated with ephedrine 5 mg boluses. If ephedrine was namic monitoring device. used during the study period, that patient would be excluded in study. MATERIALS AND METHODS The primary endpoint was the mean difference in HR and MAP between study groups at each time point. The This study was approved by the Hospital Ethics Commit- secondary endpoints were estimated blood loss (EBL), the tee (Dongguk University Ilsan Hospital Institutional Review presence of postoperative hemorrhage and the require- Board, registration no. 2012-77). The study was registered ment for additional administration of uterotonic agent. with Clinical Research Information Service, Korea (https:// A MAP difference of 10 mmHg between the two groups cris.nih.go.kr, registration no. KCT0000715). We recruited was considered clinically significant. According to the pre- 34 women undergoing elective cesarean section under spi- vious study reporting a standard deviation of 8.7 mmHg [8], nal anesthesia. The patients were 37 weeks or more into a sample of 17 patients per group was required with error their pregnancy and were classified as Class 1 or 2 accord- of 0.05 and power of 90%. ing to the American Society of Anesthesiologists physical Demographic data variables including age, height, weight, status classification system. The patients who had pre- and body mass index, ephedrine dose, and operation time eclampsia, placenta previa, other diseases affecting hemo- were analyzed using unpaired t-tests. The primary endpoints dynamic change and past medical history of hypertension were analyzed at each time point using unpaired t-tests. EBL of or diabetes were excluded. The written consent was given each group was compared using the Mann-Whitney test. Oth- by all subjects before operation. The subjects were ran- er secondary endpoints were compared using Fisher’s exact domly divided into two groups. Prior to enrolling patients, test. All statistical analysis were performed using R software group assignments were placed in 34 opaque envelopes. version 3.3.2 (R Core Team [2016]. R: A language and environ- These envelopes were mixed and placed in a container. Be- ment for statistical computing. R Foundation for Statistical fore each patient entered the operating room, the anesthe- Computing, Austria. URL: https://www.R-project.org/). sia provider randomly selected one of these opaque concealed envelopes to ensure group randomization. RESULTS None of patients were premedicated. Non-invasive blood pressure monitoring device, pulse oximeter and electrocar- The study was conducted over a continuous period of 1 diograph were attached to the patient as soon as they arrived year. A total 34 patients were recruited. No patient was ex- in the operating room. All patients received spinal anesthe- cluded except one whose data were missing (Fig. 1). The sia at L3/4 or L4/5 level using 0.5% hyperbaric Marcaine patient characteristics are shown in Table 1. No statistical

168 www.anesth-pain-med.org KSOA - 169 13.0 13.5 ± ± 97.6 97.6 84.4 Infusion group Infusion 0.291 0.721 0.469 0.390 0.589 0.354 P value 15.3 12.9 ± ± Bolus group Bolus 83.6 101.2 101.2 Excluded (n = 7) 2) · Mechanical error (n = 5) · Protocol violence (n = Excluded (n = 41) Excluded (n 18) inclusion criteria (n = · Not meeting (n = 23) · Declined to participate 4.9 4.3 12.3 4.5 8.6 14.1 6 8 3 ± ± ± ± ± ± 14 61.4 61.4 11.8 11.8 33.3 66.3 26.4 158.3 158.3 ). There were no significant differences between differences no significant were ). There Infusion group (n group Infusion = 17) Initial Heart Rate and Mean Arterial Pressure of Two Groups Two of Pressure Arterial Mean and Heart Initial Rate Infusion group (n = 17) Table 3 Table Initial hemodynamic variable hemodynamic Initial Initial HR (beats/min) Initial MAP (mmHg) Initial Again, the difference between the two groups at any time any at between the two the difference groups Again, also investigated We significant. not statistically was point in agent of uterotonic EBL, administration additional interven and the incidence of postoperative both groups uterine as tion such artery or hysterectomy embolization ( postoperative received Only patient one two the groups. Table 2. Table MAP: mean ± SD. HR: heart as mean rate, presented are Values pressure. arterial After till the end of the study. decrease showed a gradual 92.35 beats/ was of the bolus HR the mean group 300 s, 91.71 beats/min. was group of the infusion min and that - - section (n = 92) section (n = 3.1 6.3 12.5 3.9 12.0 13.5 1 3 ± ± ± ± ± ± 12 Randomized (n = 51) 13 ). ). In both both ). In 27.7 27.7 71.0 71.0 13.8 13.8 65.9 33.8 3 Screened total elective cesarean Screened total

159.6 159.6 , Bolus group (n group Bolus = 16) Hemodynamic effects of carbetocin of effects Hemodynamic Table 2 Table ( Figs. 2 Bolus group (n = 16) ) 2 Variable Previous cesarean section cesarean Previous · Protocol violence (n = 7) · Protocol violence (n = Excluded (n = 11) 4) · Mechanical error (n = The Demographic Data of Two Groups Two of Data Demographic The Operation time (min) time Operation Body mass index (kg/m massBody index delivery cesarean for Indication Breech Others (mg) dose Ephedrine use ephedrine of Number Age (yr) Age (cm) Height (kg) Weight Patients CONSORT flow chart. flow CONSORT Patients In both groups, we found a rapid increase of HR until 45 of HR until increase a rapid we found both groups, In Moreover, there was no statistical difference in the mean mean the in difference statistical no was there Moreover, www.anesth-pain-med.org no statistically significant difference at any time point. time point. any at difference significant no statistically the trends Then, of carbetocin. the administration s after 88.73 mmHg and that of the infusion group was 86.76 86.76 was group of the infusion and that 88.73 mmHg than higher was MAP of the bolus mean group The mmHg. was there but 300 s, 105 to from group of the infusion that of administration. Then, the trends showed a gradual in gradual a showed trends the Then, administration. of was MAP of the bolus the mean group 300 s, After crease. HR and MAP between the two groups ( HR and MAP between the two groups 30 s after of MAP until decrease we a rapid found groups, method the of regardless carbetocin of administration the ephedrine used between the two groups. Baseline HR and Baseline ephedrine used between the two groups. either different not statistically MAP were difference was observed was difference in demo between the two groups ephedrine during received of patient None data. graphic dose in the total of periodthe study and no difference Values are presented as mean ± SD or number only. number ± SD or as mean presented are Values Fig. 1.Fig. 1. Table Anesth Pain Med Vol. 15 No. 2

110

100 Group Bolus group Infusion group 90 HR (beats/min) 80

Fig. 2. The changes of heart rate (HR) in two groups. -15 0 15 30 45 60 75 90 105 120 135 150 165 180 195 210 225 240 255 270 285 300 Values are presented as mean Time (s) ± SD.

110

100 Group Bolus group Infusion group 90 MAP (mmHg) MAP 80

Fig. 3. The changes of mean 60 arterial pressure (MAP) in two -15 0 15 30 45 60 75 90 105 120 135 150 165 180 195 210 225 240 255 270 285 300 groups. Values are presented Time (s) as mean ± SD.

Table 3. Secondary Endpoint of Two Group uterine artery embolization and transfusion during PPH. Secondary endpoints Bolus group Infusion group Number of postoperative utero- 0 0 DISCUSSION tonic agent Estimated blood loss (ml) 520.0 ± 207.7 535.3 ± 264.4 Our study showed that the method of administration of Number of postoperative 0 1* interventions carbetocin does not influence its hemodynamic effects in Number of patients received 0 1 cesarean section and does not affect additional uterotonic transfusion agent use or incidence of postoperative intervention such Values are presented as number only or mean ± SD. *1 patient was received uterine artery embolization and the patients were as uterine artery embolization or hysterectomy. also only patients received transfusion. Carbetocin is a long-acting synthetic nonapeptide analogue of oxytocin with agonist properties. It can be admin-

170 www.anesth-pain-med.org KSOA ------] in 171 15 [ ]. A recent recent A ]. 18 , ]. However, hy ]. However, 17 [ 16 [ ] also reported a similar result with re result a similar ] also reported 14 [ ]. In the future, we aim to develop and optimize meth optimize and develop weto aim future, the In ]. In conclusion, the administration method of carbetocin carbetocin of method administration the conclusion, In There were several limitations to this study. First, the cal First, this study. to limitations several were There Our study showed that the method of administration the method of administration that showed study Our for anesthesia during spinal hypotension Intraoperative 18 for investigating the precise hemodynamic effect of car hemodynamic the precise for investigating betocin. addition, In changes. doeshemodynamic the influence not no effect on postoperative method has the administration uterotonic of administration additional complications, or blood loss. agents occurrence of hypotension during the investigation period during the investigation of hypotension occurrence we thought But, coincidence. of a mere be a result might of emergency the exclusion fluid loading, sufficient that hypo for preventing surgery treatment and other effective result. that to contributed tension but similar, statistically were bothof groups EBL culated in the actual difference been a significant have may there quantify to difficult is which bloodloss accu a colorimetric for more recommends system study Although of blood loss. amount of the measurement rate in the difference a colorimetricwe not apply could system, study in our blood betweenthe actual loss the two groups in the EBL the calculated is not expected since be to large study of our that to similar was study mentioned above [ of blood and intra loss measurement ods for the accurate does not this study Furthermore, status. volume vascular Although change. hemodynamic postoperative investigate in terms between the two groups no differences were there compli drug use or postoperative uterotonic of additional vital sign it is necessary postoperative measure to cations, group. Kim et al. Kim group. the in with a difference changes cardiovascular to gards uterine EBL. and tone hemody effect on the patient’s a significant does not have et al. Dell-Kuster of carbetocin. in the case namics be differences obstetric and hemodynamic vestigated the tween that bolus carbetocin They and infusion. found doesnot short a as infusion carbetocin of administration two methods have the uterine and that tone compromise effects and vasoconstrictor dose re cardiovascular similar quirements. 70%, when above delivery frequent elective cesarean are is not used prophylaxis pharmacological methods several by improved or prevented is potension use of va compression, of aorto-caval as prevention such no study, our In fluid loading. and intravenous sopressors ------Hemodynamic effects of carbetocin of effects Hemodynamic ]. 11 [ ] compared the effects of oxytocin the effects of oxytocin ] compared ] compared the cost-effectiveness the cost-effectiveness ] compared 8 [ 10 ]. [ ]. ] examined 12 randomized controlled controlled ] examined 12 randomized 12 [ 2 measures finger blood pressure nonin bloodpressure finger measures [ 13 ® [ In the case of oxytocin, several reports have shown an shown an have reports several of oxytocin, the case In Recent studies have suggested that carbetocin is superior is carbetocin that suggested have studies Recent According to WHO guidelines for prevention of PPH, of PPH, for prevention WHO guidelines to According The Finometer The www.anesth-pain-med.org administered as an intravenous bolus and as an infusion bolus and as an infusion as an intravenous administered section. They cesarean women30 min in 5 for undergoing in the bolus changes cardiovascular marked reported association between an infusion of diluted oxytocin and and oxytocin diluted of between infusion an association bolus to admin compared changes milder hemodynamic et al. Thomas istration. EBL or adverse effects. effects. or adverse EBL for additional uterotonic agents and uterine massage in in and uterine massage agents uterotonic for additional their women who underwent section. However, cesarean in PPH, difference not detect a significant could analysis carbetocin instead of oxytocin reduced the costs by EUR EUR by the costs reduced of oxytocin instead carbetocin et al. 27,518. Jin the requirement lowered carbetocin that and found studies compared the costs for additional drugs blood and prod additional for costs the compared used,seucts and dependsincidence the on turn in which in UK, this study, to the useverity of According of PPH. section to that of oxytocin. They analyzed 1,500 patients re 1,500 patients They analyzed of oxytocin. section that to section and in cesarean or oxytocin carbetocin ceiving to oxytocin in cost-effectiveness and prevention of PPH. PPH. of prevention and cost-effectiveness in oxytocin to et al. der Nelson van in cesarean of PPH usedof carbetocin for the prevention dence of major obstetric hemorrhage and is more expen and is more obstetric hemorrhage dence of major oxytocin than sive tional uterotonic agent has been recommended, according according been recommended, has agent uterotonic tional inci effectthe no on has carbetocin guidelines, WHO to oxytocin (10 IU, intravenous or intramuscular) is the utero or intramuscular) intravenous (10 IU, oxytocin and ce of labor stage during of choice the third agent tonic section. the use as an addi Although of carbetocin sarean by measuring the brachial cuff pressure and hydrostatic and hydrostatic pressure cuff the brachial measuring by of the finger height movement of the patient’s finger or posture. However, its its However, or posture. finger of the patient’s movement it is because use is comfortable for conscious patients calculated beeasily can correlation and the non-invasive surements similar to those of intra-arterial recordings. One recordings. those to similar of intra-arterial surements with the changes value is the measured disadvantage contractions, and increased uterine tone and increased contractions, mea waveform and gives basis on a beat-to-beat vasively selectively binds to oxytocin receptors present on the on the present receptors selectively oxytocin binds to rhythmic in resulting of the uterus, smooth musculature frequencyof existing increased of the uterus, contractions istered intravenously as a single dose immediately follow dose immediately single a as intravenously istered uterine section, delivery prevent to vaginal cesarean or ing it oxytocin, to Similar hemorrhage. postpartum and atony Anesth Pain Med Vol. 15 No. 2

CONFLICTS OF INTEREST ing oxytocin administration: a life threatening complication. J Indian Med Assoc 2006; 104: 261-2. No potential conflict of interest relevant to this article 8. Thomas JS, Koh SH, Cooper GM. Haemodynamic effects of was reported. oxytocin given as i.v. bolus or infusion on women undergoing Caesarean section. Br J Anaesth 2007; 98: 116-9. AUTHOR CONTRIBUTIONS 9. Moertl MG, Friedrich S, Kraschl J, Wadsack C, Lang U, Schlem- bach D. Haemodynamic effects of carbetocin and oxytocin giv- Conceptualization: Kyung Ok Kim. Data acquisition: Ki- en as intravenous bolus on women undergoing caesarean delivery: a randomised trial. BJOG 2011; 118: 1349-56. hyug Kwon, Kyung Ok Kim. Formal analysis: Dohyung Kim, 10. van der Nelson HA, Draycott T, Siassakos D, Yau CWH, Hats- Hyunmin Jo, Ji Eun Park. Supervision: Kyung Ok Kim. Writ- well AJ. Carbetocin versus oxytocin for prevention of post-par- ing—original draft: Dohyung Kim, Hyunmin Jo. Writing— tum haemorrhage at caesarean section in the United Kingdom: review & editing: Kihyug Kwon, Ji Eun Park. an economic impact analysis. Eur J Obstet Gynecol Reprod Biol 2017; 210: 286-91. ORCID 11. Sweeney G, Holbrook AM, Levine M, Yip M, Alfredsson K, Cap- pi S, et al. Pharmacokinetics of carbetocin, a long-acting oxyto- Kihyug Kwon, https://orcid.org/0000-0001-7766-7178 cin analogue, in nonpregnant women. Curr Ther Res Clin Exp Dohyung Kim, https://orcid.org/0000-0001-8245-8995 1990; 47: 528-40. Hyunmin Jo, https://orcid.org/0000-0002-0957-8488 12. Schutte AE, Huisman HW, van Rooyen JM, Malan NT, Schutte Ji Eun Park, https://orcid.org/0000-0002-2466-7040 R. Validation of the Finometer device for measurement of Kyung Ok Kim, https://orcid.org/0000-0001-7509-3668 blood pressure in black women. J Hum Hypertens 2004; 18: 79- 84. REFERENCES 13. Jin B, Du Y, Zhang F, Zhang K, Wang L, Cui L. Carbetocin for the prevention of postpartum hemorrhage: a systematic review 1. Say L, Chou D, Gemmill A, Tunçalp Ö, Moller AB, Daniels J, et and meta-analysis of randomized controlled trials. J Matern al. Global causes of maternal death: a WHO systematic analysis. Fetal Neonatal Med 2016; 29: 400-7. Lancet Glob Health 2014; 2: e323-33. 14. Kim TS, Bae JS, Park JM, Kang SK. Hemodynamic effects of 2. World Health Organization. WHO recommendations for the continuous intravenous injection and bolus plus continuous prevention and treatment of postpartum haemorrhage. Gene- intravenous injection of oxytocin in Cesarean section. Korean J va: World Health Organization. 2012, p. 41. Anesthesiol 2011; 61: 482-7. 3. Knight M, Callaghan WM, Berg C, Alexander S, Bouvier-Colle 15. Dell-Kuster S, Hoesli I, Lapaire O, Seeberger E, Steiner LA, Bu- MH, Ford JB, et al. Trends in postpartum hemorrhage in high cher HC, et al. Efficacy and safety of carbetocin given as an in- resource countries: a review and recommendations from the travenous bolus compared with short infusion for Caesarean International Postpartum Hemorrhage Collaborative Group. section - double-blind, double-dummy, randomized con- BMC Pregnancy Childbirth 2009; 9: 55. trolled non-inferiority trial. Br J Anaesth 2017; 118: 772-80. 4. Meshykhi LS, Nel MR, Lucas DN. The role of carbetocin in the 16. Mercier FJ, Augè M, Hoffmann C, Fischer C, Le Gouez A. Ma- prevention and management of postpartum haemorrhage. Int J ternal hypotension during spinal anesthesia for caesarean de- Obstet Anesth 2016; 28: 61-9. livery. Minerva Anestesiol 2013; 79: 62-73. 5. Petersson M. Cardiovascular effects of oxytocin. Prog Brain Res 17. Lopez-Picado A, Albinarrate A, Barrachina B. Determination of 2002; 139: 281-8. perioperative blood loss: accuracy or approximation? Anesth 6. Shahin J, Guharoy SR. Pulmonary edema possibly developing Analg 2017; 125: 280-6. secondary to the intravenous administration of oxytocin. Vet 18. Doctorvaladan SV, Jelks AT, Hsieh EW, Thurer RL, Zakowski MI, Hum Toxicol 1991; 33: 587-8. Lagrew DC. Accuracy of blood loss measurement during Ce- 7. Ghai B, Vayjnath AM, Lal S. Acute pulmonary oedema follow- sarean delivery. AJP Rep 2017; 7: e93-100.

172 www.anesth-pain-med.org KSPA

------TM ]. 1 versus versus [ TM (Ambu, Denmark), a a Denmark), (Ambu, -Classic ® TM Clinical Research Clinical O, respectively (P = 0.130). The OLP was significant OLP was The (P = 0.130). respectively O, 2 Another device, Ambu AuraGain Ambu Another device,

dren. According to a recent meta-analysis, the i-gel has a a the i-gel has meta-analysis, a recent to According dren. risk (OLP) of and a low pressure leak oropharyngeal high with LMA compared blood staining, pected difficult airways. Among various SADs, the i-gel SADs, various Among pected airways. difficult a soft non-inflatable has UK) which Ltd., (Inter-surgical been widely port, has access and a gastric cuff used in chil 8.0 cmH ± 173 - - - - eISSN 2383-7977 • OLP is comparable between AuraGain and i-gel. The AuraGain would be be would AuraGain The i-gel. and AuraGain between OLP is comparable Ambu AuraGain and i-gel have different characteristics in design each other. other. each in design characteristics different have i-gel and AuraGain Ambu 7.7 and 25.0 and 7.7 in anesthetized children: a prospective, children: a prospective, in anesthetized Airway management; General anesthesia; Laryngeal masks; Pediatrics. masks; Laryngeal anesthesia; General management; Airway Children aged between 1 month and 7 years undergoing elective surgery were were surgery elective years 7 undergoing and month 1 between aged Children ± Data of 93 patients were analyzed. The initial OLPs of the AuraGain and i-gel i-gel and AuraGain the OLPs of initial The analyzed. were 93 patients of Data TM were 27.5 27.5 were Au the of success initial The rates min post-insertion groups. in both 10 increased ly gastric the via placement catheter Suction comparable. insertion were i-gel and raGain Au with the better was view bronchoscopic fiberoptic and (P = 0.018) port easier was post-insertion (P = 0.038). manipulations additional required i-gel The (P < 0.001). raGain and i-gel the for 10.8% was period emergence the during complications of incidence The (P = 0.1). AuraGain the 2.2% for Conclusions: con anesthesia general under patients use in pediatric for i-gel the than favorable more outcomes. other sidering Keywords: Background: in children ventilation for benefits more has device which reports evaluate few However, trial controlled randomized prospective, This anesthesia. general paralyzed undergoing children. in anesthetized i-gel and AuraGain performance clinical the compared Methods: oro initial was outcome primary The groups. i-gel and AuraGain the assigned to randomly post-insertion, min 10 OLP at were outcomes (OLP). Secondary pressure leak pharyngeal suc gastric ease of and attempts of insertion success number total and rates, first-attempt score, view bronchoscopic fiberoptic pressure, peak inspiratory placement, catheter tion complications. post-insertion, and manipulation additional of requirement quality, ventilation Results: Clinical performance of Ambu AuraGain of Ambu performance Clinical i-gel controlled trial randomized Jang, Eun-Hee Kim, Nam, Young-Eun Ji-Hyun Lee, Seungpyo Kim Jin-Tae Hee-Soo Kim, and Hospital, Medicine, Seoul National University and Pain Department of Anesthesiology College of Medicine, Seoul, Korea Seoul National University Anesth Pain Med 2020;15:173-180 Med Pain Anesth https://doi.org/10.17085/apm.2020.15.2.173 pISSN 1975-5171 INTRODUCTION September 5, 2019 5, 2019 September : October 29, 2019 29, 2019 : October October 28, 2019 28, 2019 October Appropriate airway management is critical in the pediat airway management Appropriate 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 permits which (http://creativecommons.org/licenses/by-nc/4.0) License Non-Commercial Attribution Commons Creative the of terms the under Access article is an Open This distributed cited. is properly work original the provided in any medium, reproduction and distribution, use, non-commercial unrestricted 2020 Anesthesiologists, Society of Korean © the Copyright airway devices (SADs) have been used to secure and main and been used secure to airwayhave devices (SADs) during surgerytain airways in patients or emergency situa of expected and unex as well as in the management tions, ric population with a lower oxygen reserve. Supraglottic Supraglottic withric reserve. oxygen a lower population Ji-Hyun Lee and Seungpyo Nam Nam Seungpyo and Lee Ji-Hyun this study. to equally contributed Tel: 82-2-2072-3592 Tel: 82-2-747-8364 Fax: [email protected] E-mail: University College of Medicine, 101 101 Medicine, of College University 03080, Seoul Jongno-gu, Daehak-ro, Korea Department of Anesthesiology and and Anesthesiology of Department National Seoul Medicine, Pain National Seoul Hospital, University Corresponding author author Corresponding M.D., Ph.D. Kim, Jin-Tae Received Received Revised Accepted Anesth Pain Med Vol. 15 No. 2 recently released second-generation SAD, has an inflatable ficient fasting times, difficult airways, or body mass indices cuff and a gastric port. One of the key features of the Au- > 30 kg/m2 were excluded from this study. In addition, raGain is the 90-degree angulated shaft, following the anat- children who were scheduled for emergency surgery, ab- omy of the upper airway, which facilitates proper insertion dominal or thoracic surgeries and all laparoscopic proce- and is associated with a high success rate for insertion [2,3]. dures were also excluded. Although use of the AuraGain has increased, research regarding its clinical performance is limited, especially Group allocation among children [4,5]. There has been some reports comparing use of the Au- Patients were randomly assigned to one of two groups, raGain and i-gel in pediatric patients, which concluded that the i-gel group or the AuraGain group, using a stratified the i-gel may be superior to the AuraGain in terms of OLP randomization procedure (computerized random number; [5,6]. However, the incidence of additional manipulation or http://www.randomizer.org). The allocation ratio was 1 : 1, device failure which was defined as the abandonment of the and an anesthetic nurse who was not associated with the SAD and replacement with a tracheal tube or another device study performed the random allocation by preparing cod- was higher for the i-gel than for other SADs, which should be ed and sealed opaque envelopes for allocation conceal- evaluated further in pediatric populations [1,6]. In addition, ment. The patients were blinded to group allocation. The there is limited evidence in paralyzed children. Therefore, in bedside anesthesiologists, however, were not blinded. this study, we hypothesized that the clinical performance of the AuraGain would be comparable to that of the i-gel in the Anesthesia and study protocol pediatric populations. The objective of this prospective, randomized trial was to Before induction of anesthesia, all pediatric patients compare the clinical performance of the AuraGain and were sedated with intravenous thiopental sodium (5 mg/ i-gel in terms of OLP, successful insertion, ventialtion qual- kg) or propofol (2 mg/kg) and were taken to the operating ity, ease of suction catheter placement, additional manipu- room. After electrocardiographic monitoring, pulse oxygen lation after insertion, and complications in children under saturation and non-invasive blood pressure measurement general anesthesia. were initiated, and anesthesia was induced with sevoflurane 4–6 vol% in 100% oxygen. Following muscle relaxation MATERIALS AND METHODS with rocuronium (0.6 mg/kg) and mask ventilation for 90 s, the i-gel or deflated AuraGain which were lubricated with Ethics and study population 2% lidocaine jelly was gently inserted into the oropharynx by a single experienced anesthesiologist (L.J.H), according This prospective randomized, controlled, parallel-de- to group allocation. The sizes of the AuraGain and i-gel signed trial was approved by the Institutional Review Board were selected based on body weight, as suggested by the (no. H1704-083-846) and registered at http://clinicaltrials. manufacturer as follows: size 1.5 (for 5–12 kg), 2 (10–25 kg), gov (no. NCT03118245). The study was performed in accor- and 2.5 (25–35 kg) for the i-gel; size 1.5 (5–10 kg), 2 (10–20 dance with the ethical standards set forth in the 1964 Decla- kg), and 2.5 (20–30 kg) for the AuraGain. ration of Helsinki and its later amendments. One day before After insertion, the cuff of the AuraGain was inflated to an ® surgery, an anesthesiologist met with each child’s parents, intracuff pressure of 40 cmH2O using a Portex cuff inflator explained the study protocol, and obtained written informed (Smiths Medical, USA). Mechanical ventilation was started, consent from them. and adequate ventilation was confirmed by square-wave Children aged between 1 month and 7 years who were capnography and bilateral chest excursion. When adequate scheduled for simple superficial or peripheral limb surgery ventilation was not achieved, the SAD was removed and re- within 2 h, under general anesthesia, were enrolled in this inserted. Up to three insertion attempts were allowed. Tra- study. Children with American society of anesthesiologist cheal intubation was planned in cases of three failed inser- physical status over than II, recent upper respiratory tract tion attempts, and such patients were subsequently exclud- infection, any respiratory disease, a history of cervical dis- ed from the study. During insertion of the SAD, the patient’s order or surgery, risk factors for aspiration including insuf- head and neck were left in the neutral position with the

174 www.anesth-pain-med.org KSPA ------175 ]. The ]. The 3 cm ± 12 -test or the or the -test t standard devia standard ± O with the i-gel and 19 2 RESULTS RESULTS 5 cmH ± < laryngospasm, 90%), bronchospasm, 2 O with the AuraOnce. Thus, the sample size required for for required size the sample Thus, O with the AuraOnce. From April 2017 to January 2018, 98 pediatric patients 2018, 98 pediatric patients January 2017 to April From All data were analyzed using SPSS for Windows (ver. 23.0; (ver. SPSS for Windows using analyzed were All data The primary the OLPThe mea was of this study outcome deter was study of the present size sample required The 2 were screened and 4 patients who did not meet the inclu and 4 patients screened were pediatric patients Ninety-four criteriasion excluded. were two to allocated and randomly in the study enrolled were group the AuraGain from one patient them, Among groups. data. respiratory obtain to failure of because excluded was and group (46 in the AuraGain 93 children from data Thus, mean OLP 22 mean was H 41 determined was be to approximately study the present of 0.05 and a power error with an alpha per group, patients 8.0.16; NCSS statistical (ver. 2008 software PASS of 0.9, using consid required, were USA). of 98 patients A total software, 20%. of about ering rate an attrition assessed distribution was of data USA). Normality Co., IBM variables Categorical test. the Kolmogorov–Smirnov using and continu and percentages, as numbers expressed were as means expressed were variables ous chi- The ranges. interquartile and medians or (SDs) tions significance, data categorical usedtest was to test square used expected the when count was test exact Fisher’s and of > Student’s five. than less 20% cells was used was test determine to the rank-sum Mann–Whitney of value P A data. continuous of significance < was 0.05 significant. statistically considered emergence period were recorded. These included These desatu recorded. periodemergence were (SpO ration and bleeding or blood on the stain aspiration coughing, SAD. analysis Outcomes and statistical insertion. after secondary immediately The sured out suc OLP insertion, 10 min after comes were first-attempt for insertion, at of number rate success and total rate cess peak in placement, catheter and ease of suction at tempts view score, bronchoscopic fiberoptic pressure, spiratory manipula additional of requirement quality, ventilation insertion,tion after and complications. compared which study, pediatric minedbased previous a on and the i-gel [ the performance of the AuraOnce ------]. While in 9 , 8 O, oropharyn O, [ 2 Ambu AuraGain vs. i-gel for pediatric anesthesia pediatric for vs. i-gel AuraGain Ambu at 40%, was used was 40%, to at 2 ]: 1) the view was com ]: 1) the view was ]. Mechanical ventilation ventilation ]. Mechanical 10 [ 7 [ ] as follows: 1) clear, 2) mini ] as follows: 1) clear, 11 [ of 35–40 mmHg. Sevoflurane in an air-oxy in an Sevoflurane of 35–40 mmHg. 2 CO T The occurrence of complications during surgery of complications and the occurrence The Ventilation quality was assessed by auscultating the lung the lung auscultating assessed quality was by Ventilation Next, a lubricated suction catheter was inserted through inserted was through catheter suction a lubricated Next, After determination of the OLP, fiberoptic views were ob views were fiberoptic of the OLP, determination After Immediately after insertion, OLP was determined by insertion, after Immediately determined OLP was by www.anesth-pain-med.org ing, or head and neck re-positioning. The additional ma additional The re-positioning. and neck or head ing, recorded. was required nipulation obstruction. If ventilation was inadequate, additional ma additional inadequate, was obstruction.If ventilation performed, were push included which nipulations gentle thrust jaw of the chin, lifting of the device, or pulling ing bilateral chest excursion excursion chest bilateral complete 4) and partial obstruction, 3) obstruction, mal catheter is unable to pass. pass. to is unable catheter and capnography of waveform the evaluating and sound 1) easy – suction catheter enters without resistance at once, once, at without resistance enters catheter – suction 1) easy and re-insertion withdrawal catheter – suction 2) difficult and 3) suction resistance, due to once than tried more are follows: size i-gel;for the Fr of 8 2.5 and 2 1.5, size for Fr 10 ease of The 2 and 2.5 of the AuraGain. 1.5, and 10 Fr for size assessed was as follows: catheter of the suction placement size of suction catheter was selected according to allowable allowable to selected was according catheter of suction size as the manufacturer by as suggested size, catheter maximal one-third of the diameter of the view. of the diameter one-third The port decompression. for gastric SAD each the drainage two-thirds of the diameter of the view, 3) the anterior epi of the view, 3) the anterior of the diameter two-thirds of of the diameter two-thirds to one-third covered glottis than less covered epiglottis the view, and 4) the anterior pletely covered by the anterior epiglottis, but SAD function function SAD but epiglottis, the anterior by covered pletely than more covered epiglottis 2) the anterior adequate, was a fiberoptic bronchoscope (Olympus LF-DP, Olympus Cor (Olympus LF-DP, bronchoscope a fiberoptic us scored view was The the SAD. through Japan) poration, as follows score the Okuda ing OLP was re-assessed 10 min after insertion. 10 min after OLP re-assessed was of placement by (L.J.H) anesthesiologist a single tained by creasing the airway pressure up to 40 cmH up to the airway pressure creasing the the stethoscope over placing assessedgeal was leak by cartilage. the thyroid to lateral immediately neck, patient’s closing the adjustable pressure limiting valve of the breath valve limiting pressure the adjustable closing of 3 L/min flow gas witha fresh circuit, ing gen mixture, with fractional inspired O inspired with fractional gen mixture, index of 40–60. Bispectral a targeted at anesthesia maintain was started in the volume-controlled mode, with a tidal withtidal a mode, started volume-controlled the in was to adjusted was rate and the respiratory of 8 ml/kg, volume E maintain face straight up and the Frankfort plane angled at approxi at angled plane Frankfort up and the face straight bed, the of plane as horizontal the to degrees 70–80 mately et al. described Kobayashi by Anesth Pain Med Vol. 15 No. 2

Enrollment Assessed for eligibility (n = 98) Excluded (n = 4) · Not meeting inclusion criteria (n = 4) · Declined to participate (n = 0) · Other reasons (n = 0) Randomized (n = 94)

Allocation

Allocated to AuraGain group (n = 47) Allocated to i-gel group (n = 47) · Received allocated intervention (n = 47) · Received allocated intervention (n = 47) · Did not receive allocated intervention (n = 0) · Did not receive allocated intervention (n = 0)

Follow-up

Discontinued intervention (failure to data Lost to follow-up (n = 0) acquistion) (n = 1) Discontinued intervention (n = 0)

Analysis

Analysed (n = 46) Analysed (n = 47) · Exculded from analysis (n = 0) · Exculded from analysis (n = 0)

Fig. 1. Consolidated standards of reporting trials (CONSORT) diagram.

Table 1. Baseline Characteristics of Patients Undergoing Anaes- 47 in the i-gel group) were analyzed (Fig. 1, CONSORT dia- thesia with the AuraGain and the i-gel gram). Table 1 shows the baseline characteristics in both Variable AuraGain (n = 46) i-gel (n = 47) groups; there was no significant difference in demographics Age (mo) 36 ± 26 36 ±26 and type of surgery between the two groups. Sex (M/F) 32/14 31/16 There was no significant difference in initial OLP be- Weight (kg) 15.7 ± 7.0 16.1 ± 7.6 tween the AuraGain (27.5 ± 7.7 cmH O) and i-gel group Height (cm) 94.5 ± 21.0 94.9 ± 20.7 2 ± Procedure time (min) (25.0 8.0 cmH2O; mean difference [95% confidence inter- Anaesthesia time 64.2 ± 44.1 72.4 ± 42.6 val, 95% CI], 2.5 [–0.7 to 5.8] cmH2O; P = 0.130). In addi- Operation time 33.3 ± 23.9 45.4 ± 36.4 tion, post-10-min OLP did not differ statistically, between SAD size 1.5/2.0/2.5 15/16/15 16/19/12 the AuraGain (30.2 ± 7.1 cmH2O) and i-gel group (28.1 ± Type of surgery 7.9 cmH O; mean difference [95% CI], 2.2 [–1.0 to 5.4] cm- Orthopedic surgery 4 (8.7) 10 (21.3) 2 H O; P = 0.182). The OLP was significantly increased by 10 Plastic surgery 9 (19.6) 11 (23.4) 2 Urologic surgery 25 (54.3) 22 (46.8) min after insertion in both the AuraGain group (mean dif- Other superficial surgery 8 (17.4) 4 (8.5) ferences [95% CI], 2.4 [0.5 to 4.3]; P = 0.016) and the i-gel Values are presented as mean ± SD or number (percentage). SAD: group (mean differences [95% CI], 3.4 [2.0 to 4.8]; P < supraglottic airway device. 0.001) (Table 2). We did not experience insertion failure in either group. Both the AuraGain and i-gel were inserted successfully within two attempts in all participants. The initial success

176 www.anesth-pain-med.org KSPA ------177 0.5 0.974 0.038 0.1 0.071 0.130 0.182 0.018 0.039 P value P value < 0.001 Ventilation quality: 1 = clear, 2 = 1 = clear, quality: Ventilation † Complications: desaturation (< 90%), desaturation Complications: § Additional manipulation included gentle gentle included manipulation Additional 7.9 ‡ 8.0 ± ± DISCUSSION 47/0 38/6 4 (8.5) 5 (10.8) 35/8/1 6/32/7/2 45/1/1/0 28.1 28.1 25.0 i-gel (n=i-gel 47) i-gel (n i-gel = 47) 14.0 (12.0, 15.0) 14.0 The incidence of complications during the emergence pe during the emergence incidence of complications The performance the clinical of we evaluated this study, In dures. and i-gel, the efficacy of the AuraGain compare To af and 10 min device initial placement at OLP measured was in the differences no significant were There placement. ter ad In OLP between the two groups. or the post-10-min initial between two SADs. comparable quality was dition, ventilation i-gelthe af manipulation additional more required However, bronchoscopic fiberoptic a poorer insertion,ter provided riod with higher i-gel was with but with than the AuraGain, difference 10.8%; mean (2.2% vs. significance statistical out 20.5]%; P [95% CI], 8.4 [–2.6 to = in the Complications 0.1). i-gel breath-hold included laryngospasm, coughing, group (< and desaturation ing, none of these cases However, 90%). as tra such procedures management additional required One a blood on the Au stain had child intubation. cheal removal. after raGain aged between 1 month and i-gel in children the AuraGain proce surgical simple undergoing who were and 7 years, 7.1 7.7 ± ± 0 ------43/3 45/1 1 (2.2) 44/1/1 ). 44/0/2/0 27.5 27.5 30.2 0/9/26/11 13.0 (12.0, 16.0) (12.0, 13.0 AuraGain (n=AuraGain 46) AuraGain (n AuraGain = 46) Table 3 Table ‡ Ambu AuraGain vs. i-gel for pediatric anesthesia pediatric for vs. i-gel AuraGain Ambu O) 2 O) 2 Variable Variable (1/2/3/4) † ). § Table 2 Table Comparative Data for the AuraGain and the i-gel during Anesthesia during i-gel the and AuraGain the for Data Comparative Comparative Data for the AuraGain and the i-gel Immediately after Insertion after Immediately i-gel the and AuraGain the for Data Comparative ( After 10 min 10 After Although ventilation quality did not differ significantly be significantly differ qualitynot did ventilation Although Complications Peak inspiratory pressure (cmH pressure inspiratory Peak (1/2/3/4) grading* Fiberoptic quality Ventilation operation during required manipulation Additional No. of attempts of suction catheter placement placement catheter suction of attempts of No. (1st/2nd) (1/2/3)* placement catheter suction Ease of Initial (1st/2nd) placement device for attempts of No. Oropharyngeal leak pressure (cmH pressure leak Oropharyngeal www.anesth-pain-med.org raGain group did not require additional external manipula external additional did not require group raGain 0%; mean (8.5% vs. ventilation adequate maintain tions to 20.0]%, P [95% CI], 8.5 [–0.7 to difference = 0.038) ( tion, including optimization of head position and change in position of head and change optimization tion, including de volume as the tidal the insertion depth of the SAD, the Au contrast, airway due to In leak. significantly creased owing to the epiglottis. In addition, four of the i-gel partici addition, four In the epiglottis. to owing manipula intraoperative additional (8.5%) required pants through the fiberoptic bronchoscope was better with the with better the was bronchoscope the fiberoptic through with (P i-gel the than AuraGain < in patients six In 0.001). not be seen the laryngeal could structures the i-gel group, group group view the glottis and i-gel groups, tween the AuraGain catheter was not passed in one patient from each group. group. each from not passed was in one patient catheter insertion with catheter suction difficult patients of Number i-gel the in eight while group AuraGain the one in was eter insertion was attempted in all patients of the AuraGain of the AuraGain in all patients insertioneter attempted was suction The of i-gel group. 47 patients and 44 of group rates of AuraGain and i-gel 93.5% and 100% insertion were of AuraGain rates 17.5]%, P to [95% CI], 6.5 [–2.2 difference (mean = 0.071), insertion, SAD cath each After suction gastric respectively. bronchospasm, laryngospasm, coughing, aspiration. coughing, laryngospasm, bronchospasm, more than two-thirds of the diameter of the view, 3 = anterior epiglottis covering more than one-third, but less than two-thirds of the the of less two-thirds but than one-third, than more covering epiglottis anterior = 3 view, the of diameter the of two-thirds than more view. the of diameter the of less one-third than covering epiglottis 4 = anterior and view, the of diameter obstruction. 4 = complete obstruction, complete 3 = intermittent partial obstruction, intermittent re-positioning. neck and head or thrusting, jaw chin, the of lifting device, the of pulling or pushing Values are presented as median (1Q, 3Q) or number (percentage). *Fiberoptic grading: 1 = the view through the aperture bars is bars aperture is the through view 1 = the grading: *Fiberoptic (percentage). number (1Q, 3Q) or median as presented are Values covering epiglottis 2 = anterior is adequate, function (SAD) device airway supraglottic the but epiglottis, anterior by the covered completely Table 3. Table (suction catheter enters without resistance at once), 2 = difficult (suction catheter withdrawal and re-insertion are tried more than once due due once than more tried are re-insertion and withdrawal catheter (suction = difficult 2 once), at resistance without enters catheter (suction pass. to 3 = unable resistance), to Values are presented as mean ± SD or number. *Ease of suction catheter placement, as graded by the following subjective scale: 1 = easy 1 = easy scale: subjective following by the as graded placement, catheter suction *Ease of number. or ± SD as mean presented are Values Table 2. Table Anesth Pain Med Vol. 15 No. 2 view, and was associated with more difficulty in placing the tempts was 100% for both the AuraGain and i-gel. The first-at- suction catheter in children. tempt success rates for AuraGain and i-gel insertion were The results of the present study regarding OLP differ 93.5% and 100%, respectively. This finding was in concor- from that of recent, previous studies [5,6]. According Miha- dance with previous findings [4,20,21]. In this study, four para et al.[5] and Kim et al.[6], the OLP of i-gel was about 23 tients in the i-gel group (8.3%) required additional manipula- cmH2O immediately after insertion, which was similar to tions during surgery, because the tidal volume could not be our results, and it was significantly higher than the OLP of adequately achieved, whereas no patients in the AuraGain the AuraGain, which was 17–18 cmH2O [5]. However, in our group required additional manipulations. For two patients, trial, the OLP of the AuraGain group immediately after in- the i-gel had to be inserted deeper and fixed with additional sertion was 27.5 cmH2O. In addition, our previous study tape, as it was dislodged from its initial position. Another evaluating the performance of AuraGain at different head two patients required head and neck extension to achieve and neck position, the OLP in the neutral position was 26 an adequate tidal volume. Previously published studies in- cmH2O [13]. dicated that the i-gel tends to slide out and requires addi- There are some possible explanations for the differing re- tional manipulations [12,22,23]. Accoriding to Kim et al. sults between our trial and the previous study. First, the in- [23], approximately 33% of pediatric patients required ad- tracuff pressure of the AuraGain in our trial was 40 cmH2O, ditional manipulations which was mainly further insertion whereas it was 30 cmH2O in the Mihara et al.’s study [5]. On of the i-gel. Hughes et al. [22] reported that the elastic char- the other hand, there was no information about an intracuff acteristics of the i-gel may contribute to its instability upon pressure for AuraGain in Kim et al.’s study [6]. The informa- insertion and cause it to slip out. We speculate that this prob- tion about intracuff pressure is important to compare the lem occurs more commonly in children than in adults, be- OLP, because adequate cuff pressure was associated with cause of the unique anatomical features of children. The pe- higher OLP [14]. Second, we used a neuromuscular blocker diatric i-gel is a smaller version of the adult model, but the that could relax the pharyngeal muscle and improve the air- child’s upper airway anatomy is not a mere miniature version way seal by the AuraGain. In Mihara et al.’s study [5], more of an adult’s anatomy. The key differentiating features of a than half of the children maintained spontaneous ventila- child’s upper airway are a larger tongue in proportion to the tion or were ventilated by pressure support ventilation. In mouth, a smaller pharynx, a larger and more flaccid epiglottis, addition, no neuromuscular blockade was used in Kim et an anterior and superior positioned larynx, and a conical al.’s study [6]. The effect of neuromuscular blockade on OLP shaped larynx [24]. Even though the manufacturer claims that is different among the SADs [15,16]. However, the evidence the i-gel is anatomically designed to seal the larynx, pediatric is limited regarding OLP with AuraGain and i-gel in para- anatomical features may not have been taken into account in lyzed children. We speculated that the AuraGain could pro- its conception. Unlike the i-gel, the AuraGain has a provide adequate airway sealing pressure in paralyzed children nounced angulation, a feature that makes it less prone to slid- under positive pressure ventilation. ing out and stabilizes its position upon insertion [2,12]. Interestingly, the OLP of both devices improved during The initial success rate for gastric suction catheter inser- the early anesthesia period. This suggests that both devices tion was significantly lower in the i-gel group than in the have the ability to sustain a stable laryngeal seal during the AuraGain group. The suction catheter placement in the initial phase of anesthetic maintenance. There are reports i-gel was significantly more difficult than in the AuraGain, that there might be a chronological improvement in the subjectively. This may be due to the relative instability of OLP [17]. However, the reason for the increase in OLP is the i-gel in the hypopharyngeal space. The i-gel’s tendency unclear. There has been some speculation about this phe- to rotate and slip out from the mouth may displace the gas- nomenon; it has been suggested that this might be due to tric channel inlet away from the opening of the esophagus the thermoplastic properties of the gel cuff [18], or that and make it difficult for the gastric suction catheter to pass some degree of molding of the device in the posterior through. pharynx improves the airway seal [19]. In addition, saliva The fiberoptic bronchoscopic view score for the Au- may improve the sealing due to the adhesive properties of raGain was markedly better than that for the i-gel. It liquids. demonstrated a complete or partial view of the vocal cord The overall insertion success rate within the first two at- in 87.2% of the i-gel group and 100% of the AuraGain

178 www.anesth-pain-med.org KSPA ------179 . A net oved insertion insertion oved . . . supreme in infants and children. An and children. in infants supreme ORCID ® REFERENCES CONFLICTS OF INTEREST OF INTEREST CONFLICTS and the LMA

AUTHOR CONTRIBUTIONS TM Mihara T, Asakura A, Owada G, Yokoi A,K, Ka Goto T A, Yokoi Asakura Owada G, T, Mihara Hagberg CA, Jensen FS, Genzwuerker HV, Krivosic-Horber R, R, Krivosic-Horber HV, CA, Genzwuerker FS, Hagberg Jensen Schmitz BU, Hinkelbein J, et al. A multicenter study of the of the study et al. A multicenter J, Hinkelbein Schmitz BU, patients. anesthetized laryngeal in nonparalyzed, Ambu mask 2005; 101: 1862-6 Analg Anesth Au ER, comparison et al. A randomised of the Ambu® hardt raGain 2016; 71: 205-12 aesthesia work meta-analysis of the clinical properties of various types of various of properties of the clinical meta-analysis work 2017; 72: Anaesthesia airway device in children. supraglottic 1251-64. for impr laryngeal be responsible could mask 2006; 103: 264 Analg Anesth success. Vaida SJ, Yodfat UA. Angulation of the airway tube in the AMBU of the airway in the AMBU tube Angulation UA. Yodfat SJ, Vaida Jagannathan N, Hajduk J, Sohn L, Huang A, Sawardekar A, A, Sohn L, Geb Sawardekar Huang J, Hajduk N, Jagannathan . . . No potential conflict of interest relevant to this article this article to relevant of interest conflict potential No Ji- acquisition: Data Kim. Jin-Tae Conceptualization: 4 1. 2. 3 Lee, Seungpyo Nam. Writing—review & editing: Jin-Tae Jin-Tae editing: & Writing—review Nam. Seungpyo Lee, Kim. https://orcid.org/0000-0002-8384-8191 Lee, Ji-Hyun https://orcid.org/0000-0002-8700-0593 Nam, Seungpyo https://orcid.org/0000-0002-7511-4104 Jang, Young-Eun https://orcid.org/0000-0003-0697-1935 Kim, Eun-Hee https://orcid.org/0000-0002-2661-7944 Kim, Hee-Soo https://orcid.org/0000-0002-3738-0081 Kim, Jin-Tae thesia. However, the i-gel required additional manipulation manipulation additional the i-gel required However, thesia. with be insertion, associated after in a higher might which view the fiberoptic addition, In complication. cidence of the through placement and ease catheter of suction score the Therefore, with AuraGain. better the portgastric were the i-gel for use in pediat than favorable is more AuraGain anesthesia. under general ric patients reported. was Jang, analysis: Data Young-Eun Nam. Seungpyo Lee, Hyun Eun-Hee Writing: Ji-Hyun Kim. Supervision: Hee-Soo Kim. ------]. Addi 12 ]. Second, ]. Second, [ 28 , ]. Although it it ]. Although ]. Ventilation Ventilation ]. 12 27 22 [ [ – Ambu AuraGain vs. i-gel for pediatric anesthesia pediatric for vs. i-gel AuraGain Ambu 25 [ ]. This observation]. This be ex can 6 In summary, both the AuraGain and i-gel provided com and i-gel provided summary,In both the AuraGain Several limitations of this study should be mentioned. be mentioned. should of this study limitations Several In this study, adverse events were rare in both groups. A in both groups. rare were events adverse this study, In www.anesth-pain-med.org parable oropharyngeal sealing and ventilation quality in in quality ventilation and sealing oropharyngeal parable during anes blockers neuromuscular receiving children tion conduit than the i-gel, because of the better fiberoptic fiberoptic of the better the i-gel, because tion conduit than this validate to required further are but studies view score, theory. Finally, we did not perform intubation through the SADs. the SADs. we through did not perform intubation Finally, be intuba a better may the AuraGain that speculated We which might be a limitation in generalizing our results to to results our in generalizing be a limitation might which new provide can it However, children. anaesthetized all in this specific population. of SADs for the evaluation data those measuring the outcomes were not blinded to group not blinded group to were those the outcomes measuring the blind them to to impossible it was because allocation in all children, we used relaxant a muscle used.SAD Third, that evaluated a different SAD, the AuraOnce, which has a has which the AuraOnce, SAD, a different evaluated that in the with the AuraGain OLP lower compared significantly studies and other recent study present First, the sample size was calculated from a previous study study a previous from calculated was size the sample First, have irritated the upper airway and caused complications irritated the upper airway complications and caused have required are studies during period. the emergence Further this relationship. validate to was not statistically significant, the complication rate was was rate the complication significant, not statistically was the that speculate We i-gel in the group. higher relatively may in the i-gel group required manipulation additional group. This is a much lower complication rate than that re that than rate complication lower is a much This group. (11–42%) studies ported in previous complication occurred in one patient (2.2%) from the Au (2.2%) from in one patient occurred complication i-gel the from (10.8%) patients four in and group raGain conduit during difficult airway management, the poor the fi airway duringconduit difficult management, fa it a less make the i-gel may by view provided beroptic the AuraGain. to compared choice vorable with the i-gel, particularly in children withchildren in i-gel,the particularly and i-gel between the same the AuraGain quality remained intubation an as SADs terms in using of However, groups. observer the hypopharynx view to structures common bemore may downfolding epiglottic tionally, proach closer, at a more acute angle, to the vocal cord. In In cord. the vocal to angle, acute a more at closer, proach with respect rotated frequently more the i-gel was contrast, for the it difficult makes which the pharyngealto structure, plained by the 90-degree tube angle of the AuraGain, of the AuraGain, angle tube 90-degree the plained by of the view improving base, the tongue lift up may which ap to the larynx bronchoscope the fiberoptic and allowing group. A recent study reported a similar result that regard that result a similar reported study A recent group. view than fiberoptic better a provided AuraGain size, of less [ i-gel in pediatric patients Anesth Pain Med Vol. 15 No. 2

5. Mihara T, Nakayama R, Ka K, Goto T. Comparison of the clinical and systematic review. J Int Med Res 2016; 44: 405-18. performance of i-gel and Ambu AuraGain in children: a ran- 16. Goldmann K, Hoch N, Wulf H. [Influence of neuromuscular domised noninferiority clinical trial. Eur J Anaesthesiol 2019; blockade on the airway leak pressure of the ProSeal laryngeal 36: 411-7. mask airway]. Anasthesiol Intensivmed Notfallmed Schmerz- 6. Kim HJ, Park HS, Kim SY, Ro YJ, Yang HS, Koh WU. A random- ther 2006 41: 228-32. German. ized controlled trial comparing Ambu AuraGain and i-gel in 17. Yoshikawa Y, Hirata N, Nawa Y, Yamakage M. Chronological young pediatric patients. J Clin Med 2019; 8: E1235. change in oropharyngeal leak pressure of pediatric i-gelTM. 7. Kobayashi M, Ayuse T, Hoshino Y, Kurata S, Moromugi S, Paediatr Anaesth 2019; 29: 107-8. Schneider H, et al. Effect of head elevation on passive upper 18. Gabbott DA, Beringer R. The iGEL supraglottic airway: a poten- airway collapsibility in normal subjects during propofol anes- tial role for resuscitation? Resuscitation 2007; 73: 161-2. thesia. Anesthesiology 2011; 115: 273-81. 19. Jagannathan N, Sohn LE, Sawardekar A, Shah R, Ryan K, Jagan- 8. Xue FS, Mao P, Liu HP, Yang QY, Li CW, He N, et al. The effects nathan R, et al. A randomised comparison of the self-pres- of head flexion on airway seal, quality of ventilation and oro- surised air-QTM intubating laryngeal airway with the LMA gastric tube placement using the ProSeal laryngeal mask air- UniqueTM in children. Anaesthesia 2012; 67: 973-9. way. Anaesthesia 2008; 63: 979-85. 20. Jagannathan N, Ramsey MA, White MC, Sohn L. An update on 9. Keller C, Brimacombe JR, Keller K, Morris R. Comparison of newer pediatric supraglottic airways with recommendations four methods for assessing airway sealing pressure with the la- for clinical use. Paediatr Anaesth 2015; 25: 334-45. ryngeal mask airway in adult patients. Br J Anaesth 1999; 82: 21. White MC, Cook TM, Stoddart PA. A critique of elective pediat- 286-7. ric supraglottic airway devices. Paediatr Anaesth 2009; 19 Sup- 10. Okuda K, Inagawa G, Miwa T, Hiroki K. Influence of head and pl 1: 55-65. neck position on cuff position and oropharyngeal sealing pres- 22. Hughes C, Place K, Berg S, Mason D. A clinical evaluation of the sure with the laryngeal mask airway in children. Br J Anaesth i-gelTM supraglottic airway device in children. Paediatr Anaesth 2001; 86: 122-4. 2012; 22: 765-71. 11. Lee YC, Yoon KS, Park SY, Choi SR, Chung CJ. A comparison of 23. Kim H, Lee S, Shin HJ, Lee JH, Choi SR, Chung CJ. A clinical i-gelTM and Laryngeal Mask Airway SupremeTM during general evaluation of i-gelTM during general anesthesia in children. anesthesia in infants. Korean J Anesthesiol 2018; 71: 37-42. Anesth Pain Med 2015; 10: 46-51. 12. Theiler LG, Kleine-Brueggeney M, Luepold B, Stucki F, Seiler S, 24. Prakash M, Johnny JC. Whats special in a child’s larynx? J Urwyler N, et al. Performance of the pediatric-sized i-gel com- Pharm Bioallied Sci 2015; 7(Suppl 1): S55-8. pared with the Ambu AuraOnce laryngeal mask in anesthetized 25. Mizushima A, Wardall GJ, Simpson DL. The laryngeal mask air- and ventilated children. Anesthesiology 2011; 115: 102-10. way in infants. Anaesthesia 1992; 47: 849-51. 13. Lee JH, Jang YE, Kim EH, Kim HS, Kim JT. Flexion decreases the 26. Bagshaw O. The size 1.5 laryngeal mask airway (LMA) in paedi- ventilation quality of the Ambu® AuraGainTM laryngeal mask in atric anaesthetic practice. Paediatr Anaesth 2002; 12: 420-3. paralysed children: a prospective randomised crossover study. 27. Uppal V, Fletcher G, Kinsella J. Comparison of the i-gel with the Acta Anaesthesiol Scand 2018; 62: 1080-5. cuffed tracheal tube during pressure-controlled ventilation. Br 14. Zhang L, Seet E, Mehta V, Subramanyam R, Ankichetty SP, J Anaesth 2009; 102: 264-8. Wong DT, et al. Oropharyngeal leak pressure with the laryngeal 28. Stögermüller B, Ofner S, Ziegler B, Keller C, Moser B, Gasteiger mask airway SupremeTM at different intracuff pressures: a ran- L. Ambu® Aura GainTM versus Ambu® Aura OnceTM in children: domized controlled trial. Can J Anaesth 2011; 58: 624-9. a randomized, crossover study assessing oropharyngeal leak 15. Shin HW, Yoo HN, Bae GE, Chang JC, Park MK, You HS, et al. pressure and fibreoptic position. Can J Anaesth 2019; 66: 57- Comparison of oropharyngeal leak pressure and clinical per- 62. formance of LMA ProSealTM and i-gel® in adults: meta-analysis

180 www.anesth-pain-med.org KSCVA ------

Case Report Surgeries for patients with polycythemia require a col with polycythemia for patients require Surgeries laboration between the operating surgeon, oncologist or or oncologist surgeon, between the operating laboration with a While patients and anesthesiologist. hematologist, period prior surgery to be can preoperative considerable the root target options to treatment for radical considered blood viscosity. The blood drawn during this procedure during this procedure blood viscosity. blood The drawn of a mas case as in the such use, for future be stored can hemodilution is per intraoperative Last, hemorrhage. sive of blood and replac a specific amount drawing formed by with proce colloid solution. last amount This the same ing response an immediate is noteworthy, as it provides dure re and rapid status physiological in a patient’s changes to during levels surgery.covery of normal hematocrit 181 181-186 - - - - - eISSN 2383-7977 • We estimate that patients with secondary polycythemia may benefit from from benefit may polycythemia with secondary patients that estimate We A high hematocrit level in patients with erythrocytosis is linked with increased increased with linked is erythrocytosis with patients in level hematocrit A high Cardiopulmonary bypass; Erythrocytosis; Hemodilution; Polycythemia; Thrombo Polycythemia; Hemodilution; bypass; Erythrocytosis; Cardiopulmonary ], there are 3 3 are ], there 2 : A 67-year-old male was scheduled for aortic valve replacement due to severe aortic severe to due replacement aortic valve for scheduled was male 67-year-old : A acute normovolemic hemodilution to reduce their hematocrit levels while undergoing cardi undergoing while levels hematocrit their reduce to hemodilution normovolemic acute hemato the it is necessary control to bypass. However, cardiopulmonary using surgery ac effects. side can cause decrease a significant since level, crit Keywords: embolism. Background: it is necessary ade to Therefore, thromboembolism. of risk viscosityblood increased and surgery. a high-risk performing before level hematocrit the lower quately Case secondary to due high very was this patient of level hematocrit preoperative The stenosis. after hemodilution normovolemic acute perform to decided We by hypoxia. polycythemia was patient The patient. in the thromboembolism of risk the reduce to induction anesthetic effects. any side without period a post-operative and a successful surgery after discharged Conclusions: Acute normovolemic hemodilution for a patient for hemodilution normovolemic Acute aortic polycythemia undergoing with secondary stenosis due to severe aortic valve replacement - - A case report Min Gi An, Cho, Soon Eun Park, Woo Ilsang Han, Young and A-ran Lee Ho June Kang, Hospital, Ulsan, Medicine, Ulsan University and Pain Department of Anesthesiology Korea Anesth Pain Med 2020;15: Med Pain Anesth https://doi.org/10.17085/apm.2020.15.2.181 pISSN 1975-5171 ]. According to Cundy [ Cundy to ]. According 1 [ July 18, 2019 2019 18, July September 18, 2019 2019 18, September August 27, 2019 2019 27, August Polycythemia, a disease state in which the hematocrit the hematocrit in which a disease state Polycythemia, 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 permits which (http://creativecommons.org/licenses/by-nc/4.0) License Non-Commercial Attribution Commons Creative the of terms the under Access article is an Open This distributed cited. is properly work original the provided in any medium, reproduction and distribution, use, non-commercial unrestricted 2020 Anesthesiologists, Society of Korean © the Copyright phlebotomy can be performed as a management proce be performed can phlebotomy as a management once a week prior surgery to dure the hematocrit lower to the reduce significantly to a means 45% as below to level stockings can be with used can hepa low-dose in conjunction stockings during surgery. Second, thromboembolism rin prevent to this disease state this disease state be em can that procedures management intraoperative compression with polycythemia. First, on patients ployed blood viscosity that increases the riskfor thromboembo increases blood viscosity that with cardiopulmo is required caution Specifically, lism. the risk for as it reinforces thoracotomy, via nary bypass level is higher than normal, is associated with increased with is associated normal, increased than is higher level E-mail: [email protected] [email protected] E-mail: Hospital, 877 Bangeojinsunhwando- 877 Hospital, 44033, Ulsan Korea Dong-gu, ro, 82-52-250-7000 Tel: 82-52-250-7249 Fax: A-ran Lee, M.D. A-ran Lee, and Anesthesiology of Department University Ulsan Medicine, Pain Corresponding author Corresponding Revised Revised Accepted Received Received Anesth Pain Med Vol. 15 No. 2 cause of the disease, other patients require phlebotomy to ejection fraction of 17%. A normal result was obtained with lower their hematocrit level prior to surgery or hemodilu- coronary arteriography, which is used to identify coronary tion on the day of their scheduled surgery. However, acute artery disease. A chest radiography showed pleural effu- normovolemic hemodilution under anesthesia can be per- sion in the right lung, an atypical pulmonary nodule, lung formed on patients that cannot undergo phlebotomy or parenchymal distortion, bilateral upper lobe pleural thick- that require immediate treatment, such as emergency sur- ening, and emphysema, while a pulmonary function test gery [3]. Herein, we report a case of acute normovolemic revealed FEV1/FVC was 40%, FEV1 was 27%, FVE was 47%, hemodilution under anesthesia that was performed on a and TLC was 68%, indicating mixed respiratory failure. A patient scheduled for sutureless aortic valve replacement blood test showed 18.5 g/dl of hemoglobin and 57.3% of to treat severe aortic stenosis with secondary polycythemia hematocrit (Table 1), with normal leukocyte and thrombo- in order to prevent thromboembolism. We also discuss the cyte levels. In order to identify the cause of polycythemia, effectiveness of the procedure based on previous case the patient tested negative for janus kinase 2 (JAK2) V617F studies. We obtained informed consent from the patient. mutation, and the result of a plasma erythropoietin test was 20.4 IU/L. A bone marrow biopsy was not performed CASE REPORT due to patient refusal. However, arterial blood gas analysis

during room air breathing was PaO2 of 65.4 mmHg, PCO2 of

Our patient, a 67-year-old male weighing 66.8 kg and 50.3 mmHg, and SpO2 of 93% (Table 2), suggesting that the measuring 169.4 cm in height, was scheduled for sutureless patient may have experienced a secondary polycythemia aortic valve replacement to treat severe aortic stenosis. He induced by hypoxia from underlying disease rather than was diagnosed and treated for pulmonary tuberculosis 25 bone marrow disease, in which elevated hemoglobin level years ago, which resulted in severe sequelae in both lungs, could increase the risk of thromboembolism. Thus, after and also underwent surgical resection 14 years prior to consultation with a thoracic surgeon, the decision was treat abdominal liposarcoma. Additionally, our patient was made for the patient to undergo acute normovolemic he- hospitalized for treatment of atrial fibrillation and cardiac modilution under anesthesia. insufficiency 7 years ago and diagnosed with hypertension, Five-lead ECG, pulse oxygen saturation (pulse oximetry), diabetes, and chronic obstructive pulmonary disease 4 non-invasive blood pressure, arterial pressure from left ul- years ago. He was prescribed the following medications: ri- nar artery, bispectral index, and cerebral oxygen saturation varoxaban, digoxin, angiotensin receptor blocker, calcium were all measured as part of physiological monitoring in channel blocker, and an oral hypoglycemic agent. Howev- the operating room. The patient had a blood pressure of er, rivaroxaban was interrupted 3 days before surgery. 144/104 mmHg, heart rate of 110 beats/min, and oxygen The patient exhibited atrial fibrillation, premature ven- saturation of 90%. Endotracheal intubation was performed tricular contraction, left anterior fascicular block, and an- after the patient was anesthetized with administration of terior infarction from electrocardiogram (ECG), with an 2% lidocaine (60 mg), etomidate (12 mg), rocuronium (100 aortic valve blood flow velocity of 4.3 m/s, mean pressure mg), and fentanyl (150 μg); subsequently, a maintenance of 46 mmHg, and aortic valve surface area of 0.7 cm2 from dose of midazolam (5 mg), fentanyl (100 μg), and vecuro- echocardiography. The results indicated severe aortic ste- nium bromide (5 mg) were also administered. Arterial nosis, overall decrease in cardiac activity, moderate right pressure was monitored using a left femoral arterial cathe- ventricular dysfunction, moderate resting pulmonary hy- ter, pulmonary artery catheter (Swan-Ganz catheter, Ed- pertension, in conjunction with bilateral atrial extension, ward Lifescience, USA), and a central vein catheter, in nonvalvular atrial fibrillation and left ventricular systolic which the cannulation to the internal jugular vein was con- dysfunction. The patient also presented a left ventricular ducted using ultrasound guidance. Transesophageal echo-

Table 1. Pre- and Postoperative Collected Blood Count Change Variable Preoperative value At end of surgery 10 days after surgery 30 days after surgery 60 days after surgery Hemoglobin (g/dl) 18.5 8.9 9.7 10.5 11.0 Hematocrit (%) 57.3 25.9 29.7 33.1 35.5 Platelet (K/µl) 127 122 309 281 229

182 www.anesth-pain-med.org KSCVA - - 183 ). The test test ). The = 0.6) 47 76 27 90 62 100 106 267 2 7.38 29.9 7 7 7 70 62 45 52 55 93 (FiO 143 Table 3 Table ( At the end of surgery surgery of end the At At the end of surgery of end the At = 1.0) 74 36 29 29 86 60 100 102 2 463 7.47 56/54 (FiO After weaning After 7 6 6 41 : arterial oxygen saturation, HR: heart rate, HR: heart rate, saturation, oxygen : arterial 61 49 52 2 151 101 104 : regional cerebral oxygen saturation. oxygen cerebral : regional 2 After weaning After = 0.6) 39 26 60 100 2 382 7.48 29.2 41/40 ). After weaning from extracorporeal circulation, circulation, extracorporeal from weaning ). After (FiO After CPB on After Extracorporeal circulation was initiated 25 min after the the 25 min after initiated was circulation Extracorporeal Table 2 Table

start of the surgery, for 75 min, during sustained and was betweenand 30% 25 maintained was hematocrit the which ( loca and heart valve stable were vital signs the patient’s function, cardiac tions and function, as well as the overall echocardiography. based normal transesophageal on were 9.9 g/dl of he were results arterialThe analysis blood gas and FIBTEM were within the normal range within the normal range were and FIBTEM determineto microscopy, smear the infection, bacilli acid-fast the surgery; before not be completed could test and a culture disposed was of because the patient a blood collected from observed was effusion pleural indicating side the right on only the possibility of infection. , HCT: hematocrit, SaO , HCT: hematocrit, 2 9 9 74 10 82 65 46 53 53 = 0.6) 38 85 80 64 44 129 100 105 2 286 7.51 30.3 - - 50/52 After ANH After hemodilution (FiO After acute normovolemic normovolemic acute After ANH for a patient with erythrocytosis patient a ANH for = 0.6) 94 52 58 88 82 : partial CO of pressures 162 118 2 7.43 34.5 99.0 2 52/51 : alpha angle, A10: amplitude 10 minutes after start of assay, A20: amplitude 20 minutes after after 20 minutes start amplitude A20: assay, after of minutes 10 amplitude A10: angle, : alpha (FiO α After anesthesia anesthesia After 9–25 7–23 8–24 : fraction of inspired oxygen, ANH: acute normovolemic hemodilution, CPB: cardiopulmonary bypass, CPB: cardiopulmonary hemodilution, normovolemic ANH: acute oxygen, inspired of : fraction 43–65 50–71 50–72 38–62 38–79 34–159 63–83 2 Reference value Reference 30 56 (Rotational Thromboelastometry, Thromboelastometry, (Rotational 110 104 118 144 7.39 65.4 50.3 93.0 ® (room air) (room Preoperative value value Preoperative Data Change in Perioperative State in Perioperative Change Data ® , Fresenius Kabi Deutchland GmbH, Germany), as Germany), Deutchland GmbH, as Kabi , Fresenius Variable ® (mM/L) - ROTEM Intraoperative Time Course of ABGA and Hemodynamic Variables Hemodynamic ABGA Course and Time of Intraoperative (mmHg) (%) (mmHg) (%) 3 2 2 2 2 Variable : partial pressure of arterial oxygen, PCO oxygen, : partial arterial of pressure 2 (°) A10 (mm) A10 A20 (mm) MCF (mm) α MCF (mm) CT (s) A10 (mm) A10 A20 (mm) CT (s) CFT (s) DBP (mmHg) DBP MAP (mmHg) HR (beats/min) SBP (mmHg) HCT (%) Nine hundred and sixty millimeters of blood was drawn drawn blood was of millimeters sixty and hundred Nine

FIBTEM

EXTEM rSO Hemodynamics HCO SaO ABGA pH PaO PCO www.anesth-pain-med.org moglobin (15 g/dl) and hematocrit (44%) were measured. measured. (44%) were moglobin (15 g/dl) and hematocrit of ROTEM results Test both EXTEM that Germany) GmbH, indicated Pentapharm dl of hemoglobin and 58% of hematocrit. After acute nor acute After hematocrit. of 58% and hemoglobin of dl blood pressure hemodilution, the patient’s movolemic as well as he (88 beats/min), heartand rate (118/82 mmHg) Volulyte 19.7 g/ revealed arterial analysis blood gas the intra-operative from the central vein catheter at a rate of 50 ml/min for 20 20 for ml/min 50 of rate a at catheter vein central the from (HES, starch min, while injecting 960 ml of 6% hydroxyethyl cardiography was set up for intraoperative assessment of of assessment set up for intraoperative was cardiography assess function and to the condition of the heart cardiac valves. CT: clotting time, CFT: clot formation time, time, CFT: formation time, clot CT: clotting firmness. clot start MCF: maximum assay, of Table 3. Table ABGA: artery blood gas analysis, FiO gas analysis, ABGA: artery blood PaO rSO pressure, arterial MAP: mean pressure, blood diastolic DBP: pressure, blood SBP: systolic Table 2. Table Anesth Pain Med Vol. 15 No. 2 moglobin and 29% of hematocrit; the ROTEM® test result- major criteria or the first 2 major criteria and the 1 minor cri- ed in 101 seconds of clotting time (CT) in EXTEM, which terion. Secondary polycythemia, defined as an increase in was elongated to 104 s in FIBTEM and 41 mm of amplitude red blood cell mass due to elevated serum erythropoietin 10 min after the start of the assay (A10) in EXTEM, and was level, arises as a compensatory mechanism for chronic hy- reduced to 6 mm in FIBTEM, indicating a minor decrease poxia from chronic lung diseases, obstructive sleep apnea, in the fibrinogen level [4]. Two units of packed red blood congenital heart diseases, and smoking or, in rare cases, from cells, 3 units of fresh frozen plasma, and 8 units of platelets erythropoietin production from an erythropoietin-releasing were transfused after consulting with the operating sur- tumor, such as those that develop with hepatocellular and re- geon, due to the fact that the patient showed a bleeding nal carcinoma, among others. Our patient underwent sur- tendency after weaning from extracorporeal circulation. gery without a preoperative assessment, as he refused a bone Cerebral oxygen saturation during surgery measured marrow biopsy or testing for the JAK2 exon 12 mutations, 52/51, which was maintained after acute normovolemic which are required for accurate diagnosis. No further tests, hemodilution but reduced to 41/40 during extracorporeal including bone marrow biopsy, were performed, as hemo- circulation. Cerebral oxygen saturation eventually recov- globin levels recorded for more than 2 months post-opera- ered to 56/54 after weaning from extracorporeal circula- tively were within the normal range (Table 1). tion. The patient was transported to the intensive care unit The main purpose of polycythemia treatment is to pre- in a sedated state with endotracheal intubation, which was vent thromboembolism, which induces cardiocerebrovas- removed 4 days after admission to the intensive care unit cular complications. For this reason, the hematocrit level is and was then transferred to the general ward the following maintained below 45% via phlebotomy [2] and cell reduc- day. The patient was discharged 15 days after the surgery tion therapy, such as hydroxyurea, which are also used in without further complications. Meanwhile, the patient was patients over 60 years of age or those who have a history of diagnosed with secondary polycythemia without further thrombosis. However, the correlation between a high he- testing, as the blood test results acquired over 2 months matocrit level and increased incidence of thromboembo- post-operatively showed hemoglobin and hematocrit to be lism in secondary polycythemia is controversial. According lower than normal (Table 1). to the literature, Braekkan et al. [6] reported the risk of venous thromboembolism to be proportional to hematocrit DISCUSSION level, and Ristić et al. [7] described polycythemia to be the single most significant risk factor for pulmonary embolism Polycythemia is a condition where the red blood cell in chronic hypoxemic patients. However, Nadeem et al. [8] count is higher than normal and can be categorized as reported that secondary polycythemia alone might not sig- polycythemia vera and secondary polycythemia. The 2017 nify increased risk for venous thromboembolism. World Health Organization diagnostic criteria describes In a clinical setting, while secondary polycythemia polycythemia vera as a disease in which the red blood cell caused by hypoxia from chronic lung diseases and cyanotic count increases due to disorders regarding red blood cell heart diseases is treated with phlebotomy, cases related to production and provide 3 major and 1 minor diagnostic smoking, erythropoietin-releasing tumor, and anabolic ste- criteria. The first major criterion is hemoglobin greater roid injections are not treated with phlebotomy [9]. Al- than 16.5 g/dl in men and 16.0 g/dl in women, hematocrit though our patient was a good fit for phlebotomy, as he was greater than 49% in men and 48% in women, or red blood elderly and had hypertension, diabetes and atrial fibrilla- cell mass greater than 25% above the mean predicted val- tion, which are associated with an increased risk for throm- ue. The second major criterion consists of a bone marrow boembolism, phlebotomy was not carried out, as the pa- biopsy indicating hypercellularity through prominent tient could not complete the treatment for the duration re- erythroid, granulocytic, and megakaryocytic proliferation, quired to reach the target level (once a week for 6 weeks) with polymorphic mature megakaryocytic cells of varying [10]. Due to severe aortic stenosis characterized by a low left sizes. The third major criterion is presence of JAK2 V617F ventricular ejection fraction (17%), accelerated phleboto- or JAK2 exon 12 mutation and the 1 minor criterion is se- my, in which the procedure is carried out twice a week, was rum erythropoietin level lower than normal [5]. A diagnosis deemed unsafe, due to the risk of sharp deterioration in the of polycythemia vera requires that the patient exhibit all 3 patient’s condition. After consultation with the operating

184 www.anesth-pain-med.org KSCVA

------]. 14 : tar 185 t ]. In addition, ex addition, ]. In ). Previous work work ). Previous 13 [ Table 2 Table ( : initial hematocrit, HCT hematocrit, : initial 0 – 0.03, 3.8 L for this patient]) [ L for this patient]) – 0.03, 3.8 ]. The patient in this case report also report in this case patient ]. The ) (HCT t 15 [ /HCT 0 ]. Therefore, the target hematocrit in this case hematocrit target the ]. Therefore, CONFLICTS OF INTEREST CONFLICTS 15 [ SUPPLEMENTARY MATERIALS MATERIALS SUPPLEMENTARY No potential conflict of interest relevant to this article this article to relevant conflict of interest potential No Acute normovolemic hemodilution can be hemodilution a good can alter normovolemic Acute this of version Korean containing Supplementary data Currently, the target hematocrit level that should be be should that level hematocrit target the Currently, ml was calculated using the Bourke and Smith formula V formula and Smith the Bourke using calculated ml was = EBV × ln(HCT article is available at https://doi.org/10.17085/apm.2020. at articleavailable is 15.2.181. reported. was transport and tissue perfusion. However, recent findings findings recent perfusion. and tissue transport However, the increase 22% can below level a hematocrit that show infarction, of myocardial rate prevalence perioperative period, well as of as the likelihood hospitalization and cost, a blood transfusion requiring patients is circulation hemodilution during extracorporeal cessive oxygen cerebral decline regional in sharp a cause to shown saturation set 25–30%. to was aortic with stenosis severe presenting for patients native secondary polycythemia replace valve and undergoing time con due to for phlebotomy eligible not are that ment as Nonetheless, conditions. or their physiological straints level hematocrit low excessively an aforementioned, com several to lead can circulation during extracorporeal Further management. careful requires and, thus, plications range. hematocrit is needed the optimal work identify to get hematocrit, EBV: estimated blood [0.417 volume estimated EBV: get hematocrit, × + 0.045 height × weight heart in blood pressure, change no significant was There acute from saturation oxygen cerebral and regional rate, hemodilution normovolemic satura oxygen cerebral decline in regional showed a sharp 30% with normovole acute reached tion when hematocrit mic hemodilution satura oxygen cerebral in regional exhibited 20% decrease 30% during ex than lower became tion when hematocrit circulation. tracorporeal cir extracorporeal getting is patient the while maintained below level hematocrit the past, In is unknown. culation min to thought was circulation 20% during extracorporeal oxygen and improve impairment microcirculation imize ------]. ]. ]. 12 13 11 [ [ ANH for a patient with erythrocytosis patient a ANH for ]. Acute normovolemic hemodilution normovolemic Acute ]. 3 The target hematocrit of acute normovolemic hemodilu normovolemic of acute hematocrit target The Acute normovolemic hemodilution involves collecting a collecting hemodilution involves normovolemic Acute www.anesth-pain-med.org crease only contributing to stroke volume increase [ increase volume stroke to contributing only crease cardiovascular system, which can be manifested as a sup be manifested can which system, cardiovascular in output cardiac and in heart rate of change pression in cardiac output from acute normovolemic hemodilution normovolemic acute from output in cardiac effectthe to be attributed can anesthesia under patients in nervous on the autonomic and of the anesthetic system output and tissue oxygen extraction fraction, as well as as de fraction, extraction oxygen and tissue output of blood di as a result resistance vascular systemic creased increase blood viscosity. A reduced reduces lution, which normovolemic hemodilution to prevent side effects side of ab hemodilution prevent to normovolemic [ hematocrit normal with cardiac polycythemia increased in patients causes tients with severe polycythemia, such as coronary arteryas coronary such polycythemia, with severe tients uses acute circulator, an extracorporeal using graft bypass rhage so that the blood drawn during the procedure can be can during procedure the bloodthe drawn so that rhage effects side of allogen prevent to for self-transfusion stored emergency surgeries High-risk pa for ic blood transfusion. specific amount of blood, based on the target hematocrit, hematocrit, target blood,based the of on amount specific of colloid solution, and it is amount the same and injecting hemor with risk high for massive used in patients mainly surgeon, it was decided that the patient would undergo undergo would the patient decided it was that surgeon, hemodilution under anesthesia. normovolemic acute We set the target hematocrit level to 45%, considering the 45%, considering the to level set hematocrit the target We blood during cell loss diseases underlying and red patient’s blood (V) volume the surgery, and the exchangeable of 960 dilution, as hematocrit below 22% could lead to postopera to lead 22% could below dilution, as hematocrit infarction, myocardial stroke, as such complications, tive and pulmonary edema failure, renal arrest, cardiac However, patients undergoing cardiac surgery under car cardiac undergoing patients However, with hemo caution needdiopulmonary additional bypass mand and stimulated postoperative erythropoietin release erythropoietin release postoperative stimulated and mand myo reduced in turn, blood viscosity which, decreasing by complications cardiac cause injury can that cardial pertrophy who is undergoing aortic valve replacement, replacement, aortic valve who is undergoing pertrophy he normovolemic acute 28% via to lowering hematocrit de and metabolic transport, modilution optimized oxygen tion is determined based on the patient’s condition and the tion is determined based on the patient’s with a patient type of surgery, In exists. as no specific target hy ventricular left by accompanied aortic stenosis, severe acute normovolemic hemodilution in an awake state. state. hemodilution in an awake normovolemic acute stenosis. Also, acute normovolemic hemodilution under hemodilution under normovolemic acute Also, stenosis. in the change to response for an effective allows anesthesia or phlebotomy to compared status physiological patient’s Therefore, the absence of heart rate increase under anes under increase heart of rate absence the Therefore, aortic with severe this a good fit for patients makes thesia Anesth Pain Med Vol. 15 No. 2

AUTHOR CONTRIBUTIONS search on Cancer (IARC). 2017. 6. Braekkan SK, Mathiesen EB, Njølstad I, Wilsgaard T, Hansen JB. Conceptualization: Ilsang Han, A-ran Lee. Data acquisi- Hematocrit and risk of venous thromboembolism in a general tion: Ho June Kang. Supervision: Young Woo Cho. Writ- population. The Tromso study. Haematologica 2010; 95: 270-5. ing—original draft: Ilsang Han, Min Gi An. Writing—review 7. Ristić L, Rančić M, Radović M, Cirić Z, Kutlešić Kurtović D. Pul- & editing: Soon Eun Park, A-ran Lee. monary embolism in chronic hypoxemic patients with and without secondary polycythemia--analysis of risk factors in ORCID prospective clinical study. Med Glas (Zenica) 2013; 10: 258-65. 8. Nadeem O, Gui J, Ornstein DL. Prevalence of venous thromboembolism in patients with secondary polycythemia. Clin Appl Ilsang Han, https://orcid.org/0000-0002-6475-9310 Thromb Hemost 2013; 19: 363-6. Young Woo Cho, https://orcid.org/0000-0001-9683-1367 9. Assi TB, Baz E. Current applications of therapeutic phlebotomy. Soon Eun Park, https://orcid.org/0000-0002-7184-2067 Blood Transfus 2014; 12(Suppl 1): s75-83. Min Gi An, https://orcid.org/0000-0001-5138-8955 10. Kong JH, Lee SN, Eom HS, Lee HW, Han JY, Yoo Heon, et al. As- Ho June Kang, https://orcid.org/0000-0002-0123-2570 sessment of effects of phlebotomy in patients with polycythe- A-ran Lee, https://orcid.org/0000-0003-1045-2644 mia vera and secondary polycythemia. Korean J Blood Transfus 2013; 24: 265-74. REFERENCES 11. Ickx BE, Rigolet M, Van Der Linden PJ. Cardiovascular and metabolic response to acute normovolemic anemia. Effects of an- 1. Edmunds LH Jr, Colman RW. Thrombin during cardiopulmo- esthesia. Anesthesiology 2000; 93: 1011-6. nary bypass. Ann Thorac Surg 2006; 82: 2315-22. 12. Licker M, Sierra J, Kalangos A, Panos A, Diaper J, Ellenberger C. 2. Cundy J. The perioperative management of patients with poly- Cardioprotective effects of acute normovolemic hemodilution cythaemia. Ann R Coll Surg Engl 1980; 62: 470-5. in patients with severe aortic stenosis undergoing valve re- 3. Im H, Min JJ, Yang J, Lee SM, Lee JH. Anesthetic management of placement. Transfusion 2007; 47: 341-50. a patient with polycythemia vera undergoing emergency repair 13. Licker M, Sierra J, Kalangos A, Panos A, Diaper J, Ellenberger C. of a type-A aortic dissection and concomitant coronary artery Cardioprotective effects of acute normovolemic hemodilution bypass grafting: a case report. Korean J Anesthesiol 2015; 68: in patients with severe aortic stenosis undergoing valve re- 608-12. placement. Transfusion 2007; 47: 341-50. 4. Ji SM, Kim SH, Nam JS, Yun HJ, Choi JH, Lee EH, et al. Predictive 14. Meier J, Kleen M, Habler O, Kemming G, Messmer K. New value of rotational thromboelastometry during cardiopulmo- mathematical model for the correct prediction of the exchange- nary bypass for thrombocytopenia and hypofibrinogenemia af- able blood volume during acute normovolemic hemodilution. ter weaning of cardiopulmonary bypass. Korean J Anesthesiol Acta Anaesthesiol Scand 2003; 47: 37-45. 2015; 68: 241-8. 15. Han SH, Ham BM, Oh YS, Bahk JH, Ro YJ, Do SH, et al. The effect 5. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, of acute normovolemic haemodilution on cerebral oxygen- et al. WHO classification of tumours of haematopoietic and ation. Int J Clin Pract 2004; 58: 903-6. lymphoid tissues. 4th ed. Lyon: International Agency for Re-

186 www.anesth-pain-med.org KSTA - - - - - , P = 0.015) and end-diastolic end-diastolic and , P = 0.015) 2 ]. This disease has drawn the the drawn disease]. This has 1 Clinical Research Clinical , P = 0.011). However, there was no differ no was there However, = 0.011). P , 2 vs. 22 ml/m 2 vs. 63 ml/m 2 in cases other than HCM [ other than in cases SAM the fact that due to of anesthesiologists attention and during anesthesia an obstruction of the LVOT causes be may that instability hemodynamic induces severe ventricular outflow tract (LVOT) during the systole phase. phase. during the systole (LVOT) tract outflow ventricular occur known to even are of SAM patterns various However, 187 - eISSN 2383-7977 • Although systolic anterior motion (SAM) of the mitral valve anterior leaflet is is leaflet anterior mitral valve the of (SAM) motion anterior systolic Although Preoperative screening of echocardiography in LT recipients detects 1.2% of of 1.2% detects recipients LT in echocardiography of screening Preoperative Liver transplantation; Mitral chordae tendineae; Mortality; syn Post-reperfusion tendineae; chordae Mitral transplantation; Liver We retrospectively evaluated 1751 LT recipients from January 2011 to June 2017 2017 June to 2011 January from recipients LT 1751 evaluated retrospectively We Of the enrolled recipients, 21 (1.2%) had chordal SAM in preoperative echocardiog in preoperative SAM chordal had (1.2%) 21 recipients, Of enrolled the drome; Systolic anterior motion. anterior Systolic drome; end-systolic volume index (median 18 ml/m 18 (median index volume end-systolic 52 ml/m (median index volume intraoperative of prevalence The in echocardiography. function diastolic and in systolic ence Over (42.9% vs. P = 1.000). 45.3%, any difference show not did syndrome post-reperfusion a mortality show not did also overall and 90-day cumulative follow-up, 4.8-year mean the rank P > 0.05, both). (Log difference Conclusions: with intraopera related is not but volume, ventricular left with small It is found SAM. chordal mortality all-cause in postoperative short- and long-term and syndrome post-reperfusion tive LT. Keywords: Background: preva the situations, anesthetic many in perturbation hemodynamic cause to well-known in liver SAM) (chordal tendineae mitral chordae of SAM of implication clinical and lence SAM assess chordal of to aimed impact the We evaluated. been not has (LT) transplantation mortality. all-cause short and long-term and syndrome postreperfusion intraoperative on Methods: the and parameters Echocardiography-derived echocardiography. preoperative had who without and SAM with chordal those between syndrome post-reperfusion of prevalence of presence the to mortalityaccording rate cumulative The compared. were SAM chordal survival curve. Kaplan-Meier by the evaluated was SAM chordal Results: a smaller had SAM with chordal patients SAM, chordal without those to Compared raphy. Systolic anterior motion of mitral chordae chordae of mitral anterior motion Systolic implications in prevalence and clinical tendineae: liver transplantation Hwang Kyoung-Sun Kim, and Gyu-Sam Hye-Mee Kwon, Medicine, Laboratory for Cardiovascular and Pain Department of Anesthesiology of Medicine, Seoul, Korea Center, University of Ulsan College Dynamics, Asan Medical Anesth Pain Med 2020;15:187-192 2020;15:187-192 Med Pain Anesth https://doi.org/10.17085/apm.2020.15.2.187 pISSN 1975-5171 INTRODUCTION June 17, 2019 2019 17, June September 23, 2019 September September 3, 2019 3, 2019 September [email protected] [email protected] Systolic anterior motion (SAM) of the mitral chordae chordae of the mitral motion (SAM) anterior Systolic 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 permits permits which which (http://creativecommons.org/licenses/by-nc/4.0) (http://creativecommons.org/licenses/by-nc/4.0) License License Non-Commercial Non-Commercial Attribution Attribution Commons Commons Creative Creative the the of of terms terms the the under under Access Access article article is an Open is an Open This This distributed distributed cited. cited. is properly is properly work work original original the the provided provided in any medium, in any medium, reproduction reproduction and and distribution, distribution, use, use, non-commercial non-commercial unrestricted unrestricted 2020 2020 Anesthesiologists, Anesthesiologists, Society of Society of Korean Korean © the © the Copyright Copyright tendineae (chordal SAM) is commonly observed is commonly SAM) with sep (chordal tendineae (HCM) cardiomyopathy in hypertrophic tal hypertrophy obstructing the left by hypotension severe cause and may Tel: 82-2-3010-3868 Tel: 82-2-470-1363 Fax: E-mail: Medical Center, University of Ulsan Ulsan of University Center, Medical 88 Olympic-ro Medicine, of College 05505, Seoul Songpa-gu, 43-gil, Korea Department of Anesthesiology and and Anesthesiology of Department for Laboratory Medicine, Pain Asan Dynamics, Cardiovascular Corresponding author author Corresponding M.D. Gyu-Sam Hwang, Received Received Revised Accepted Anesth Pain Med Vol. 15 No. 2 low-responsive to the conventional treatment [2]. during the entire period of observation were assessed. In chordal SAM, the chordae tendineae moves anteriorly Postreperfusion syndrome was defined as a more than 30% during the systolic phase and is known to be associated drop of the mean arterial pressure from the baseline that with mitral valve prolapse [3]. It is a rare endocardial persists for at least one minute during the first five minutes change with a prevalence of 3.9% among patients with mi- after reperfusion of the transplanted liver. Time until graft tral valve prolapse and 1% among the normal population failure was defined as death after transplantation or [3]. However, its hemodynamic impact during anesthesia re-transplantation, whichever came earlier. Information or effects on postoperative clinical outcomes are unknown. about the patient’s death was collected from our LT patient We hypothesized that the incidence of chordal SAM might list and electronic medical records. The mean observation be higher among patients with end-stage liver disease who period was 4.8 ± 2.0 years, with a mean period of 4.3 ± 2.4 have hyperdynamic circulation compared to that among the years for patients with SAM and 4.8 ± 2.0 years for those general population. Moreover, we also hypothesized that pa- without SAM. tients with chordal SAM will be more vulnerable to postreperfusion syndrome because of increased hyperdynamic circula- Statistical analysis tion due to a sudden drop in systemic vascular resistance during graft reperfusion and the use of cardiovascular drugs Continuous variables were described as mean ± SD or like epinephrine could induce a structural change of the median (1Q, 3Q), and categorical variables were described heart. as the number of patients and percentage. Continuous Therefore, this study aims to examine the prevalence of variables were analyzed with the Shapiro Wilk normality chordal SAM in echocardiography before liver transplanta- test followed by the Student’s t-test or Mann-Whitney test, tion (LT), characteristics of patients with chordal SAM, and while categorical variables were analyzed with either the the effects of chordal SAM on reperfusion syndrome during chi-square test or Fisher’s exact test. The differences in LT, postoperative mortality, and liver failure. mortality rates between the two groups were analyzed using the Kaplan-Meier survival curve and log-rank test. The MATERIALS AND METHODS “moonBook” [4] and “survival” [5] R package were used for statistical analyses. Statistical analyses were performed us- This observational study was approved by the Institu- ing R (version 3.3.1, R foundation for statistical Computing, tional Review Board at the Asan Medical Center (no. 2019- Austria). A P value < 0.05 was considered statistically sig- 0174), and patients with end-stage liver disease who un- nificant. derwent LT at our hospital between January 2011 and June 2017 were retrospectively reviewed. Patients under the age RESULTS of 18, patients undergoing a re-transplantation, patients who did not undergo echocardiography preoperatively, Of the LT patients between January 2011 and June 2017, patients with chronic kidney disease, and patients with a total of 1,751 patients was enrolled after the exclusion missing data were excluded. At our hospital, all LT patients and 21 (1.2%) showed chordal SAM. The representative undergo transthoracic echocardiography. In this study, we manifestation of chordal SAM is presented in Fig. 1 and collected information about patients’ state, including Supplementary Video 1. Table 1 shows the patients’ demo- transthoracic echocardiography results, and laboratory test graphics and cause of liver cirrhosis according to chordal results from electronic medical records and retrospectively SAM. There were no differences in the age, sex, Model for analyzed them. Transthoracic echocardiography (Hewl- End-Stage Liver Disease score, and the prevalence of un- ett-Packard Sonos 2500 or 5500 imaging system, Hewl- derlying diseases such as hypertension and diabetes melli- ett-Packard Inc., USA) was performed by a skilled echocar- tus between the two groups. Table 2 shows the results of diography technician using a 2.5 MHz transducer and the echocardiography between the two groups. results were confirmed by an attending cardiologist. The There was no difference in the grade of mitral regurgita- incidence of reperfusion syndrome and the epinephrine tion (P = 0.815) or in left ventricular systolic and diastolic dose during the reperfusion period was collected. The 90- functions between the two groups (Table 2). However, re- day mortality as well as overall mortality and graft failure garding heart volume, patients with chordal SAM had a

188 www.anesth-pain-med.org KSTA ). 189 Fig. 3 Fig. P = 0.733 0.175 0.131 0.877 0.777 0.737 Overall mortality 1.000 1.000 1.000 1.000 0.825 0.388 0.065 0.884 P value ). There were also no differences in alsono differences were ). There Fig. 2 Fig. ( P = 0.901 Without SAM With SAM 6 (28.6) 2 (9.5) 5 (23.8) 0 (0.0) 6 (28.6) 6 (28.6) 1 (4.8) 1 (4.8) 90-day mortality 10 (47.6) 10 12 (57.1) 12 (8, 16) 55.0 (50.0, 59.0) 26.2) 23.4 (21.7, Chordal SAM (n SAM Chordal = 21) 5 0 Comparison of rate of 90-day and overall mortality between overall and 90-day of rate of Comparison 10 15

7.5 2.5

12.5 Percentage of non-survivors of Percentage = ( SAM of chordal the presence to 0.900) according Fig. 2. Fig. the of motion anterior systolic chordae without with or patients mitral valve. of motion anterior systolic SAM: mitral valve. the two groups. Further, the two groups also did not differ two the groups Further, the two groups. 2.6%, P mortality (4.8% vs. in the 90-day = 1.000), overall 10.6%, P mortality (9.5% vs. = failure graft 1.000), 90-day P 3.1%, (4.8% vs. = (9.5% vs. failure graft 1.000), and overall 12.3%, P = 0.964) mortality (Log-rank P for and overall 90-day cumulative mortality 90-day = mortality 0.548; Log-rank P for overall , - - - 2 SAM of mitral chordae in LC patients in LC chordae mitral of SAM 76 (4.4) 76 13 (9, 22) 13 66 (3.8) 407 (23.5) 407 337 (19.5) 337 424 (24.5) 424 490 (28.3) 266 (15.4) 125 (7.2) 842 (48.7) 23.5 (21.5, 25.8) 23.5 (21.5, 54.0 (48.0, 58.0) 1,059 (61.2) 1,059 vs. 63 [54, 74] ml/m 74] [54, 63 vs. 2 Without chordal SAM (n SAM chordal Without = 1,730) , P P , =vol end-diastolic and 0.015) 2 ) 2 Variable shows a comparison of intraoperative hemody a comparison of intraoperative shows Demographic of Liver Transplant Recipients according to Prevalence of Chordal Systolic Anterior Motion (SAM) of Mitral Value Mitral of (SAM) Motion Anterior Systolic Chordal of Prevalence to according Recipients Transplant Liver of Demographic Representative figure of echocardiographic finding of of finding echocardiographic of figure Representative vs. 22 [19, 27] ml/m 27] [19, 22 vs. Alcoholic cirrhosis Alcoholic disease Biliary carcinoma hepatocellular Combined Hepatitis B virus Hepatitis C virus Hepatitis Table 3 Table 2

Etiology of liver cirrhosis liver of Etiology Hypertension use blocker Beta use Diuretics Body mass index (kg/m massBody index Disease Liver End-Stage for Model score Diabetes Age (yr) Age (male) Sex www.anesth-pain-med.org Values are presented as median (1Q, 3Q) or number (%). number (1Q, 3Q) or as median presented are Values Table 1. Table Fig. 1.Fig. long in parasternal mitral valve of motion anterior systolic chordae mitral valve. of motion systolic the represents Arrow axis view. 1.000) and the epinephrinethe and 1.000) dose used (P =between0.925) ure after LT. There were no differences in the incidence of in the incidence of no differences were There LT. after ure 45.3%, P (42.9% vs. syndrome reperfusion intraoperative = namic changes (presence of postreperfusion syndrome) syndrome) of postreperfusion (presence changes namic and the epinephrine dose mortality, used as well as 90-day fail graft overall and failure, graft mortality, 90-day overall P = without chordal of patients that to compared 0.011) SAM. smaller end-systolic volume index (median index 25] ml/ [15, 18 volume end-systolic smaller m ml/m (median68] index [42, ume 52 Anesth Pain Med Vol. 15 No. 2

Table 2. Echocardiography of Liver Transplant Recipients according to Prevalence of Chordal Systolic Anterior Motion (SAM) of Mitral Value Echocardiographic parameters Without chordal SAM (n = 1,730) Chordal SAM (n = 21) P value Grade of mitral regurgitation 0.815 0 1,532 (88.6) 19 (90.5) 1 165 (9.5) 2 (9.5) 2 33 (1.9) 0 (0.0) Parameters of Left ventricular Structures and Systolic function LV dimension in systole (mm) 30 (27, 33) 28 (25, 30) 0.048 LV dimension in diastole (mm) 50 (47, 54) 48 (45, 51) 0.092 LV posterior wall thickness in systole (mm) 14 (13, 15) 14 (13, 15) 0.749 LV posterior wall thickness in diastole (mm) 9 (8, 10) 9 (9, 10) 0.262 Interventricular septal thickness in systole (mm) 13 (12, 15) 14 (13, 15) 0.167 Interventricular septal thickness in diastole (mm) 9 (8, 10) 9 (8, 10) 0.106 Left atrium (mm) 39 (36, 43) 39 (35, 45) 0.936 End-systolic volume index (ml/m2) 22 (18, 27) 18 (15, 25) 0.015 End-diastolic volume index (ml/m2) 63 (54, 74) 52 (42, 67) 0.011 Stroke volume (ml) 70 (58, 84) 63 (48, 78) 0.087 LV Mass index (g/m2) 153.8 (128.6, 182.5) 159.1 (114.1, 176.7) 0.672 LV ejection fraction (%) 64.5 (61.4, 67.3) 64.4 (62.9, 66.3) 0.627 S’ medial (cm/s) 8.4 (7.5, 9.6) 9.0 (8.3, 9.9) 0.066 Parameters of Diastolic function E/A ratio 1.11 (0.88, 1.37) 1.11 (0.84, 1.27) 0.550 ≤ 1.0 674 (39.0) 10 (48) > 1.0 1,056 (61) 11 (52) Peak E velocity (cm/s) 73 (61, 87) 70 (61, 88) 0.672 Peak A velocity (cm/s) 66 (55, 79) 63 (58, 78) 0.921 Deceleration time (ms) 209 (181, 238) 223 (195, 238) 0.244 e’ medial (cm/s) 7.5 (6.3, 8.7) 7.0 (6.3, 7.6) 0.090 a’ medial (cm/s) 9.4 (8.1, 10.7) 10.7 (9.8, 11.9) 0.007 E/e’ 10 (8, 12) 11 (9, 11) 0.313 Values are presented as number (%) or median (1Q, 3Q). LV: left ventricle, E/A: early and late diastolic velocity ratio, E/e’: ratio of early diastolic to tissue doppler imaging velocities.

Table 3. Intraoperative Hemodynamic Changes and Outcomes after Post-liver Transplantation Variables Without chordal SAM (n = 1,730) Chordal SAM (n = 21) Total (n = 1,751) P value Intraoperative pRBC transfusion 7 (2, 14) 5.0 (0, 14) 7 (2, 14) 0.425 Post-reperfusion syndrome 783 (45.3) 9 (42.9) 792 (45.2) 1.000 Epinephrine dose (µg)* 0 (0, 10) 0 (0, 10) 0 (0, 10) 0.925 90-day mortality 45 (2.6) 1 (4.8) 46 (2.6) 1.000 Overall mortality 184 (10.6) 2 (9.5) 186 (10.6) 1.000 90-day graft failure 54 (3.1) 1 (4.8) 55 (3.1) 1.000 Overall graft failure 212 (12.3) 2 (9.5) 214 (12.2) 0.964 Values are presented as median (1Q, 3Q) or number (%). SAM: systolic anterior motion of mitral valve, pRBC: packed red blood cell. *Epinephrine usage during post-reperfusion syndrome.

DISCUSSION and overall mortality during the observation period. End-stage liver disease is known to cause cardiac structur- The prevalence of chordal SAM discovered in the preop- al impairments and dysfunctions, such as tachycardia, sys- erative echocardiography was 1.2%, and patients who had tolic and/or diastolic functions, and/or electrophysiology, chordal SAM did not significantly differ in the incidence of which is defined as cirrhotic cardiomyopathy (CCMP) [6]. postreperfusion syndrome during LT from patients who Structural changes of the heart generally involve left ventric- did not have chordal SAM. Moreover, the two groups of pa- ular enlargement and hypertrophy and cardiac tissues show tients did not significantly differ in the 90-day mortality myocardial fibrosis and subendocardial edema. Further, the

190 www.anesth-pain-med.org KSTA - - - - - 2 191 16 ]. 3 3 [ 281 6 6 7 8 6 7 8 554 With SAM 8 832 4 5 4 5 10 1109 Time in Years 14 Without SAM 1432 2 3 2 3 19 1580 ]. We hypothesized that chordal SAM, SAM, chordal that hypothesized ]. We 20 15 1628 – 13 Log-rank P = 0.548 Log-rank P = 0.900 0 1 0 1 21 1730 Number at risk 1.0 0.9 0.8 0.7 0.6

One limitation of this study is that although we examined although is that One of this study limitation SAM is a phenomenon in which the anterior motion of motion of the anterior which is a phenomenon in SAM B Probablity Survival Overall though not the typical SAM of the anterior mitral leaflet, leaflet, mitral of the anterior SAM not the typical though However, syndrome. on reperfusion some impact have may Moreover, differences. significant no showed results our in the postoperative differences no significant were there and long-term mortality LT. after 90-day specific study our patients, of LT number large a relatively should also be studied on a larger study population population study also a larger on should be studied the of obstruction an causes leaflet mitral anterior the Al collapse. cardiovascular a severe and eventually, LVOT, myocar be to known induced is commonly by SAM though and asymmetrical interventricular thickening septal dial use of hypovolemia, severe by be caused it can thickening, secretion catecholamine and/or elevated dobutamine, de without anatomical in patients even stress by caused can LT Particularly, close attention. necessitating fects, of the inferior ligation due to hypovolemia severe cause bleeding during surgery. and massive Therefore cava vena ischemic heart dis with CCMP, occur in patients can SAM a postreperfu who develop syndrome or hepatorenal ease, drugs doses high of cardiovascular because syndrome sion to protocol it is standard Therefore, used cases. in such are hypovolemia of unexplained severe as a cause suspect SAM been have studies case relevant and numerous during LT, [ reported With SAM Without SAM ------20 1685 SAM of mitral chordae in LC patients in LC chordae mitral of SAM 21 ]. Moreover, dia ]. Moreover, 1691 With SAM 11 ]. – 8 12 ]. Although the systolic systolic the Although ]. 7 Time in Days Without SAM 21 30 60 90 90 30 60 1706 Log-rank P = 0.548 21 0 0 1730 Number at risk

0.6 0.8 0.7 1.0 0.9 Cumulative 90-day (A) and overall mortality (B) compared between the groups of patients with or without chordae systolic anterior anterior systolic chordae without with or patients of groups the mortality between (B) compared overall (A) and 90-day Cumulative 90-Day Survival Probablity Survival 90-Day With SAM In our study, a comparison of clinical features between pa a comparison features study, of clinical our In A Without SAM www.anesth-pain-med.org studies reported that chordal SAM is more common among common among is more SAM chordal that reported studies significant no syndrome, prolapse valve with mitral patients behind this reason The study. in our found was difference between chordal SAM and hyperdynamic circulation. Further circulation. and hyperdynamic SAM between chordal im needed the clinical identify to are studies additional more, previous addition, whereas In differences. such of plications cantly differ in other systolic indices, such as ejection fraction, as ejection fraction, such indices, differ in other systolic cantly the relationship is needed regarding further research therefore suggests that chordal SAM occurred in patients with a small with a small in patients occurred SAM chordal that suggests hyperdy index) with volume end-diastolic greater heart (low did not signifi the two groups However, circulation. namic with chordal SAM had a smaller left ventricle (LV) dimension dimension (LV) left ventricle a smaller had SAM with chordal 30, P (28 vs. in systole = dimension LV 0.048). Considering that function, this result systolic of cardiac is an indicator in systole postoperative mortality following LT [ mortality LT following postoperative patients that revealed SAM with and withouttients chordal stolic dysfunction frequently occurs, and particularly, and pre occurs, frequently dysfunction stolic increased to is closely related disorder diastolic operative ed during rest, patients with CCMP have been reported to been to reported with have CCMP patients ed during rest, situa function during stress systolic cardiac reduced show and bleeding [ as exercise such tions, such as isoproterenol, is diminished in patients with liver withliver patients in diminished is isoproterenol, as such [ models seen as rat in in cirrhosis, elevat normal or generally are output functions and cardiac increase of heart rate in response to beta receptor agonists, agonists, beta to receptor in response of heart rate increase Fig. 3. Fig. mitral valve. of motion anterior systolic SAM: patients. the between found was difference No mitral valve. of motion Anesth Pain Med Vol. 15 No. 2 population was small, as chordal SAM is a rare disease. Sub- REFERENCES sequent studies should recruit a larger study population. Further, as this study is a retrospective analysis, we could not 1. Manabe S, Kasegawa H, Arai H, Takanashi S. Management of include the use of echocardiography upon the onset of post- systolic anterior motion of the mitral valve: a mechanism-based reperfusion syndrome. Even if the incidence of postreperfu- approach. Gen Thorac Cardiovasc Surg 2018; 66: 379-89. sion syndrome may not differ, the onset of SAM that causes 2. Moon YJ, Park JH, Oh J, Lee S, Hwang GS. Harmful effect of epi- hemodynamic changes can be observed, so subsequent nephrine on postreperfusion syndrome in an elderly liver studies should utilize echocardiography during LT. transplantation recipient with sigmoid ventricular septum: a case report. Medicine (Baltimore) 2016; 95: e4394. In conclusion, chordal SAM was found in 1.2% of pa- 3. Pearson AC, Pasierski TJ, Orsinelli DA, Gray P, Huschart K. Sys- tients before LT, and these patients had smaller cardiac tolic anterior motion of the mitral chordae tendineae: preva- systolic and diastolic volumes than those without chordal lence and clinical and Doppler-echocardiographic features. Am SAM. Unlike with the SAM of the anterior mitral leaflet, the Heart J 1996; 131: 748-53. incidence of intraoperative postreperfusion syndrome or 4. Moon KW. R statistics and graphs for medical papers. Seoul, postoperative 90-day and overall mortality did not signifi- Hannaare. 2015. cantly differ according to chordal SAM. Therefore, it seems 5. Therneau TM. A Package for survival analysis in S. R package safe for patients with chordal SAM to undergo LT, but more version 2.37-7. 2014 [cited 2019 Apr 27]. Available from: http:// prospective studies with echocardiography data during CRAN.R-project.org/package= survival. postreperfusion period are needed. 6. Kwon HM, Hwang GS. Cardiovascular dysfunction and liver transplantation. Korean J Anesthesiol 2018; 71: 85-91. SUPPLEMENTARY MATERIALS 7. Ramond MJ, Comoy E, Lebrec D. Alterations in isoprenaline sensitivity in patients with cirrhosis: evidence of abnormality of Supplementary data including video 1 and Korean version the sympathetic nervous activity. Br J Clin Pharmacol 1986; 21: of this article are available at https://doi.org/10.17085/ 191-6. apm.2020.15.2.187. 8. Wachsberg RH. Cardiac response to exercise in cirrhosis. Gut 2002 51: 755; author reply 755. CONFLICTS OF INTEREST 9. Wong F, Girgrah N, Graba J, Allidina Y, Liu P, Blendis L. The cardiac response to exercise in cirrhosis. Gut 2001; 49: 268-75. No potential conflict of interest relevant to this article 10. Møller S, Henriksen JH. Cirrhotic cardiomyopathy: a pathophys- was reported. iological review of circulatory dysfunction in liver disease. Heart 2002; 87: 9-15. AUTHOR CONTRIBUTIONS 11. Møller S, Henriksen JH. Cirrhotic cardiomyopathy. J Hepatol 2010; 53: 179-90. 12. Mittal C, Qureshi W, Singla S, Ahmad U, Huang MA. Pre-trans- Conceptualization: Hye-Mee Kwon. Data acquisition: plant left ventricular diastolic dysfunction is associated with Kyoung-Sun Kim. Formal analysis: Hye-Mee Kwon, Gyu- post transplant acute graft rejection and graft failure. Dig Dis Sam Hwang. Supervision: Gyu-Sam Hwang. Writing—orig- Sci 2014; 59: 674-80. inal draft: Hye-Mee Kwon. Writing—review & editing: Gyu- 13. Harley ID, Jones EF, Liu G, McCall PR, McNicol PL. Orthotopic Sam Hwang. liver transplantation in two patients with hypertrophic obstruc- ORCID tive cardiomyopathy. Br J Anaesth 1996; 77: 675-7. 14. Essandoh M, Otey AJ, Dalia A, Dewhirst E, Springer A, Henry M. Hye-Mee Kwon, https://orcid.org/0000-0001-7788-9555 Refractory hypotension after liver allograft reperfusion: a case Kyoung-Sun Kim, https://orcid.org/0000-0002-6643-9177 of dynamic left ventricular outflow tract obstruction. Front Med Gyu-Sam Hwang, https://orcid.org/0000-0002-3627-1107 (Lausanne) 2016; 3: 3. 15. Lim YC, Doblar DD, Frenette L, Fan PH, Poplawski S, Nanda NC. Intraoperative transesophageal echocardiography in orthotopic liver transplantation in a patient with hypertrophic cardiomyopathy. J Clin Anesth 1995; 7: 245-9.

192 www.anesth-pain-med.org Anesth Pain Med 2020;15:193-198 https://doi.org/10.17085/apm.2020.15.2.193 Case Report pISSN 1975-5171 • eISSN 2383-7977

Carpal tunnel syndrome caused by thrombosed persistent median artery - A case report -

Sang Yoon Jeon1, Kwangmin Lee2, and Weon-Joon Yang2 Received May 16, 2019 1 Revised October 1, 2019 Department of Anesthesiology and Pain Medicine, Dongkang Medical Center, Ulsan, 2 Accepted October 2, 2019 Cheju Halla General Hospital, Jeju, Korea

Background: A rare case of carpal tunnel syndrome caused by a thrombosed persistent median artery is presented here. Case: The diagnosis was delayed due to the overlapping cervical radiculopathy. Acute severe pain and nocturnal paresthesia were chief complaints. Ultrasonography, magnetic res- Corresponding author onance imaging, and computed tomography angiography revealed that the median nerve Sang Yoon Jeon, M.D. was compressed by the occluded median artery. Instead of surgery, conservative therapy Department of Anesthesiology and was tried. It worked well for six months. Pain Medicine, Dongkang Medical Conclusions: The importance of using modalities for decision making of diagnosis and Center, 239 Taehwa-ro, Jung-gu, Ulsan treatment is emphasized in this report. 44455, Korea Tel: 82-52-241-1004 Fax: 82-52-241-1180 Keywords: Carpal tunnel syndrome; Computed tomography angiography; Persistent median E-mail: [email protected] artery; Thrombosis.

Carpal tunnel syndrome (CTS) is one of the most com- (MRI), and 3D computed tomography (CT) angiography to mon entrapment neuropathies. Its prevalence is 3.8% [1]. diagnose the patient with CTS caused by thrombosis of the Any condition that constantly compresses the median PMA and treated him conservatively. nerve can impede capillary circulation in the median nerve, leading to ischemia, demyelination, and axonal de- CASE REPORT generation [1]. Patients generally present symptoms of pain, nocturnal paresthesia, and numbness in the distribu- We obtained the patient’s verbal consent to publish this tion of the median nerve [1]. In severe cases, motor symp- case. A 42-year-old man was referred to our pain clinic via toms with weakness and atrophy of thenar muscles as well the emergency center with a chief complaint of acute se- KSPS as hypesthesia are also shown [1]. vere pain in the right hand. The symptom started three The median artery is a transitory artery that forms the days before he was referred. The pain worsened at night. arterial axis of the forearm [2]. It generally vanishes by the Numeric rating scale score was 8 over 10. He was a chassis eighth week of gestation [2]. It occasionally persists in worker who had been doing a lot of handworks. He had no adulthood with a prevalence of 6.6% [3]. Persistent median medical, trauma, or surgery history except a right cervical artery (PMA) is at risk of thrombosis, leading to CTS [4–6]. radiculopathy at the level of C6. The cervical radiculopathy In this paper, we report a rare case of carpal tunnel syn- was diagnosed clinically and radiographically with cervical drome caused by a thrombosed persistent median artery. spine CT 2 weeks before at the neurosurgery clinic. It had We used ultrasonography, magnetic resonance imaging caused mild pain and paresthesia from the neck to the

193 Anesth Pain Med Vol. 15 No. 2 right hand (Fig. 1). These symptoms had been somewhat found that it was the right median artery traveling along with relieved by oral medications (gabapentin, tramadol, acet- the median nerve from the forearm. It was occluded by hyper- aminophen). However, when he was referred to our pain echoic thrombosis at the proximal carpal tunnel level (Fig. 3). clinic, the localized pain in the right hand was aggravated The patient was firstly diagnosed with CTS. Because he had severely and the medication had no effect. On physical ex- suspicious lesions in cervical CT and the prescribed oral amination, he presented no weakness. However, the pain medication was effective for his symptoms, differential di- was aggravated by doing palmar flexion of right wrist. We agnosis was not executed. Thus, the diagnosis of CTS was also observed tenderness on the palmaris longus tendon delayed. and positive Tinel’s sign. For further imaging study, we performed MRI. During Under the impression of CTS, we investigate it through ul- the interval time before taking MRI, although we found trasonography. In the ultrasonography, we observed that an thrombosis of the PMA, since he had been diagnosed with oval mass was compressing the median nerve which was cervical radiculopathy, we prescribed him more dose of edematous in the right carpal tunnel (Fig. 2). The mass was gabapentin. However, he showed no improvement of the scanned from the wrist to the forearm. By doppler image, we pain. In the MRI, we found that the right median nerve was compressed by a tubular enhancing structure considered as the median artery located at the volar aspect of the median nerve at the level of hook of hamate (Fig. 4B). The median artery was occluded by thrombus. It was relatively large at about 2.7 mm in diameter at that level. At the level of the pisiform, we found the right median nerve which became edematous (Fig. 4A). Interestingly, the PMA was traveling along with two veins. After consulting a cardiovascular surgeon considering the need of thrombectomy of the right PMA, we mapped arteries through 3D CT angiography (Fig. 5). In the arteriography, we observed four arteries originated from the right brachial artery. Of these four arteries traveling to the anterior forearm, one remained artery except the ulnar artery, the an- Fig. 1. Transverse and sagittal images at the level of C5-6 of the cervical computed tomography show that the disc is bulging mildly and the right uncovertebral joint is prominent without significant foraminal narrowing.

Fig. 2. Ultrasonogram of the thrombosed persistent median artery (dotted circle) and the compressed median nerve (arrow) in the Fig. 3. Longitudinal doppler ultrasonogram of the patient’s right patient’s right proximal (prox) carpal tunnel. persistent median artery (PMA).

194 www.anesth-pain-med.org CTS caused by thrombosed PMA terior interosseous artery, and the posterior interosseous artery was the PMA. The radial artery originated directly from the axillary artery. Moreover, we found that not only the right median artery, but also the left median artery existed. The left median artery was originated from the left brachial artery too. Both were occluded by the thrombus from the distal radioul- nar joint level to the metacarpal base level, at which palmar collateral vessels reconstituted the arterial flow of both hands (Fig. 6). Since there was no ischemic sign in the hand with the help of collateral vessels, we decided to treat the patient conservatively. We prescribed oral antiplatelet drug (ci- lostazol) and made ultrasound-guided peri-neural steroid injection (triamcinolone 20 mg mixed with 0.1% ropivacaine 2 ml) at the right carpal tunnel. After that, his symptoms gradually subsided. They did not recur in one month. The patient was satisfied with the result. He was lost to follow-up.

DISCUSSION

CTS may be clinically classified into three stages with respect to severity: nocturnal hand pain and paresthesia ra- diating from wrist to shoulder and being relieved by hand shaking, sensory symptoms during the day and motor deficit, and thenar atrophy and disappearance of sensory Fig. 5. 3D computed tomography angiogram of the patient’s right symptom [1]. The Katz hand diagrams can help patient lo- upper extremity. Each persistent median artery (arrow) and radial calize symptoms in the hand [7]. They are classified into artery (arrowhead) are originated from each brachial artery and axillary artery, respectively.

A B KSPS

Fig. 4. Persistent median artery in carpal tunnel. Axial gadolinium-enhanced spin-echo T1-weighted magnetic resonance images at levels of pisiform (A) and hook of hamate (B) show persistent median artery (arrow) and two small veins in the carpal tunnel located at volar aspect of median nerve (arrowhead), causing mild impingement of median nerve. www.anesth-pain-med.org 195 Anesth Pain Med Vol. 15 No. 2

C7, brachial plexopathy in upper trunk, proximal median A B neuropathy, thoracic outlet syndrome, and CNS disorders [1]. When a patient suffers from neuropathic symptoms believed to be caused by cervical radiculopathy, we must not exclude other possible causes. Moreover, if the symptoms are localized to the dermatome of median nerve, differential diagnoses and investigations of peripheral entrapment neuropathies including CTS are required. In comparison with CTS of which the distribution of sensory symptoms Fig. 6. Computed tomography angiograms of the right upper ranges between thumb and half of ring finger, C6 or C7 cer- extremity at levels of hook of hamate (A) in which the persistent median artery (PMA) (arrow) is occluded and base of metacarpal vical radiculopathy has the distribution of sensory symp- bones (B) in which the PMA’s flow is reconstituted by palmar toms limited to thumb and index finger or middle finger. collaterals. C6 or C7 cervical radiculopathy might be provoked by Spurling’s test and Jackson’s compression test [8]. Thus, three patterns [7]. Among them, classical or probable pat- physical examination should include other areas of the tern is indicative of CTS [7]. According to Keith et al. [8], neck and the upper extremity [8]. clinical tests including manual muscle tests and several According to Upton and McComas [9], double crush syn- provocative tests such as Phalen’s test, Tinel’s test, and me- drome (DCS) describes a clinical entity that when a single dian nerve compression test may increase the sensitivity peripheral nerve is compressed in two or more sites, the first and specificity to diagnose CTS when they are combined compression leads to disruption of axonal transport along together, although each alone has low value for identifying the nerve, thus increasing the vulnerability of distal axons to CTS. Therefore, it is required to obtain focused history on the second compression. There was also a case of DCS in symptom onset, pain localization and irradiation, provoca- which the thoracic outlet syndrome was masked by CTS [10]. tive factors, relieving factors, predisposing factors, and Thus, the diagnosis was delayed [10]. Therefore, even if a pa- working activities [7]. Moreover, combination of symptoms, tient is diagnosed to have a certain neuropathy, we should clinical tests, and electrodiagnostic tests including nerve check other confounding factors that may co-exist. conduction study and electromyography may be better to In the present case, both PMAs were found to be occlud- diagnose CTS and provide positive correlation with posted by the thrombus. However, the patient experienced surgical outcomes [8]. acute symptoms in the right hand without symptoms in the In fact, the aims of electrodiagnostic tests are to confirm left hand. This showed that the occlusion of the PMA might a focal neural damage, to quantify neurophysiological se- not always cause CTS. We assumed that there might be two verity, to define the nerve pathophysiology, and to find factors that caused CTS only in the right hand: the mass ef- confounding factors [7]. However, since false negative and fect and the DCS. As we saw in the ultrasonography and the false positives can occur, electrodiagnostic tests may con- MRI, the occluded right PMA was dilated. That is, high pres- firm CTS, but cannot rule out CTS [1]. Thus, electrodiag- sure produced by occlusion of the PMA caused luminal dila- nostic tests are recommended when differentiation is re- tation which directly compressed the right median nerve, the quired, when thenar atrophy and/or persistent numbness so-called mass effect. This effect made the blood supply from (that is, severe symptoms) are present, and when clinical collateral vessels to the right median nerve so short that isch- and/or provocative tests are positive and surgical manage- emic nerve injury occurred which resulted in edematous sta- ment is being considered [8]. Ultrasonography has almost tus. Moreover, since the patient was diagnosed with right C6 the same sensitivity in diagnosing CTS as electrodiagnostic cervical radiculopathy, the proximally compressed root might test [1]. It is useful for finding the occupying lesion and de- make the right median nerve weaker to distal compression termining its severity by measuring cross-sectional area of and poorer blood supply than the left. In fact, it was likely that the median nerve [1]. However, other imaging modalities the mass effect was more dominant than the effect of DCS be- like MRI are not recommended routinely [1]. cause the cervical CT images showed mild disc bulging with- CTS must be differentiated from several neuropathies out significant foraminal narrowing and the patient’s symp- which include cervical radiculopathy, especially C6 and tom disappeared after the conservative therapy was done. Ac-

196 www.anesth-pain-med.org CTS caused by thrombosed PMA tually, it would be better if we examined more about cervical Patients with CTS can be treated by conservative cares radiculopathy with provocative tests for cervical radiculopa- including local and systemic steroids, vitamins B6 and B12, thy and electrodiagnostic test to measure the effect of the DCS non-steroidal anti-inflammatory drugs, ultrasound, yoga, of the cervical radiculopathy and to predict the benefit of sur- carpal bone mobilization and wrist splints, and surgical gical procedure which was proposed. On the other hand, al- treatment in the form of carpal tunnel release [1]. When though the left PMA was occluded, there was no mass effect. patients suffer from severe acute symptoms caused by oc- In addition, no DCS existed in the left median nerve. Thus, cluded PMAs, some reports recommend surgery [4,5]. In there was no symptom in the left hand. Therefore, the mass another report, when collateral vessels exist, conservative effect was the main mechanism that caused his symptoms. therapy using anti-coagulants was successful [6]. Since we Although this case showed that thrombosis of the PMA confirmed the collateral’s existence by CT angiography caused CTS, one study reported that the incidence of PMA without observing ischemic signs, we tried conservative in a group of CTS patients was 2.4% [11]. An ipsilateral PMA treatment which worked well. does not seem to increase the incidence of CTS [11]. Howev- Since acute CTS is unusual without trauma, investigating er, PMA seems to be associated with anomalies of the medi- the etiology by imaging modality is recommended. In the an nerve which consists of three forms: a normal median present case, using ultrasonography, we could diagnose nerve with an eccentric PMA, a bifid median nerve, and high CTS and find the occluded PMA as the cause simultane- division of the median nerve with an intermediate position ously and promptly. However, we could not acquire the ex- of the PMA whose occurrence percentages are 37.5%, act lesion of the compressed median nerve or the occluded 18.75%, and 43.7%, respectively [12]. It was reported that PMA because of the low resolution of ultrasonography. about 8% of PMAs reached the palm [12]. In some instances, With the aid of MRI, it was possible to obtain the exact the PMA participated in the formation of the superficial pal- anatomy of the patient’s wrist which might have had an mar arch supplying blood flow in hands [12]. PMA accom- anomaly. MRI also revealed the accurate lesion and the se- panying veins have also been reported [13]. verity of the median nerve compressed which helped us In our patient, PMAs were not associated with median decide on the management and predict the benefit from nerve anomalies. He had a normal right median nerve with surgical intervention. 3D CT angiography provided us the an eccentric PMA. We also found some vascular variants, in- information about variants of arteries and existence of col- cluding palmar collaterals extending from each PMA, two ac- lateral vessels which was also helpful for deciding manage- companying veins along with the right PMA, and high origi- ment. It would have been useful for surgery to reduce sur- nations of both radial arteries originated from both axillary gical and iatrogenic injuries. arteries. With these vascular variants, the fact that he was a In conclusion, when a patient who is suspected to have chassis worker who frequently used vibrating tools with hands acute CTS comes to clinic, despite low incidence of PMA, it might have promoted the formation of thrombus in the PMAs. is important to investigate the existence of PMA and make As we incidentally found that his symptoms were caused differential diagnosis. When a thrombosed PMA is found to by occluded PMA by ultrasonography, it was hard to get be the cause of CTS, if there are collateral vessels without impression about what the cause was before scanning with signs of ischemia, conservative therapy instead of surgery KSPS ultrasonography. Since CTS caused by occluded PMA is may be tried to treat the patient. rare, it seems that data about clinical features of CTS caused by occluded PMA distinguished from other causes CONFLICTS OF INTEREST are insufficient. In a case reported by Dahmam et al. [4], there was a change of temperature in hand, although this No potential conflict of interest relevant to this article was not found in our case or other cases [5,6]. This differ- was reported. ence may be dependent on the dominance of the median artery of the hand. Its sensitivity may be low because the AUTHOR CONTRIBUTIONS median artery usually shrinks. However, if a patient complaints CTS accompanying temperature or color changes Conceptualization: Sang Yoon Jeon. Data acquisition: in hand that may imply vascular disorder, occlusion of Sang Yoon Jeon. Formal analysis: Sang Yoon Jeon. Supervi- PMA might be considered as a possibility. sion: Weon-Joon Yang. Writing—original draft: Kwangmin www.anesth-pain-med.org 197 Anesth Pain Med Vol. 15 No. 2

Lee. Writing—review & editing: Kwangmin Lee, Sang Yoon 6. Srivastava A, Sharma P, Pillay S. Persistent median artery Jeon, Weon-Joon Yang. thrombosis: a rare cause of carpal tunnel syndrome. Australas J Ultrasound Med 2015; 18: 82-5. ORCID 7. Alfonso C, Jann S, Massa R, Torreggiani A. Diagnosis, treatment and follow-up of the carpal tunnel syndrome: a review. Neurol Sang Yoon Jeon, https://orcid.org/0000-0003-1251-1396 Sci 2010; 31: 243-52. Kwangmin Lee, https://orcid.org/0000-0003-4061-9740 8. Keith MW, Masear V, Chung K, Maupin K, Andary M, Amadio Weon-Joon Yang, https://orcid.org/0000-0001-6505-9490 PC, et al. Diagnosis of carpal tunnel syndrome. J Am Acad Or- thop Surg 2009; 17: 389-96. 9. Upton AR, McComas AJ. The double crush in nerve entrapment REFERENCES syndromes. Lancet 1973; 2: 359-62. 10. Seok JH, Lee JH, Sim KS, Ban JS, Lee JH, Kim EJ. Overlapped 1. Ibrahim I, Khan WS, Goddard N, Smitham P. Carpal tunnel syn- multiple distal entrapment neuropathies hindering diagnosis of drome: a review of the recent literature. Open Orthop J 2012; 6: thoracic outlet syndrome -a case report-. Anesth Pain Med 69-76. 2012; 7: 348-51. 2. Kopuz C, Baris S, Gulman B. A further morphological study of 11. Altinkaya N, Leblebici B. Prevalence of persistent median artery the persistent median artery in neonatal cadavers. Surg Radiol in carpal tunnel syndrome: sonographic assessment. Surg Ra- Anat 1997; 19: 403-6. diol Anat 2016; 38: 511-5. 3. Singla RK, Kaur N, Dhiraj GS. Prevalence of the persistant medi- 12. Gassner EM, Schocke M, Peer S, Schwabegger A, Jaschke W, an artery. J Clin Diagn Res 2012; 6: 1454-7. Bodner G. Persistent median artery in the carpal tunnel: color 4. Dahmam A, Matter-Parrat V, Manguila F, Giannikas D, Marin Doppler ultrasonographic findings. J Ultrasound Med 2002; 21: Braun F. Acute carpal tunnel syndrome due to a thrombosed 455-61. persistent median artery: unusual cause in athletes. J Trauma- 13. Feintisch AM, Ayyala HS, Datiashvili R. An anatomic variant of tol Sport 2015; 32: 126-8. persistent median artery in association with carpal tunnel syn- 5. Kele H, Verheggen R, Reimers CD. Carpal tunnel syndrome drome: case report and review of the literature. J Hand Surg caused by thrombosis of the median artery: the importance of Asian Pac Vol 2017; 22: 523-5. high-resolution ultrasonography for diagnosis. Case report. J Neurosurg 2002; 97: 471-3.

198 www.anesth-pain-med.org KSPS ------

, Orthopedic Orthopedic 3 2 1,5 Case Report Department of Anesthesiology 5 ]. 2 ]. The causes of peripheral neu of peripheral causes ]. The 5 , 4 , Seung Young Lee , Seung Young [ 1 , and Hwa-Yong Shin , and Hwa-Yong ]. The most significant symptom is weakness symptom significant most ]. The 4 4 [ , Je Jin Lee ]. 1 5 [ Although there have been many case reports on peroneal on peroneal reports case been many have there Although Peroneal neuropathy is the third most common focal focal common most third the is neuropathy Peroneal

relief relief cyst Baker’s by caused neuropathy peroneal neuropathy, of com a case we present Here, reported. been rarely has pain relief. If this conservative approach fails, surgical exci surgical fails, If this conservative approach relief. pain [ be considered could sion neuropathy of ankle dorsiflexion nerve direct injury, are infection, compression, ropathy Treat mellitus. diabetes like diseases, generalized and focused on symptomatic are neuropathy of peroneal ments

199 - - - - - , Hee Sung Kim 3 eISSN 2383-7977 • , Dong-Rim Kim In this case, we found the Baker’s cyst, the cause of the common peroneal peroneal common the of cause cyst, the Baker’s the found we In this case, Baker’s cysts are usually located in the posteromedial side of the knee and and knee the of side posteromedial in the located usually cysts are Baker’s Pathology, Chung-Ang University Hospital, Pathology, 1 4 ]. Baker’s ]. Baker’s 2 Osteoarthritis, knee; Peroneal neuropathies; Popliteal cyst; Ultrasonography. Popliteal neuropathies; Osteoarthritis, Peroneal knee; , 1 [ : We describe the rare case of a 57-year-old woman with a popliteal cyst who present cyst who a popliteal with woman a 57-year-old case of rare the describe : We ]. Baker’s cysts may cysts may ]. Baker’s 3 2nd Armored Brigade, Republic of Korea Army, Paju, Departments of of Departments Paju, Army, of Korea Republic Brigade, Armored 2nd Department of Anesthesiology and Pain Medicine, Chung-Ang University Hospital, Seoul, Medicine, Chung-Ang University and Pain Department of Anesthesiology [ Yong Bum Park Yong dysesthesia, and limping gait were relieved. Although her pain and dysesthesia were re were dysesthesia pain and her Although relieved. gait were limping and dysesthesia, gait. limping of because surgery the underwent she lieved, Conclusions: aspira and examination ultrasound simple by just it immediately treated and neuropathy, tion. Keywords: Surgery and Seoul, Korea Medicine, Chung-Ang University College of Medicine, and Pain Background: neuropathy. cause seldom Case with com diagnosed electronically was She leg. lower pain in her gait and ed with limping examination, On ultrasound pain clinic. our to transferred and neuropathy peroneal mon compress head, fibular the to extend to found cyst was popliteal sized cm 2.0 × 1.2 about a cyst and the of aspiration ultrasound-guided Therefore, nerve. peroneal common the ing pain, the procedure, the after Immediately performed. were block nerve peroneal common Ultrasound-guided treatment of common of common treatment Ultrasound-guided cyst: caused by Baker’s peroneal neuropathy a clinical note - - A case report Hana Cho 1 2 Anesth Pain Med 2020;15:199-204 Med Pain Anesth https://doi.org/10.17085/apm.2020.15.2.199 pISSN 1975-5171 ]. 3 , 1 [ June 5, 2019 5, 2019 June : July 3, 2019 3, 2019 : July July 2, 2019 2, 2019 July Complications include compartment syndrome, throm syndrome, compartment include Complications A popliteal cyst (Baker’s cyst) gener is a fluid-filled mass A popliteal cyst (Baker’s 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 permits which (http://creativecommons.org/licenses/by-nc/4.0) License Non-Commercial Attribution Commons Creative the of terms the under Access article is an Open This distributed cited. is properly work original the provided in any medium, reproduction and distribution, use, non-commercial unrestricted 2020 Anesthesiologists, Society of Korean © the Copyright bophlebitis, and entrapment neuropathy. Without neurop Without neuropathy. and entrapment bophlebitis, and is focused on is non-operative treatment initial athy, mon symptoms include swelling and pain, but many are are many but pain, and swelling include symptoms mon asymptomatic cysts are mainly caused by intra-articular pathologies such such pathologies intra-articular by caused mainly cysts are as osteoarthritis and meniscus tears Com and complications. with symptoms various present ated in the popliteal fossa. Baker’s cysts are commonly de commonly cysts are Baker’s fossa. in the popliteal ated within mostly velopedin the posterior aspectknee, the of bursa the gastrocnemio-semimembranosus Tel: 82-2-6299-3164 Tel: 82-2-6299-2585 Fax: [email protected] E-mail: Pain Medicine, Chung-Ang University University Chung-Ang Medicine, Pain Dongjak- Heukseok-ro, 102 Hospital, Korea 06973, Seoul gu, Corresponding author author Corresponding M.D., Ph.D. Shin, Hwa-Yong and Anesthesiology of Department Accepted Received Received Revised Anesth Pain Med Vol. 15 No. 2 mon peroneal neuropathy, which developed due to com- lone was prescribed for 3 days and electromyography on pression of an extraneural popliteal cyst, as well as a review her lower leg was planned. of the literature. Seventeen days after symptom onset, a motor nerve conduction study and needle electromyography (EMG) were CASE REPORT performed. The motor nerve conduction study showed no response of the left peroneal nerve contrary to the normal A 57-year-old woman visited the emergency room with findings in both the tibial and right peroneal nerves. A sen- left foot drop and mild pain, which had started suddenly 3 sory nerve conduction study of the left superficial and deep days prior. The pain severity was 3/10 on the visual analog peroneal nerve also showed no response (Table 1). scale (VAS) score. The patient had a medical history of dia- In the needle EMG results, abnormal spontaneous activ- betes mellitus for a year and hypertension. She had re- ities (positive sharp waves, fibrillation potentials) were received an operation of osteochondral autograft transfer on corded in the left tibialis anterior, peroneus longus, exten- her left knee 10 years ago. On physical examination, she sor halluces longus, and extensor digitorum brevis muscle, presented with a tingling sensation and numbness in her which are innervated by the common peroneal nerve. Mo- left lateral lower leg and foot dorsum, and was positive for tor unit action potential analysis and recruitment showed Tinel’s sign. The motor strength of ankle dorsiflexion and no activity in these muscles. A needle EMG of the other big toe extension were grade I, and the motor strength of muscles did not reveal any abnormalities (Table 2). hip flexion and hip abduction were grade IV. Upon a simple Considering the initial nerve conduction study and nee- radiological study of the left knee, severe osteoarthritis was dle EMG findings, left common peroneal neuropathy revealed. Findings were compatible with Kellgren-Law- around the knee level with severe partial axonotmesis or rence grade III. There were no other remarkable findings. severe conduction block was highly suspected. For further Common peroneal neuropathy was suspected; thus, ankle evaluation, magnetic resonance imaging (MRI) study of foot orthosis was applied and she was referred to the or- her left knee was planned. thopedic department. Meanwhile, the patient’s pain was getting worse; therefore, Seven days after symptom onset, she visited orthopedic 150 mg of pregabalin, 1,300 mg of acetaminophen, and 150 mg department. Under the same diagnosis, 10 mg of predniso- of tramadol were prescribed. One month after symptom

Table 1. Nerve Conduction Study Performed 17 Days after Symptom Onset Nerve Segment Distal latency (ms) Amplitude (mV) Conduction velocity (m/s) Motor nerve conduction study Rt. Tibial 4.38 15.7 46 Peroneal EDB 4.64 0.8 50.9 TA - 4 cm below FH 2.29 1.9 - TA - FH 2.97 1.7 59.1 TA - 6 cm above FH 3.96 1.6 60.6 Lt. Tibial 4.32 14.4 43.2 Peroneal EDB NR NR NR TA - 4 cm below FH NR NR NR TA - FH NR NR NR TA - 6 cm above FH NR NR NR Distal latency (ms) Peak latency (ms) Amplitude (μV) Sensory nerve conduction study Rt. Superficial peroneal 1.25 1.98 17.2 Deep peroneal 2.6 3.49 7.3 Sural 1.82 2.66 24.4 Lt. Superficial peroneal NR NR NR Deep peroneal NR NR NR Sural 1.61 2.24 25.6 EDB: extensor digitorum brevis, TA: tibialis anterior, FH: fibula head, NR: no response.

200 www.anesth-pain-med.org KSPS - - 201 C C C C C C C C C NA NA NA NA pattern Recruitment ). The aspirat ). The N N N N N N N N N NA NA NA NA PPP Fig. 2 Fig. ( N N N N N N N N N NA NA NA NA Dur Voluntary MUAP Voluntary N N N N N N N N N NA NA NA NA Amp 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Fasc 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 CRD An ultrasound image of the aspiration of the Baker’s cyst, Baker’s the of aspiration the of image An ultrasound 0 0 0 + + 0 0 0 0 0 0 0 + + 0 Fib Six weeks after symptom onset, MRI of her left knee was MRI of her left knee was onset, weeks symptom Six after Fig. 2. Fig. fibular the to extends and space popliteal the arises from which (dagger). head peroneal nerve performedperoneal were block with of volume a and mucinous thick, yellow, ed fluid was performed was 5 ml. Nerve block with 0.1875% ropivacaine nerve after Immediately triamcinolone. block, and 20 mg prescribed 50 mg We relieved. were and paresthesia pain tra of 150 mg of acetaminophen, 1,300 mg of pregabalin, for 3 weeks. of naproxen and 1,000 mg madol, Spontaneous activity Spontaneous 0 0 0 0 0 0 + + 0 0 + 0 0 + 0 PSW - - activity Insertional Insertional Inc. Inc. Inc. Inc. Peroneal neuropathy by Baker’s cyst by Baker’s neuropathy Peroneal L4-L5 L5-S1 maximus Gluteus medius Gluteus latas fascia Tensor medialis Vastus (long) femoris Biceps (short) femoris Biceps anterior Tibialis Extensor hallucis longus hallucis Extensor brevis digitorum Extensor hallucis Abductor Peroneus longus Peroneus (medial) Gastrocnemius posterior Tibialis Muscles Needle Electromyography Performed 17 Days after Symptom Onset Symptom after Days 17 Performed Electromyography Needle Ultrasound images of the Baker’s cyst. It follows the the cyst. It follows Baker’s the of images Ultrasound ). Thus, ultrasound-guided aspiration and common and common aspiration ultrasound-guided ). Thus, Upon ultrasound examination of her left knee, about 2.0 about of her left knee, examination ultrasound Upon Fig. 1 Fig. Lt. Lumbar paraspinal (both) paraspinal Lumbar × 1.2 cm sized popliteal cyst the to extend to found was www.anesth-pain-med.org Fig. 1.Fig. and space popliteal the arises from which route, uncommon femoral lateral to posterior (dagger) head fibular the to extends (asterisk). nerve peronaeal common the compressing condyle Table 2. Table fibular head, compressing the common peroneal nerve nerve the common peroneal compressing head, fibular ( was 8/10 compared to 3/10 on her first visit. visit. first 3/10 on her to compared 8/10 was onset, she was referred to our pain clinic. Physical exam Physical clinic. pain our to referred she was onset, the emer at visit her first as same the were findings ination score got her pain worse as the VAS gency room; however, fasciculation, Amp: amplitude, Dur: duration, PPP: polyphasic potentials, o: none, +: weakly positive, Inc.: increased, N: normal, C: complete, C: complete, N: normal, increased, Inc.: positive, +: weakly o: none, potentials, polyphasic PPP: duration, Dur: amplitude, Amp: fasciculation, activity. NA: no MUAP: motor unit action potential, PSW: positive sharp waves, Fib: fibrillation potentials, CRD: complex repetitive discharge, Fasc: Fasc: discharge, repetitive CRD: complex potentials, fibrillation Fib: waves, sharp positive PSW: potential, unit action motor MUAP: Anesth Pain Med Vol. 15 No. 2

Fig. 3. Axial proton density-weighted magnetic resonance Fig. 4. Axial proton density-weighted magnetic resonance imaging imaging with fat suppression of the knee. Cystic lesion (asterisk) with fat suppression of the knee. Increased signal intensity (arrow) compressing the common peroneal nerve (arrowhead) at the level in proximal anterior compartment of lower leg. of the fibular head (arrow).

Fig. 6. Pathologic findings of the cyst excised from the knee revealed synovial lining, and the diagnosis was Baker’s cyst (H&E, ×200).

Fig. 5. An ultrasound image of the aspiration of the Baker’s cyst at the second visit. fore, a second common peroneal nerve block were performed with 0.1875% ropivacaine and triamcinolone 20 mg performed (Fig. 3). Axial proton density-weighted MRI at her second visit to our pain clinic (Fig. 5). The motor with fat suppression of the knee showed that the cystic le- strength of ankle dorsiflexion and big toe extension were sion was compressing the common peroneal nerve at the grade II, even though the surgical removal of the perineu- level of the fibular head. In addition, there was an in- ral cyst was determined at the orthopedic department. creased signal intensity in the proximal anterior compart- Ten weeks after symptom onset, surgical excision of the ment of lower leg, which indicated denervation injury (Fig. cyst was performed and pathologic findings revealed that 4). The menisci showed a degenerative change without cyst was a Baker’s cyst (Fig. 6). Four months after surgery, tear, and bone and cartilage imaging showed findings com- she had no pain but the sensorimotor deficit remained. patible with severe osteoarthritis. Informed consent to publication are obtained from the Seven weeks after symptom onset, pain severity was 0/10 patient. on VAS score, but limping gait was still maintained. There-

202 www.anesth-pain-med.org KSPS ------]. 9 , 5 203 , ]. For ]. For 4 8 [ , 7 , 5 [ ]. If the examination ]. If the examination 2 [ ]. Peroneal neuropathy could present with diverse with diverse present could neuropathy ]. Peroneal 5 Like most other diseases, eliminating the cause is the best the is cause the eliminating diseases, other most Like In the present case, our patient suffered from foot drop, foot drop, from suffered patient our case, the present In , 4 tus. The treatment was rapid, so we thought the treatment the treatment so we thought rapid, was treatment The tus. slow was recovery the motor However, would be effective. surgery. so do we to planned expectation, We our than er the goal relief. of pain achieve to able least at were this aspect, In neuropathy. for common peroneal treatment diag applicable, and immediately is easily ultrasound since had been performed, the diagnosis would have made earli made been performed,had have would diagnosis the cysthe we that assumed location, Despite unusual the er. cyst of reasons. for a number would betic lesion Baker’s we find a of her left knee, examination ultrasound First, cyst This popliteal head. cystlarge the fibular to extend was we not exclude but could be to a ganglion, likely most was cyst. of the aspirat Second, the characteristics the Baker’s yel fluid, i.e., of the synovial as that the same ed fluid were history a medical she had Third, and mucinous. thick, low, melli diabetes and osteoarthritis, kneeof surgery, severe [ the nerve where on depending is affected, but symptoms sensory mostly are symptoms foot and drop loss of the injury location the identify we could this reason, includes assessment The based findings. on the clinical includedwhich a motor examinations, electrodiagnostic sensoryconduction study, needle and study, conduction is also as MRI helpful such studies Imaging EMG. placed the probe on the lateral side of her left kneeex of her side to lateral on the placed probe the and surprisingly and lesion amine the nerve pathway we cyst a huge Thus, head. found the left fibular near by compression was neuropathy of cause the that thought we aspirated compression, the relieve cystica To lesion. nerve; peroneal common the cystic the blocked and fluid the proce after reliefs experienced dramatic the patient score. Soon, 0/10 on the VAS severity to pain reduced dure. of the examination we missed the pathological was What of a poplite presentation the lateral fact, fluid. In aspirated al cystic be diagnosed rule to should a me lesion fast out cystniscal neoplasm and soft tissue Treatments differ from medication to surgery according to to surgery to medication according from differ Treatments symptoms. and causes examination, On and mild pain. the physical paresthesia, I on ankle dorsiflexion toe ex was and big grade the motor observed were sensation and tingling Numbness tension. nerveon the common peroneal territory. the electro Also, neu peroneal of common indicative was result diagnostic neu of common peroneal the cause find out To ropathy. We we performed examination. an ultrasound ropathy, ------– ]. 1 3 [ , 2 [ ]. Even Even ]. 2 , 1 [ Peroneal neuropathy by Baker’s cyst by Baker’s neuropathy Peroneal ]. If there is no neuropathological neuropathological no is there If ]. 3 , 2 ]. Peroneal neuropathy is associated is associated neuropathy ]. Peroneal DISCUSSION DISCUSSION 7 , 5 , 4 [ ]. Diagnosis is based on the patient’s past past is based on the patient’s ]. Diagnosis 2 ]. The deep peroneal nerve deep peroneal ]. The innervates sensory 5 , ]. Usually, Baker’s cyst presents with cyst asymptom an presents Baker’s ]. Usually, 4 [ 6 [ The common peroneal nerve arises from the sciatic nerve the sciatic common peroneal arisesThe from In our case, it was not easy to reveal the cause of neurop the cause reveal to not easy it was case, our In Distention of the popliteal bursa, such as the gastrocne such of the popliteal bursa, Distention ]. Baker’s cyst is usually connected to the knee joint by a a by kneejoint the cystto connected usually is Baker’s ]. www.anesth-pain-med.org ankle eversion ankle eversion nerve nerve as direct such damage, with causes, various nerve syndrome and metabolic traction, compression, tor control of toe extension and ankle dorsiflexion. and su The of toe extension control tor sensory nerveperficial of peroneal information provides of control motor has and calf, lateral and dorsum foot the nerve mo and has between and secondinformation the first toe, and travels along the medial border of the biceps femoris. femoris. biceps the of border medial the along travels and and it is divided of the fibula, the head around then turns It nerve peroneal superficial and deep peroneal the into nerve, which is formed from the L4-S4 ventral rami. This This rami. ventral the L4-S4 nerve, is formed which from of the popliteal fossa the upper angle nerve from originates for pain control and was scheduled to revisit there soon. soon. there scheduled and was revisit to control for pain our in treatment we surgical consider not did Therefore department. weakness. So we considered about surgical treatment. treatment. surgical about So we considered weakness. orthopedic surgery from only referred she was However, and EMG results without knowing the exact cause. Thus, Thus, the exact cause. without knowing and EMG results When she relief. symptom was the focus of the treatment motor had already she had clinic, pain our to came first cause Baker’s cyst is usually asymptomatic, her severe pain pain her severe cyst asymptomatic, is usually Baker’s cause difficult. diagnosis made have weakness could and muscle symptoms her based diagnosed just on initially was She athy due to the uncommon location of the Baker’s cyst, cyst, Baker’s the of location uncommon the to due athy Be of popliteal area. side on the lateral located was which workup such as MRI [ MRI as such workup is required conservative only treatment complication, partment syndrome, thrombophlebitis, and entrapment and entrapment thrombophlebitis, syndrome, partment [ neuropathy and imaging history,medical examination, pathological cysts sometimes present it can however, or mild pain; course atic com including complications, severe to with moderate tween the gastrocnemius and semimembranosus, there are are there and semimembranosus, tween the gastrocnemius of popliteal occurrence of the lateral reports a few case tra-articular diseases and inflammation, such as meniscus such diseasestra-articular inflammation, and osteoarthritis and arthritis, rheumatoid tears, of a popliteal cystlocation common the most be is though mio-semimembranosus bursa, is known as Baker’s cyst as Baker’s is known bursa, mio-semimembranosus 3 associated with is commonly and opening, in valvular Anesth Pain Med Vol. 15 No. 2 nosable, and a treatable device, it would be the best choice ORCID to examine common peroneal neuropathy and other types of peripheral neuropathy. Furthermore, it is cost effective. Hana Cho, https://orcid.org/0000-0002-9077-9972 In our case, using ultrasound, we easily found the Baker’s Dong-Rim Kim, https://orcid.org/0000-0001-6448-783X cyst at the level of the fibular head, which was causing the Je Jin Lee, https://orcid.org/0000-0002-9986-9026 neuropathy. If the diagnosis was faster, perfect recovery of Seung Young Lee, https://orcid.org/0000-0003-2734-1342 the nerve may have been achieved using only the ultra- Yong Bum Park, https://orcid.org/0000-0002-3741-2311 sound-guided procedure. It is a good idea to perform a Hee Sung Kim, https://orcid.org/0000-0002-8154-2391 minimal examination in consideration of the general loca- Hwa-Yong Shin, https://orcid.org/0000-0002-8721-3070 tion and condition of the lesion. We think performing ultrasound examination on peripheral neuropathy patients REFERENCES to examine various lesions could be a good option. Even if the ultrasound-guided procedure does not allow for per- 1. Herman AM, Marzo JM. Popliteal cysts: a current review. Ortho- fect recovery of the nerve, it could at least provide pain re- pedics 2014; 37: e678-84. lief and satisfaction to patients waiting for surgery or exam- 2. Frush TJ, Noyes FR. Baker’s cyst: diagnostic and surgical consid- ination, like that in our case. erations. Sports Health 2015; 7: 359-65. 3. Demange MK. Baker’s cyst. Rev Bras Ortop 2015; 46: 630-3. CONFLICTS OF INTEREST 4. Marciniak C. Fibular (peroneal) neuropathy: electrodiagnostic features and clinical correlates. Phys Med Rehabil Clin N Am No potential conflict of interest relevant to this article 2013; 24: 121-37. 5. Baima J, Krivickas L. Evaluation and treatment of peroneal neu- was reported. ropathy. Curr Rev Musculoskelet Med 2008; 1: 147-53. 6. Manik P, Vasudeva N. Unusual lateral presentation of popliteal AUTHOR CONTRIBUTIONS cyst: a case report. Nepal Med Coll J 2006; 8: 284-5. 7. Masakado Y, Kawakami M, Suzuki K, Abe L, Ota T, Kimura A. Conceptualization: Hwa-Yong Shin. Data acquisition: Clinical neurophysiology in the diagnosis of peroneal nerve pal- Hana Cho, Yong Bum Park, Hee Sung Kim. Formal analysis: sy. Keio J Med 2008; 57: 84-9. Hee Sung Kim. Funding: Hwa-Yong Shin. Supervision: 8. Ferraresi S, Garozzo D, Buffatti P. Common peroneal nerve inju- Hwa-Yong Shin. Writing—original draft: Hana Cho, Seung ries: results with one-stage nerve repair and tendon transfer. Young Lee. Writing—review & editing: Hana Cho, Dong- Neurosurg Rev 2003; 26: 175-9. Rim Kim, Je Jin Lee, Seung Young Lee. 9. Lee DI. New paradigm for the neuropathic pain. Korean J Pain 2004; 17: 99-103.

204 www.anesth-pain-med.org KSPS ------]. These ]. These 6 – 3

Streptococcus Streptococcus

Case Report Case Report Streptococcus constellatus

) which was masked by the simultaneous occurrence of of occurrence simultaneous by the masked was ) which We report a case of septic CST discovered after blood blood after of septic a case CST report discovered We and blurred vision. The study was approved by the Institu by approved was study The vision. and blurred Center Medical of the Presbyterian Board Review tional E2018-023). (no. life-threatening condition; therefore, prompt diagnosis and diagnosis prompt therefore, condition; life-threatening necessary. of CST and symptoms in are Signs treatment perioras such findings, ocular and headache, fever, clude [ and others ophthalmoplegia, bital swelling, those to similar of HZO. are and symptoms signs per were (MRI) imaging resonance magnetic and culture for hospital our to transferred who was formed on a patient headache, fever, continuous and had of HZO treatment 205 - - - - - ]. constellatus 2 [ eISSN 2383-7977 • Herpes zoster ophthalmicus (HZO) is an infectious disease that results from from results disease that is an infectious (HZO) ophthalmicus zoster Herpes CST may be obscured by HZO, prompt diagnosis and treatment is necessary treatment and diagnosis prompt by HZO, be obscured may CST subsp. constellatus Cavernous sinus thrombosis; Herpes zoster; Streptococcus constellatus; Trigemi constellatus; Streptococcus zoster; Herpes thrombosis; sinus Cavernous : We report a case of septic cavernous sinus thrombosis (caused by (caused thrombosis sinus cavernous septic report case of a : We Conclusions: case arrive. such when Keywords: ganglion. nal Case constellatus diagnosis. in delayed resulting in this patient, HZO Department of Anesthesiology and Pain Medicine, Presbyterian Medical Center, Jeonju, Medicine, Presbyterian Department of Anesthesiology and Pain Korea Background: trigeminal the of branch ophthalmic the in virus zoster varicella latent of reactivation the signs without as rash with or such symptoms zoster-like with herpes manifests HZO ganglia. ac condition a life-threatening is (CST) thrombosis sinus Cavernous involvement. ocular of nerves. cranial the eyes and the involving symptoms and by signs companied Herpes zoster in the ophthalmic branch of the branch the ophthalmic zoster in Herpes sinus obscuring cavernous trigeminal ganglia due to thrombosis subsp. - - A case report Lee, Joo Heo, Ki Man Kim, Han Gyeol Ji Hye Lee, Hyun Jung and Da Wa Seung Min Baek, Anesth Pain Med 2020;15:205-208 Med Pain Anesth https://doi.org/10.17085/apm.2020.15.2.205 pISSN 1975-5171 ], in which the varicella zoster the varicella zoster ], in which 1

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]. CST can be of two types. Septic Septic ]. CST be of two can types.

6 – 3 [ December 11, 2019 11, December October 14, 2019 14, October

December 5, 2019 December Cavernous sinus thrombosis (CST) of a is the formation thrombosis sinus Cavernous Herpes zoster is a common disease zoster approxi affecting Herpes 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 which (http://creativecommons.org/licenses/by-nc/4.0) License Non-Commercial Attribution Commons Creative the of terms the under Access article is an Open This distributed cited. is properly work original the provided in any medium, reproduction and distribution, use, non-commercial unrestricted 2020 Anesthesiologists, Society of Korean © the Copyright high mortality rate mortalityhigh rate aseptic CST is usu an infection whereas, CST by is caused CST is a surgery, or vascular. with associated ally trauma, blood clot in the cavernous sinus and is associated with a associated is and sinus cavernous the in bloodclot ophthalmicus (HZO). Signs and symptoms of HZO are sim are of HZO and symptoms Signs (HZO). ophthalmicus in with along herpes ocular to manifestations, ilar zoster and others poor pain, eye photophobia, vision, cluding virus(VZV) nervethe of ganglion reac is root dorsal the in (V1) in the ophthalmic appears that zoster Herpes tivated. herpes is called zoster ganglia of the trigeminal branch mately one in three people one in three mately E-mail: [email protected] [email protected] E-mail: Center, 365 Seowon- ro, Wansan-gu, Wansan-gu, ro, 365 Seowon- Center, Korea 54987, Jeonju 82-63-230-1593 Tel: 82-63-230-8919 Fax: Ji Hye Lee, M.D. Lee, Ji Hye and Anesthesiology of Department Medical Presbyterian Medicine, Pain Corresponding author author Corresponding Received Received Accepted Revised Revised Anesth Pain Med Vol. 15 No. 2

CASE REPORT because of 6th cranial nerve (abducens nerve) palsy. There was no evidence of infection in the facial region (except A 44-year-old man was brought to a primary care hospi- HZO), respiratory tract, urinary tract, or on the skin. Thus, tal with a rash and vesicle on the left side of his forehead the study focused on fever and cause of 6th cranial nerve since 3 days. Moreover, he had a headache since 6 days. palsy. Serologic tests for VZV (immunoglobulin M [IgM] and im- The white blood cell count was normal (10,100 mm3), munoglobulin G [IgG]) were conducted using the en- but the erythrocyte sedimentation rate (120 mm/h) and zyme-linked immunosorbent assay in the primary care C-reactive protein level (10.17 mg/dl) were elevated. Blood hospital. The patient tested positive for VZV IgG and IgM. culture was performed; however, the patient did not pro- He was diagnosed with HZO, and treated with antiviral vide consent for a cerebrospinal fluid (CSF) analysis. The drugs and analgesics. Before hospitalization, he had con- brain MRI revealed lateral bulging and irregular marginal tinuous fever (38°C and higher). After three days of hospi- enhancement in the cavernous sinus, which is consistent talization, the patient presented with worsening of left-sid- with bilateral CST and superior ophthalmic vein thrombo- ed frontal headache, nausea, blurred vision, and diplopia. sis (Fig. 1). He was transferred to our hospital for further evaluation We admitted the patient to the intensive care unit and and treatment. asked a neurologist and an infectious medicine doctor to The patient was alert but febrile (38.3°C) when he arrived assist with the treatment. Patient’s history was taken again at our hospital. There was no marked facial or periorbital and he was kept under observation during the course of swelling, except for the crust on his forehead. The cardio- the treatment. Although he had no medical history of dia- pulmonary and neurological findings were normal. His betes mellitus, hypertension, or etc., he did undergo dental heart rate, blood pressure, and respiratory rate were 78 treatment about 3 months ago and had experienced pain beats/min, 110/60 mmHg, and 20 breaths/min. An oph- in the left maxillary area approximately 1 month ago. Given thalmologist examined his eyes and the visual acuity was the dental history, high body temperature, and aggravated 6/12 bilaterally. There were no abnormalities in the ocular symptoms, we started his antibiotic treatment despite the tissues (cornea, conjunctiva, sclera, uvea, or retina) and no antiviral treatment that he had received at the primary care visual field defects. We suspected that his horizontal diplo- hospital. Second-generation cephalosporin was adminis- pia and lateral rectus muscle paresis in the left eye were tered until we received his blood culture results. Strepto-

A B

Fig. 1. Both superior ophthalmic veins presenting with engorgement and thrombus in the posterior region (A: axial, B: coronal view).

206 www.anesth-pain-med.org KSPS ------]. 7 [ 207 Streptococcus Streptococcus ]. In the current current the In ]. 5 , 3 [ ]. ]. 6 10 [ – , which belongs to the the to belongs , which 3 [ ]. Although the symptoms of the symptoms ]. Although 6 – 3 [ ]. The exact incidence rate of CST is exact incidence rate ]. The 4 [ constellatus subsp. subsp. ]. Septic CST occurs because of the infection ]. Septic CST of the infection occurs because 5 [ The signs and symptoms of HZO and CST are similar. In In similar. and CST are of HZO and symptoms signs The Cavernous sinus is connected to the dural venous sinus sinus venous is connected the dural to sinus Cavernous cordingly. per he had the treatment, after even However, our to transferred and was fever and high headache sistent did not patient The and stroke. rule to hospital meningitis out per was blood for a CSF culture but consent study, provide and CST confirmed was on formed fever, of high because been the have may treatment dental preceding The MRI. of CST in this patient. cause tions via the venous system. The incidence of CVST The is less system. the venous tions via 1% of all strokes than pregnancy, Infection, CVST. like it is rare but not known, and disorders, thrombophilic contraceptives, oral receiving CST risk. CST increased to is a contribute obesity could condition life-threatening in rela appear the symptoms vary,CST cases, most in may sinus, the cavernous near structures the anatomical tion to ve their because eyes, and orbit, nerves, cranial as such symptoms Typical sinus. is in the cavernous drainage nous photo periorbital edema, unilateral headache, of CST are of addition, involvement In eyeballs. and bulging phobia, or sensory in palsy nerve result nervethe cranial may inju ry, as sensory such and maxillary deficit of the ophthalmic nerve of the 5th cranial branches as transient such vasculopathy, cause can addition, HZO stroke and ischemic or hemorrhagic ischemic attacks nerve the trigeminal at occurred lesions skin patient, our In as seen of HZO, in cases the visit, before days three V1 site, diagnosed was patient The withalong and myalgia. fever ac treated and was in the primary hospital with HZO care activation of VZV, has no reported cases of CVST. Herpes Herpes CVST. of cases no reported has of VZV, activation myocardial and a risk for stroke factor however, is, zoster in increases stroke the incidence of Moreover, infarction. a history of HZO who have patients eth nasal, or indirect with direct skull in the midline of the be septic or CST may veins. sinus and sphenoidal moidal, surgery, hema trauma, of aseptic CST are aseptic. Causes in be idiopathic or it could malignancy, disorder, tological origin or sinuses, or sphenoidal the ethmoidal through spreading Septic system. the venous through or orbit ear, teeth, from aseptic CST common than CSTis more detected blood culture the patient’s study, constellatus part of the resi are in this group Streptococci milleri group. How tract. and the respiratory cavity of the oral flora dent infec and deep-seated suppurative cause they may ever, ------HZO with cavernous sinus thrombosis sinus cavernous with HZO ]. Herpes zoster pa zoster ]. Herpes was detected in the detected was the in 2 , 1 [ ]. Herpes zoster, that is re is that zoster, Herpes ]. 9 – 7 [ DISCUSSION ]. The ocular symptoms in HZO can be ex can HZO in symptoms ocular The ]. 2 , 1 [ The signs and symptoms of VZV and symptoms signs The primary infection, also Herpes zoster is frequently encountered in primary care encountered is frequently zoster Herpes www.anesth-pain-med.org primary infection accompanied with purpura fulminans. fulminans. primarywith purpura accompanied infection the VZV in adults and primary contrast, By infection is rare symptoms severe more has thrombosis, giant cell arteritis, and granulomatous aortitis. aortitis. and granulomatous cell arteritis, giant thrombosis, (CVST). thrombosis sinus venous CST is a type of cerebral with CVST VZVThe in pediatric patients reported is mostly which may manifest in the form of transient ischemic at ischemic form the transient in of manifest may which aneurysm, sinus stroke, ischemic or hemorrhagic tacks, trigeminal ganglion. ganglion. trigeminal vasculopathy, to attributed pox,known as chicken are motor palsy palsy motor of the ocular nerve the inflammation through plained by of VZV in the the reactivation by caused sinus cavernous ulcer in the cornea, uveitis, and acute retinal necrosis. In In necrosis. retinal and acute uveitis, ulcer in the cornea, of symptoms manifest may with HZO addition, patients optic nerve, and oculo edematous swelling, optic neuritis, including ptosis and swelling, injected appearance, pete injected appearance, swelling, and ptosis including and scarring keratitis in the conjunctiva, hemorrhage chial tion of vesicle and cluster of papules in the trigeminal trigeminal the in papules of and cluster tion of vesicle upper nerve on the forehead, located divisions dermatome occur, may Ocular manifestations and nose. eyes, eyelids, the virus reactivates, but like zoster sine herpete, the occa herpete, sine zoster like but the virus reactivates, with the presents HZO do not appear. lesions skin sional infection and the erup herpes of zoster symptoms general the development of a unilateral rash. A rash and a vesicle and a vesicle A rash rash. of a unilateral the development the nerve along appear where segment characteristically risks in about 1–4% throughout life 1–4% throughout risks in about ill influenza-like of symptoms systemic of complain tients prior to fever, and low-grade malaise, as fatigue, such ness, hospitals. The lifetime risk of herpes zoster is estimated to to lifetime risk is estimated The of herpes zoster hospitals. with in 20% of these appears cases, 30% and, HZO be about served during one year of follow-up since the patient was was served the patient since follow-up of during one year discharged. treatment in the intensive care unit, the symptoms im the symptoms unit, care in the intensive treatment trans being after discharged was the patient and proved, ob were complications No room. the general to ferred sings of infective endocarditis; however, it did not reveal it did not reveal of infective endocarditis;sings however, per was therapy Antithrombotic findings. special any of formed heparin. 7 days After with molecular weight low coccus constellatus subsp. constellatus coccus subsp. constellatus cephalosporin we switched from therefore bloodculture, detect to performed echocardiography We clindamycin. to Anesth Pain Med Vol. 15 No. 2

Herpes zoster-associated vasculopathy is treated with Seung Min Baek, https://orcid.org/0000-0003-0290-0208 antiviral agents. However, infectious CST is treated with Da Wa Jung, https://orcid.org/0000-0002-1566-7903 high-dose antibiotics. CST has a high mortality rate; therefore, prompt treatment is necessary. We started the treat- REFERENCES ment for CST immediately while continuing, the HZO treatment. HZO misdiagnosis may delay the diagnosis of CST because vasculopathy makes it difficult to differenti- 1. Ragozzino MW, Melton LJ 3rd, Kurland LT, Chu CP, Perry HO. ate the symptoms of CST and HZO. If high fever, severe Population-based study of herpes zoster and its sequelae. Med- headache, and eye symptoms are observed with HZO, the icine (Baltimore) 1982; 61: 310-6. patient history should be accurately evaluated to exclude 2. Johnson JL, Amzat R, Martin N. Herpes zoster ophthalmicus. CST by performing not only CSF analysis but also MRI, Prim Care 2015; 42: 285-303. blood culture, etc. 3. Coutinho JM. Cerebral venous thrombosis. J Thromb Haemost In conclusion, CST is a life-threatening condition and its 2015; 13 Suppl 1: S238-44. diagnosis may be obscured by HZO. Therefore, prompt di- 4. Einhäupl K, Stam J, Bousser MG, De Bruijn SF, Ferro JM, Marti- nelli I, et al.; European Federation of Neurological Societies. agnosis and treatment are necessary in such cases. EFNS guideline on the treatment of cerebral venous and sinus thrombosis in adult patients. Eur J Neurol 2010; 17: 1229-35. CONFLICTS OF INTEREST 5. Lai PF, Cusimano MD. The spectrum of cavernous sinus and orbital venous thrombosis: a case and a review. Skull Base Surg No potential conflict of interest relevant to this article 1996; 6: 53-9. was reported. 6. Weerasinghe D, Lueck CJ. Septic cavernous sinus thrombosis: case report and review of the literature. Neuroophthalmology AUTHOR CONTRIBUTIONS 2016; 40: 263-76. 7. Siddiqi SA, Nishat S, Kanwar D, Ali F, Azeemuddin M, Wasay M. Conceptualization: Ji Hye Lee, Hyun Joo Heo. Data ac- Cerebral venous sinus thrombosis: association with primary quisition: Ki Man Kim, Han Gyeol Lee, Seung Min Baek, Da varicella zoster virus infection. J Stroke Cerebrovasc Dis 2012; Wa Jung. Supervision: Ji Hye Lee. Writing—original draft: Ji 21: 917.e1-4. Hye Lee. Writing—review & editing: Ji Hye Lee, Hyun Joo 8. Paul G, Paul BS, Singh G. Unseen face of varicella-zoster infec- Heo. tion in adults. Indian J Crit Care Med 2016; 20: 731-4. 9. Khan R, Yasmeen A, Pandey AK, Al Saffar K, Narayanan SR. Ce- ORCID rebral venous thrombosis and acute pulmonary embolism following varicella infection. Eur J Case Rep Intern Med 2019; 6: Ji Hye Lee, https://orcid.org/0000-0003-3269-3844 001171. Hyun Joo Heo, https://orcid.org/0000-0003-2507-6629 10. Nagel MA, Jones D, Wyborny A. Varicella zoster virus vasculop- Ki Man Kim, https://orcid.org/0000-0002-4257-9167 athy: the expanding clinical spectrum and pathogenesis. J Neu- Han Gyeol Lee, https://orcid.org/0000-0001-7835-0172 roimmunol 2017; 308: 112-7.

208 www.anesth-pain-med.org KSRA ------

, 1 , 1 ]. 3 , 2 , Seong Su Lee 1 1 , Mi Young Kwon , Mi Young 1 Clinical Research Clinical , Go Eun Kim 2 , Ha Na Cho 1 , and Mi Jung Yun 1 From a clinical perspective, however, the effect of peri of effect the however, perspective, clinical a From them in primary afferent fibers such as suppression of ei as suppression fibersthem in primary such afferent of excit or the discharge of action potentials ther spread been [ reported have atory transmitters, 209 , Joon Woo Lee , Joon Woo , Ji Eun Kim 1 1 , Byung Uk Kim 1 The analgesic effect of perineural opioid in clinical practice are still controver are practice in clinical opioid perineural of effect analgesic The The analgesic effect of ropivacaine with fentanyl for continuous femoral nerve nerve femoral continuous for fentanyl with ropivacaine of effect analgesic The Anesthesia and analgesia; Femoral nerve; Fentanyl; Nerve block; Ropivacaine. block; Nerve Fentanyl; nerve; Femoral analgesia; and Anesthesia Fourty patients of ASA PS I or II receiving total knee arthroplasty with spinal anes arthroplasty knee with spinal total receiving PS II ASA I or of Fourty patients The pain visual analogue scale, incidences of side effects and satisfaction were not not were satisfaction and effects side of incidences scale, analogue pain visual The Department of Radiology, Seoul National University Bundang Hospital, Seongnam, Seongnam, Bundang Hospital, University National Department of Radiology, Seoul Department of Anesthesiology and Pain Medicine, National Medical Center, Seoul, Medicine, National Medical Department of Anesthesiology and Pain Korea 1 2 Shill Lee Son Min Seok Koo block after knee replacement arthroplasty was not superior to that of the ropivacaine alone. alone. ropivacaine the of that to superior arthroplasty not was replacement knee after block Keywords: 0.375% ropivacaine, 30 ml and an infusion of 0.2% ropivacaine at 8 ml/h (n = 20). Group Group 20). = (n ml/h 8 at ropivacaine 0.2% of infusion an and ml 30 ropivacaine, 0.375% of an infusion and as a bolus fentanyl with 50 μg of 29 ml added ropivacaine, RF; 0.375% infu anesthetic 8 ml/h (n = 20). Local at fentanyl 1 μg/ml of with mixed 0.2% ropivacaine 48 for continued and operation of started end the was at catheter nerve a femoral via sion were 0-1-10) mg/ml, (0.15 with hydromorphone analgesia patient-controlled Intravenous h. ana visual distribution, contrast tip and catheter of Position analgesics. adjuvant used for 48 h after for recorded were effects side consumption, hydromorphone pain, of scale logue noted. were received pain control the for satisfaction Patient operation. Results: op 48 h after at usage hydromorphone the (P > 0.05), but groups two the between different R (P = 0.047). Group in the RF than Group in the lower were eration Conclusions: Background: with fentanyl ropivacaine of effect analgesic compared trial controlled randomized This sial. ar knee total unilateral following block nerve femoral continuous for alone ropivacaine or throplasty. Methods: of injection R; bolus Group groups. two into allocated randomly and enlisted were thesia Analgesic effect of ropivacaine with fentanyl in with fentanyl of ropivacaine effect Analgesic for with ropivacaine alone comparison knee femoral nerve block after continuous arthroplasty: a prospective, replacement double-blinded study randomized, Gunn Hee Kim Anesth Pain Med 2020;15:209-216 Med Pain Anesth https://doi.org/10.17085/apm.2020.15.2.209 • eISSN 2383-7977 pISSN 1975-5171 ], and the peripheral action of action of ], and the peripheral 1 [ INTRODUCTION April 25, 2019 April July 15, 2019 15, July June 19, 2019 19, June The direct analgesic activity of the opioid drugs in the activity of the opioid drugs analgesic in the direct The 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 permits which (http://creativecommons.org/licenses/by-nc/4.0) License Non-Commercial Attribution Commons Creative the of terms the under Access article is an Open This distributed cited. is properly work original the provided in any medium, reproduction and distribution, use, non-commercial unrestricted 2020 Anesthesiologists, Society of Korean © the Copyright central nervous system central Fax: 82-2-2262-4766 82-2-2262-4766 Fax: [email protected] E-mail: Pain Medicine, National Medical Medical National Medicine, Pain Seoul Jung-gu, Eulji-ro, 245 Center, 04564, Korea 82-2-2260-7370 Tel: Corresponding author Corresponding M.D., Ph.D. Yun, Jung Mi and Anesthesiology of Department Received Received Revised Accepted Anesth Pain Med Vol. 15 No. 2 neural opioid are controversial. In a systematic qualitative quence (www.randomizer.org): ropivacaine (R) or ropiva- review [4], it was reported that the buprenorphine are reas- caine with fentanyl (RF) group. Anesthesiologists who did suring agent for use in extension of duration in peripheral not participate in the patient care and assessment of vari- nerve blocks of local anesthetic. Bazin et al. [5] reported ables generated random allocation table, enlisted partici- that the durations of analgesia provided by a composite of pants and assigned them to interventions. Suitable subjects lignocaine and bupivacaine, added with morphine, bu- were allocated to treatment in order of enrollment. For the prenorphine, or sufentanil, were prolonged in 80 patients double-blind assignment, a anesthesia nurse who did not after brachial plexus block for orthopedic surgery. know of the study prepared treatments and ensured them Kardash et al. [6], however, documented that the addi- with their treatment number concealed in envelop. The tion of 75 μg of fentanyl to mepivacaine had no significant study drug was offered to the anesthesiologist responsible effects on characteristics of supraclavicular blocks. The 1 for the patient care and administering the dose. μg/kg of fentanyl added to 0.75% ropivacaine did not pro- Description of both the visual analogue scale (VAS) of vide significant benefit in terms of onset time, condition pain and the use of the IV-PCA device was given to all pa- and duration of combined sciatic-femoral nerve block in tients before anesthesia. Patients were premedicated with patients receiving elective hallux valgus repair [7]. Until 1–2 mg of IV midazolam. On entrance in the operating now, most of the clinical studies were performed using a room, general monitoring including electrocardiography, single neural blockade. The analgesic effect of continuous automated oscillotonometry and pulse oximetry. Systolic perineural infusion of fentanyl added to local anesthetic and diastolic blood pressure and heart rate were recorded has not yet been fully clarified. every 5 min during the operation. All the patients were in- We investigated the analgesic effect of ropivacaine with fused with 6 ml/kg of crystalloid solution before beginning fentanyl in comparison with ropivacaine alone for a con- of the regional anesthesia. tinuous femoral nerve blockade following total knee ar- The femoral nerve catheter was inserted before the in- throplasty. duction of spinal anesthesia by one anesthesiologist experienced in these techniques who was blinded to the study. MATERIALS AND METHODS For the femoral nerve blockade, the patient was placed in supine position and a linear 6–13 MHz probe (SonoSite This prospective, double blinded, randomized controlled M-Turbo®, SonoSite Bothell, USA) was positioned both in a trial was conducted at one hospital between October 2015 transverse and longitudinal direction to the femoral crease and August 2016. Institutional Review Board of our hospi- at 2 cm below the inguinal crease and 2.0 cm lateral to the tal approved clinical protocol and informed consent docu- femoral artery. Once the femoral nerve was identified, the mentation (no. H-1507-056-001). Written informed con- probe was positioned in a longitudinal direction to the sents were acquired from all the patients. This clinical in- femoral nerve. Subsequently, a 22-gauge 50 mm insulated vestigation was registered at clinicalTrials.gov. needle (Stimuplex®, B. Braun, Germany) was inserted us- Patients who were planned to receive unilateral total ing the in-plane approach near the femoral nerve. A nerve knee replacement arthroplasty (TKA) under spinal anes- stimulator (Pajunk, Fisher & Paykel, New Zealand) was thesia were evaluated for their eligibility. Adult of Ameri- used to prove exact location of the femoral nerve. The can Society of Anesthesiologists physical status I–II were block needle was advanced cephalad toward the femoral enlisted in the study. nerve with an initial output of 1 mA (1 Hz) until quadriceps Patients who had contraindications to a regional anes- femoris muscle contractions and patella snap were ob- thetic technique (e.g., local infection, sepsis, coagulation tained. The position was then considered appropriate abnormality), allergy to local anesthetic or fentanyl, estab- when contractions of the quadriceps and patella snap are lished neurologic deficits in the lower extremities, and in- still elicited when the voltage is reduced to an output of 0.5 ability to know the pain scales or use intravenous pa- mA, but those responses are lost when the voltage is re- tient-controlled analgesia (IV-PCA) device were excluded duced to output of 0.3 mA as it can avoid intraneural place- from this study. ment. If the muscular twitch was stopped immediately fol- Patients were randomly assigned to one of two groups in lowing the administration of 1 ml of the study solution, the a 1 : 1 ratio using a computer-generated randomization se- needle location was regarded appropriate and the catheter

210 www.anesth-pain-med.org KSRA ------211 , Samsung Pharm. Pharm. , Samsung ® ]. The difference of mean VAS (0–100) (0–100) VAS of mean difference ]. The 5 [ Statistical analyses were carried out using the statistical statistical the carried using out were analyses Statistical The respiratory rate was monitored by the ward nurses nurses the ward by monitored was rate respiratory The not par a blind anesthesiologist by gathered was All data In the postanesthetic care unit, the patients were provid were patients the unit, care postanesthetic the In of with and degree 30 rest at both intensities pain The injection of 50 mg/ intramuscular received patients The of 15 at 10, 15 h after the operation, accepting an alpha er an alpha accepting the operation, 10, 15 h after of 15 at recruit were patients more Four and 90% power. of 0.05 ror up. of follow loss for the possible ed compensate to USA). Continuous Co., 25 (IBM SPSS Statistic IBM software normal following the t-test using analyzed were variables the using compared were variables Categorical test. ization ml of ketoprofen (TOPREN INJ 50 mg 50 INJ (TOPREN ml of ketoprofen with the IV-PCA. when discontented Korea) Ltd., Co., Ind. opera 12, 24, 48 h after at doses of ketoprofen salvage The side the end of operation, from tion, time for self-voiding urinary pruritus, re dizziness, vomiting, effects (nausea, urinary discomfort, chest tention, leakage) catheterization, (1–5: 1, very 2, score unsatisfied; satisfaction and patients’ very 5, 4, satisfied; were satisfied) 3, moderate; unsatisfied; as secondary measures. recorded outcome than less was rate If the respiratory every 4 h in all patients. in was doses of IV naloxone incremental 10 breath/min, via jected as needed administered 3 L/min was and oxygen cannula. a nasal and patient administration both in the anesthesia ticipated determined was based size on the result sample The care. study of a similar used group between the control operation 10, 15 h after at used anesthetic local alone and the group anesthetic local in patients Twenty 15, 20, respectively. plus opioid were difference needed VAS obtain a mean to were group each Korea) at a rate of 8 ml/h, which was continued into the the into continued was which 8 ml/h, of rate a at Korea) vol operation, for period Duration for 48 h. postoperative ume of infused noted. crystalloid were during operation Corp., AceMedical device(AutoMed3200, edwith IV-PCA a 0-1- mg/ml, (0.15 hydromorphone containing Korea), Ltd., PCA10). The a 1 ml of bolus to on de adjusted was system interval with no background and lockout a 10 min mand, was patient solution. The of the hydromorphone infusion 30 out is over VAS or her pain if his the button press to told 12, 24, (ml) at bolus use of IV-PCA cumulative of 100. The the from stored noted it was as was operation 36, 48 h after memoryelectronic of the PCA machine. (0 a VAS using evaluated flexionpassive of the knee were = and 100 no pain = operation 6, 24, 48 h after at worst pain) as a primary measures. outcome ------300 300 TM Femoral nerve block and fentanyl and block nerve Femoral , AceMedical Corp., Ltd., Ltd., Corp., , AceMedical ® ], at 8 ml/h for 48 h after operation) (n operation) after h 48 for ml/h 8 at ], = , Spinal 0.5% Heavy, 5 mg/ml, AstraZene 5 mg/ml, 0.5% Heavy, , Spinal 8 , ® 7 [ At the completion of the operation, 30 ml of a local anes local 30 ml of a of the operation, the completion At Patients received spinal anesthesia with bupiva of anesthesia 10 mg spinal received Patients Patients were allocated randomly to group R (bolus ad group to randomly allocated were Patients The distribution of contrast dye in the femoral sheeth sheeth in the femoral dye of contrast distribution The One blind radiologist who specialized in interventional in interventional specialized who One radiologist blind Three milliliters of contrast medium (Omnipaque of contrast milliliters Three = far possible location, unknown anatomic at loculated www.anesth-pain-med.org and were checked for loss of cold sense for loss and checked in the anterior and were as well weakness as for motor in all major medial thigh, quadriceps including femoris. muscles was inserted. For the confirmation of catheter function, 10 function, 10 of catheter the confirmation inserted.was For the injected dose was as a test through ml of 1% lidocaine blood patients for all in aspiration negative after catheter a 10-min period depending on the group allocation. The The allocation. a 10-min periodgroup on the depending start was catheter femoral via of 0.2% ropivacaine infusion an infusored using (AutoFuser surgeon. surgeon. over the FNB catheter injectedthetic solution was through caine (Marcaine caine performed All TKA one orthopedic Sweden). were by ca, during continuous femoral nerve femoral unilat (FNB) after block during continuous TKA.eral ml of fentanyl fentanyl of ml performed was study the postop assess to present 20). The effects and side of two regimens infusion analgesia erative after operation, n operation, after =RF (bolus dose of 0.375% 20) or group and 29 ml added with 50 μg [1 ml] of fentanyl, ropivacaine, added with 1 μg/ of 0.2% ropivacaine infusion a continuous ministration with 30 ml of 0.375% ropivacaine and a con with 30 ml of 0.375% ropivacaine ministration 8 ml/h for 48 h at with infusion a 0.2% ropivacaine tinuous from nerve sheath. nervefrom sheath. psoas muscle fascia, type 2 fascia, psoas muscle = under the ili spread external type 3 fascia, muscle acus = of the the roots near spread type 4 plexus, lumbar = nerve, type 5 femoral along spread were classified such as type 1 such classified were = under the spread internal to SI joint, cranial to hip joint, distal to L4-5 disc L4-5 type to level, distal joint, hip to cranial joint, SI to 3 = L4-5 disc to type level, 4 proximal proximal, = distal, type 5 hip joint, to distal = indetermined. eter tip position were as following; type 1 as following; tip position were eter = medial, be cranial promontory, and sacral joint (SI) tween sacroiliac disc L4-5 to type distal level, 2 hip joint, to = lateral lateral, radiology randomly interpreted and qualified the radio interpreted randomly radiology cath The decision. based his on region pelvic the of graphs the spot of the catheter tip and the diffusion of the contrast of the contrast diffusion and the tip the catheter the spot of confirmed fluoroscope. a C-arm media using were mg Inj., 10 ml, Iohexol 647 mg/ml, GE Health Care AS Ko Care GE Health 647 mg/ml, 10 ml, Iohexol Inj., mg and the catheter through administered were Korea) rea, Anesth Pain Med Vol. 15 No. 2 chi-square test (sex, American Society of Anesthesiologists The pain VAS were not significantly different between physical status score, satisfaction score) or the Fisher’s ex- the two groups (Table 2). The ropivacaine with fentanyl act test (side effects). A P value of < 0.05 was regarded sta- group showed significantly lower usage of hydromorphone tistically significant. at 48 h after the operation compared to the ropivacaine alone group (Table 2). The frequencies of ketoprofen injec- RESULTS tions, time to self voiding (Table 2), side effects and satisfaction of patients (Table 3) were similar between the two At the start, 44 patients were approached, 2 of whom did groups. not consent to be involved in the current study. The 42 pa- The type of catheter tip position (1–5) (3/11/2/4/0 vs. tients of remainder were enrolled and randomly allocated 3/10/3/4/0 for group R vs. RF, P = 0.970) and contrast dis- for the study. One patient per each group was dropped tribution (1–5) (4/4/0/5/7 vs. 3/3/1/3/10 for group R vs. RF, from the study due to leakage of local anesthetics through P = 0.678) were not different between the two groups. the catheter. The 40 patients finished the study and their data were statistically analyzed. DISCUSSION The patient characteristics and duration of surgery were similar in the two groups (Table 1). There were no statisti- The purpose of the current study was to examine if the cally significant differences between the two groups. additional fentanyl to ropivacaine for the continuous FNB

Table 1. Patient Characteristics Table 3. Side Effects and Satisfaction Score Variable Group R (n = 20) Group RF (n = 20) Group R Group RF Variable (n = 20) (n = 20) P value Age (yr) 69.1 ± 7.5 67.4 ± 6.4 Nausea 8 (40) 10 (50) 0.751 Sex (F/M) 20/0 18/2 Vomiting 3 (15) 4 (20) 1.000 Weight (kg) 59.3 ± 9.8 62.7 ± 7.44 Dizziness 1 (5) 3 (15) 0.605 Height (cm) 150.5 ± 5.6 152.2 ± 6.1 Pruritus 1 (5) 1 (5) 0.765 ± ± Operation time (min) 112.6 22.0 105.7 18.3 Urinary retention 10 (50) 13 (56) 0.523 Crystalloid (ml) 562.5 ± 153.7 702.5 ± 178.2 Foley catheter 9 (45) 11 (55) 1.000 ASA PS I/II 9/11 7/13 Chest discomfort 0 (0) 1 (5) 0.231 Values are presented as the mean ± SD or number of patients. Satisfaction score (1–5) 2.9 ± 0.8 3.3 ± 0.6 0.089 There was no statistically significant difference between groups in Values are presented as the number of patients (%) or mean ± SD. any parameter. R: ropivacaine, RF: ropivacaine + fentanyl, ASA PS: R: ropivacaine, RF: ropivacaine + fentanyl. American Society of Anesthesiologist physical status.

Table 2. Visual Analog Scale of Pain, Rescue Analgesics and Time to Self-voiding Variable Group R (n = 20) Group RF (n = 20) P value Pain VAS (resting) POP 6 h 43.1 ± 29.2 43.0 ± 20.3 0.990 POP 24 h 47.8 ± 25.2 42.7 ± 16.4 0.459 POP 48 h 42.1 ± 16.2 32.6 ± 16.4 0.079 Pain VAS (movement) POP 6 h 64.7 ± 27.7 64.9 ± 23.1 0.979 POP 24 h 74.3 ± 14.9 63.3 ± 22.9 0.090 POP 48 h 65.9 ± 18.1 54.5 ± 19.0 0.068 Hydromorphone (mg) POP 12 h 1.29 ± 1.08 0.70 ± 0.90 0.348 POP 24 h 2.00 ± 1.65 1.13 ± 1.40 0.264 POP 36 h 2.75 ± 2.24 1.40 ± 1.62 0.123 POP 48 h 3.52 ± 2.53 1.40 ± 1.74 0.047* Ketoprofen (yes/no) POP 12 h 3/17 1/19 0.605 POP 24 h 5/15 3/17 0.695 POP 48 h 6/14 4/16 0.537 Time to self-voiding (min) 778.2 ± 492.4 886.0 ± 472.8 0.840 Values are presented as the mean ± SD or number of patients. R: ropivacaine, RF: ropivacaine + fentanyl, VAS: visual analog scale (0–100), POP: postoperative. *P < 0.05.

212 www.anesth-pain-med.org KSRA ------]. 6 213 [ ]. So, the ]. So, 18 , 17 [ ]. Patients who who Patients ]. 15 ]. The authors re authors ]. The 19 [ ]. Furthermore, there have been reports that pre that been reports have there ]. Furthermore, 16 [ The administration of same drug into the various routes routes the various drug of same into administration The However, there are studies that failed to observe failedto that signifi studies are there However, exam study double-blinded randomized, A prospective, Twenty patients undergoing upper extremity surgery surgery extremity upper undergoing patients Twenty for axillary added lidocaine to effects of fentanyl The bra VAS measured was higher in comparison with that of our of our in comparison higher with was that measured VAS of the primary the result of these spite differences, In study. present the of that to similar was VAS, is that point, end of ad the importance of both route reflect may that study effect analgesic in inflammation of degree and ministration opioid. of perineural cant improvement of quality of analgesia when morphine morphine when analgesia of quality of improvement cant plexus for brachial approach injectedwas interscalene via block efficacy the clinical sented administration of the peripheral injection as intraarticular of morphine such horn would dorsal the spinal to of approximation degree anal of opiate not be for the determination factor the only Multiple with anesthetics. local gesic effect coadministered and degree of administration route dose, including factors effect of analgesic the to contribute may of inflammation opioid. peripheral ropivacaine to fentanyl effects of adding inedthe analgesic nerve patient-con femoral using block for continuous TKA for 24 h after analgesia trolled significant did not show fentanyl the additional ported that effect TKA. after of analgesic enhancement doses of The (100 μg as a bolus and and 3 μg/ml for infusion) fentanyl volume (0.75%) and infusion ropivacaine of concentration those used study. than in our higher much (10 ml/h) were so the baseline anesthesia, general received patients The with supraclavicular blocks were prospectively randomized randomized prospectively were blocks with supraclavicular anesthet added either local the to fentanyl 75 μg receive to 1.5% with epinephrine mepivacaine ic (30 ml or 5 μg/ml) An equivalent study. in a clinical intramuscularly given of the two in one given sites was saline normal of volume was VAS pain fashion. The in a double-blind as a control the pa in the operation h after 1 at only lower significantly anesthetic added local to fentanyl received who tients patients in 66 adult evaluated were block plexus chial surgery [ forearm and hand for planned for and 100 μg of fentanyl of lidocaine mixture received suc higher had nerve IV, and 2 ml of normal saline block of sensory rate cess in comparison blockade with the pa 2 ml of normal saline plus lidocaine given who were tients IV saline and 2 ml of normal μg of or 100 block for neural IV. fentanyl ------]. ]. 11 14 [ Femoral nerve block and fentanyl and block nerve Femoral ]. The authors local authors ]. The 13 [ ] anesthesia without sig ] anesthesia 10 [ ]. With the method of more the method of more ]. With 3 [ ] or lidocaine ] or lidocaine 9 ]. 12 [ For the interscalene brachial plexus block, the addition of 75 block, plexus brachial interscalene the For At the dorsal horn of the spinal cord, the impulse from from the impulse cord, horn of the spinal the dorsal At In separate areas of rhesus monkey spinal cord, the opi cord, spinal monkey of rhesus areas separate In The analgesic effect of epidural opioid seem to be related opioid seem be to related effect of epidural analgesic The The analgesic effect of epidural opioid added anes local to effect of epidural analgesic The The disagreement in the analgesic effect of peripheral effect of peripheral in the analgesic disagreement The www.anesth-pain-med.org the onset of sensory in comparison blockade and motor with used plus 1.5 ml 30 ml of 1.5% lidocaine that group the control of isotonic (n saline = study clinical 39) in a randomized troversial. troversial. (n lidocaine 1.5% of ml 30 to fentanyl of μg = speeded 41) up onal nerve block, intraarticular or wound infiltration, the the or wound infiltration, nerveonal intraarticular block, con effect are anesthetic of opioid added local to analgesic modification of nociception can take place at the peripher at place take of nociception can modification nerves al terminals of afferent ax peripheral as such opioid of administration peripheral peripheral nerve are modulated before it is transmitted it is transmitted nerve before peripheral modulated are with Along and response. perception evoke to centrally nervous intrinsic system, these in the central mechanisms ported a drop of it in this area following dorsal root trans root dorsal following of it in this area ported a drop section. ate receptor binding was measured measured was binding receptor ate horn and re the upper to dorsal binding ized the receptor high densities including the substantia gelatinosa of the the of gelatinosa substantia the including densities high cord spinal phy to make the distribution of opiate receptors visible. Sil visible. receptors the distribution of opiate make to phy are antagonist of opiate of the binding indicative grains ver with really of the brain areas in many localized separately brains, opiate receptor sites were labeled in vivo by a po by in vivo labeled were sites receptor opiate brains, autoradiogra by localized and it was antagonist opiate tent thoracic epidural infusion of bupivacaine and adrenaline [ and adrenaline of bupivacaine infusion epidural thoracic rat In cord. in spinal sites of receptor with the location dural ropivacaine [ ropivacaine dural (2 fentanyl additional The effects. side fentanyl-related nificant effect of a low-dose the analgesic improved μg/ml) markedly thetic has been proved through several clinical studies. The The studies. clinical several through been proved thetic has ex 1% ropivacaine (100 μg) and of fentanyl coadministration pedited of sensory the beginning during epi blocks and motor ripheral inflammation. inflammation. ripheral opioid added to local anesthetic seems to be related with with seems anesthetic opioid added be local to to related nerve of peripheral of approximation degree the dose, the existence horn and dorsal of pe the spinal to blocked phone usage at 48 h after operation were significantly low significantly were operation after 48 h at phone usage in comparison with the R group. er in the RF group would improve the analgesic effect of ropivacaine alone. alone. effect ropivacaine of the analgesic would improve in the group RF than in the group lower were VAS pain The hydromor The significantes. no statistical were there R but Anesth Pain Med Vol. 15 No. 2 such as perineural area or nerve terminal could possibly The position of catheter tip did not influence on the an- produce different efficacy: axonal receptors might be func- algesic effect as there was no intergroup difference. The tionally less efficient in pain modulation than receptors at position of the catheter tip was of type 2 (lateral; lateral to the nerve terminals, especially when considering the pos- the SI joint, cranial to the hip joint, and distal to the L4-5 sible influence of inflammatory condition in peripheral disc level; Fig. 1) in 11 (55%) patients of group R and in 10 area, as it is generally assumed that peripheral antinoci- (50%) patients of group RF. With respect to the distribution ceptive effects are mainly provided by an action on primary patterns of the contrast dye, the least were of type 3 (spread afferent neurones [2]. near the roots of the lumbar plexus; 0,5% in both groups), During inflammation, opioid agonists could approach and various other types were noted (Fig. 2; type 5). The more esasily to neuronal opioid receptors as the perineuri- Lower hydromorphone usage in the group RF than in the um is disrupted by the inflammation [20]. In sciatic nerve group R seemed to influence the similar incidences of opi- fibers, the axonal transport of opioid receptors was en- oid related side effects between the two groups. hanced a few days after the commencement of peripheral The patients’ satisfaction was not different between the inflammation. In the inflamed tissue, the number of opioid two groups (P = 0.089) and the reason for this result seems receptors on cutaneous nerve fibers increased but they to be that both the VAS score and the incidence of side ef- were abolished by ligating the sciatic nerve [21]. In the fects were similar between the two groups. The limitations present study, the results seem to be related with axonal of the FNB, that it reduces the pain mainly in the patient’s receptors of femoral nerve and noninflammatory condition anterior knee area and the high incidence of nausea in that is immediate postoperative and by the administration both groups (40% in Group R and 50% in Group RF) are of preoperative antibiotics. Although it is not possible to thought to have contributed to the mean satisfaction score strongly recommend the use of opioids for femoral nerve of below 4 in both groups. block, as the results of the present study showed that there Control group receiving the same dose of IV fentanyl was was no difference in the pain VAS score between the two not included in the current study. It has been reported that groups, it is possible to infer the mechanism of action of the mean serum fentanyl concentration after epidural infu- opioids. On the basis of the findings of the present study, sion of 1 μg/ml [8] or 2 μg/ml [11] were lower than the min- opioids are thought to exert an analgesic effect when ap- imum effective analgesic concentration for fentanyl in se- plied to the peripheral nerves that are close to the dorsal rum [11,22]. In the present study, the degree of degenera- horn of the spinal cord. In addition, the analgesic effect of tion or preoperative pain of the knee joint to be operated, opioids on the peripheral nerves with no inflammatory re- were not assessed. It was assumed that the postoperative sponse will be small. We believe that these suggestions imply the clinical implications for the present study.

Fig. 2. The distribution of contrast dye (type 5 = loculated at Fig. 1. The position of catheter tip (type 2 = lateral, lateral to unknown anatomic location, possible far from nerve sheath, open sacroiliac joint, cranial to hip joint, open arrow). arrow).

214 www.anesth-pain-med.org KSRA ------215 . Scand l 99: 1166-

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Cherng CH, Yang CP, Wong CS. Epidural fentanyl speeds the speedsthe fentanyl Epidural CS. Wong CP, Yang CH, Cherng Anesth Analg 2000; 91: 384-7 Analg Anesth an improve block plexus brachial the addition of morphine to surgery? shoulder after 1995; 75: 23-6 algesia Br J Anaesth con for pain and morphine/bupivacaine bupivacaine, phine, Anesthesiology 1992; 77: knee after videoarthroscopy. trol anesthesia. Anesth Analg 2005; 101: 1834-7 Analg Anesth anesthesia. set Reg of sensory anesthesia. lidocaine during epidural block 2001; 26: 523-6 Med Pain Anesth of bupivacaine, infusion in a low-dose analgesia epidural racic cross double-blind A randomized, and fentanyl. adrenaline Anaesthesio Acta with study and without fentanyl. over 2001; 45: 221-32. Sci U S A 1976; Acad Natl Proc brain. in rat localization graphic 73: 3729-33 root dorsal after distribution and changes cord: spinal mate 1976; 112: 407-12 Res section. Brain expedites the onset of sensory time supplement and Fentanyl Daru anesthesia. lidocaine in interscalene blocking motor 2010; 18: 298-302 the onset prolongs but analgesia improves A.Namiki Fentanyl mechanism. peripheral of axillary by block plexus brachial P. The addition of opioids to local anaesthetics in brachial brachial in anaesthetics local to opioids of addition The P. block:plexus buprenor effects morphine, of the comparative 1997; 52: 858-62 Anaesthesia phine and sufentanil. dou A randomized, block. on supraclavicular us fentanyl 20: 311-5 1995; Anesth Reg ble-blind study. nerve with block 0.75% ropiva sciatic-femoral al. Combined dose of fentanyl. inactive a systemically effects adding of caine: 2000; 17: 348-53 J Anaesthesiol Eur of levobupivacaine al. Efficacy, and pharmacokinetics safety, infusion epidural continuous after with and without fentanyl trial. Anesthesiology 2003; a multicenter in children: 74. onsetsensoryof ropivacaine during epidural blocks motor and Kardash K, SchoolsKardash A, plex of brachial Concepcion M. Effects Bazin JE, Massoni C, Bruelle P, Fenies V, Groslier D, Schoeffler D, Groslier V, Fenies C, Bruelle JE, Massoni P, Bazin Lerman J, Nolan J, Eyres R, Schily P M, Stoddart Eyres J, Nolan Lerman J, Magistris L, Casati A, Albertin A, Deni F, Danelli G, Borghi B, et Borghi G, Danelli L, A, Magistris Casati Albertin A, Deni F, Pert CB, Kuhar MJ, Snyder SH. Opiate receptor: Opiate SH. autoradio Snyder MJ, CB, Kuhar Pert Niemi G, Breivik H. Epidural fentanyl markedly improves tho improves markedly fentanyl H. Epidural Breivik G, Niemi Nishikawa K, Kanaya N, Nakayama M, Igarashi M, Tsunoda K, M, Tsunoda M, Igarashi Nakayama N, K, Kanaya Nishikawa Cherng CH, Wong CS, Ho ST. Epidural fentanyl speeds the on fentanyl Epidural ST. Ho CS, CH, Wong Cherng Khoury GF, Chen AC, Garland DE, Stein C. Intraarticular mor C. DE, AC, Chen Stein Intraarticular Garland Khoury GF, Lamotte C, Pert CB, Snyder SH. Opiate receptor binding in pri binding C, receptor Lamotte Opiate CB, SH. Snyder Pert Flory N, Van-Gessel E, Donald F, Hoffmeyer P, Gamulin Z. Does Gamulin P, Hoffmeyer E, F, Donald Van-Gessel Flory N, Moharari R, Sadeghi J, Khajavi M, Davari M, Mojtahedzadeh M. Mojtahedzadeh M, Davari M, Khajavi J, R, Sadeghi Moharari ...... 5 6 7 8. 9 16 17 10 11 12 13 14 15 - - - - . 7 9 7 Femoral nerve block and fentanyl and block nerve Femoral

ORCID

REFERENCES ol of pain in peripheral tissue by opioids. N N opioids. by tissue in peripheral ol of pain al mechanisms of opioid analgesia. Anesth Anesth analgesia. opioid of mechanisms al https://orcid.org/0000-0002-0014-829 https://orcid.org/0000-0002-7106-522 https://orcid.org/0000-0002-7223-631 CONFLICTS OF INTEREST OF INTEREST CONFLICTS AUTHOR CONTRIBUTIONS ey MA, Haskins SC, Cheng J, Liu SS. Local pe anesthetic Liu SS. ey MA, SC, Haskins J, Cheng Millan MJ. Multiple opioid systems and pain. Pain 1986; 27: 1986; 27: Pain and pain. opioid systems Multiple MJ. Millan Stein C. Peripher Stein Stein C. contr Stein The Kirks ripheral nerve block adjuvants for prolongation of analgesia: of a for prolongation nerveripheral adjuvants block PLoS One review. 2015; 10: e0137312 qualitative systematic Analg 1993; 76: 182-91. 1993; Analg 1995; 332: 1685-90. J Med Engl 303-47. Conceptualization: Mi Jung Yun. Data acquisition: Go Go acquisition: Data Yun. Jung Mi Conceptualization: No potential conflict of interest relevant to this article this article to relevant of interest conflict potential No In summary, ropivacaine with fentanyl (1 μg/ml) for the (1 μg/ml) with fentanyl summary,In ropivacaine 4. 3. 2. 2. 1. www.anesth-pain-med.org Ji Eun Kim, https://orcid.org/0000-0002-8265-1952 Kim, Eun Ji https://orcid.org/0000-0001-5838-4893 Yun, Jung Mi Ha Na Cho, https://orcid.org/0000-0002-9077-9972 https://orcid.org/0000-0002-9077-9972 Cho, Na Ha https://orcid.org/0000-0002-0667-9494 Kwon, Young Mi https://orcid.org/0000-0002-2012-9616 Seok Koo, Min Shill LeeShill Son, https://orcid.org/0000-0001-9738-3973 https://orcid.org/0000-0001-9152-2709 Kim, Uk Byung Joon Woo Lee, Lee, Woo Joon Go Kim, Eun https://orcid.org/0000-0003-1225-4617 Lee, Seong Su Gunn Hee Kim, Hee Gunn review & editing: Mi Jung Yun, Gunn Hee Kim. Hee Gunn Yun, Jung Mi & editing: review Na Cho. Formal analysis: Mi Jung Yun, Joon Woo Lee. Su Woo Joon Yun, analysis: Jung Formal Mi Cho. Na Writ Kim. Eun Ji Seok Koo, Min Kwo, pervision: Young Mi Writing— Yun. Jung draft:ing—original Mi Kim, Hee Gunn Eun Kim, Seong Su Lee, Shill Lee Son, Byung Uk Kim, Ha Ha Lee Kim, Lee, Shill Seong Uk Su Son, Byung Kim, Eun was reported. reported. was anesthetic seem warranted. seemanesthetic warranted. algesic effect after TKA in comparison with the ropivacaine effect TKA after algesic in comparison with the ropivacaine effect of various the analgesic about studies Further alone. opioids added of local to of administration doses and route pain would not much being influenced with them. influenced being with them. not much would pain an increased significantly provide not did FNB continuous Anesth Pain Med Vol. 15 No. 2

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216 www.anesth-pain-med.org General - - - - - ]. Specifically, stress stress ]. Specifically, 2 , 1 ]. Therefore, it is important to to it is important ]. Therefore, 2 [ Clinical Research Clinical

operative complications, greater demand for painkillers, painkillers, for demand greater complications, operative risk with of along increased stay, of hospital and extension mortality and morbidity patient and anxiety good for prognosis preoperative reduce and may be associated with abnormal hemodynamics as a with be hemodynamics associated abnormal and may varia autonomic or endocrine consequenceof changes the risks of anxiety levels of surgery, increase tion. Higher mortalityand morbidity including [ risk of post increased wound healing, delayed to lead can 217 - - eISSN 2383-7977 • Higher levels of anxiety increase the risks of surgery, including morbidity and and morbidity including surgery, of risks the anxiety increase of levels Higher It is important to remember that older patients with higher depression scores scores depression with higher patients older that remember It is important to Aged; Anxiety; Caregivers; Depression; Preoperative period. Preoperative Depression; Anxiety; Caregivers; Aged; We administered a questionnaire to older patients scheduled to undergo surgery surgery undergo to scheduled patients older to a questionnaire administered We There were 140 older patients and family protectors who participated in the study. study. in the participated who protectors family and patients older 140 were There tors (n = 114, 81.4%) indicated that they were anxious. Most of the older patients and their their and patients older the Most of anxious. were they that indicated 81.4%) (n = 114, tors and anesthesia, about knowledge insufficient had they that responded protectors family pain. postoperative and surgery, following awaken to failure about worried mostly were they sig were There scores. depression higher showed anxiety scores with higher patients Older family cohabitating of presence the on depending scores in depression differences nificant members. Conclusions: period. preoperative the anxiety during higher have Keywords: The majority of older patients (n = 114, 81.4%) undergoing surgery and their family protec family their and surgery undergoing 81.4%) 114, (n = patients older of majority The Background: the during depression anxiety and measure to were this study mortality. of objectives The patients older of concerns and knowledge of degree the identify to and period preoperative concerns. these of causes the and anesthesia, regarding protectors family their and Methods: for tools included questionnaire The surgery. the to prior day one protectors family their and Preoper Amsterdam the Scale, Analogue (Anxiety-Visual depression and anxiety quantifying Short and YZ Form, Korean Anxiety Inventory State-Trait Scale, Information and Anxiety ative using anxiety of causes concrete the about also asked We Scale). Depression Geriatric Form forms. pre-created Results: The question of preoperative anxiety and anxiety and of preoperative The question protectors in older patients and family depression Cho, Myoung-hun Kim, Oh, Kwangrae Sehun Lim, Younmi and Seunghee Ki Sungho Moon, University Inje Hospital, Paik Busan Medicine, Pain and Anesthesiology of Department Busan, Korea College of Medicine, Anesth Pain Med 2020;15:217-225 Med Pain Anesth https://doi.org/10.17085/apm.2020.15.2.217 pISSN 1975-5171 INTRODUCTION August 5, 2019 5, 2019 August October 23, 2019 23, 2019 October October 2, 2019 2, 2019 October Anxiety for patients undergoing surgery is a common surgery undergoing is a common Anxiety for patients 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 permits which (http://creativecommons.org/licenses/by-nc/4.0) License Non-Commercial Attribution Commons Creative the of terms the under Access article is an Open This distributed cited. is properly work original the provided in any medium, reproduction and distribution, use, non-commercial unrestricted 2020 Anesthesiologists, Society of Korean © the Copyright fragmentary information about anesthesia via the Internet the Internet via anesthesia about information fragmentary Excessive anxiety affect im can individuals. other or from of corticosteroids the release through mechanisms mune tions or vague anxiety about anesthesia, whether they have whether they have anxiety anesthesia, about tions or vague obtained or have a surgeon from information received emotional response. Many individuals have mispercep individuals have Many response. emotional Fax: 82-51-898-4216 82-51-898-4216 Fax: [email protected] E-mail: Inje University College of Medicine, 75 75 Medicine, of College University Inje Busan 47392, Busanjin-gu, Bokji-ro, Korea 82-51-890-6520 Tel: Seunghee Ki, M.D. Ki, Seunghee and Anesthesiology of Department Hospital, Busan Paik Medicine, Pain Corresponding author author Corresponding Revised Revised Accepted Received Received Anesth Pain Med Vol. 15 No. 2 comfort [3]. metrics in questionnaire questions: (Anxiety-Visual Ana- Degeneration of the autonomic nervous system occurs logue Scale [A-VAS], Amsterdam Preoperative Anxiety and gradually with aging, leading to gradual reduction in an in- Information Scale [APAIS], State-Trait Anxiety Inventory dividual’s ability to adapt [4]. In addition, the homeostatic Korean YZ Form [STAI-KYZ], Short Form Geriatric Depres- balance is more easily altered by exogenous stimuli [5]. sion Scale [SGDS]), F-test, and linear multiple regression. Older patients facing surgery may be more vulnerable to Based on these calculations, a sample size of 129 individu- this physiological response [6]. Anxiety may be caused by als was required in the study, and a total of 140 people were anesthesia, surgery, and recovery, among others [7]. De- selected, allowing for dropouts. Effect size and power re- pression is also a common problem in older patients, caus- ferred to the values suggested by Cohen. ing emotional suffering and increased mortality [8]. There- Surveys and interviews were conducted in the ward on fore, for an older patient undergoing surgery, anxiety and the day before surgery. After a brief explanation by the re- depression are issues that must be addressed together [9]. searcher, older patients and their family protectors were Early interventions to minimize preoperative anxiety and asked to complete the questionnaire. During the survey, the stress response may affect outcomes [1,8,10]. The pur- when an individual asked the researcher a question about poses of the present study were to measure anxiety and de- an item on the questionnaire, the explanation was repeat- pression during the preoperative period, and to identify the ed. Factors known to influence anxiety such as calmness, degree of knowledge and concerns of older patients and open attitude, and friendly atmosphere were kept the same their family protectors with respect to anesthesia, as well as for all older patients and their family protectors. It took the causes of these concerns. Ultimately, we provide relief about 15 min for the individuals to complete the questions. by providing information to patients and their family pro- Data regarding sociodemographic factors (age, sex, reli- tectors. gion, educational background, economic power, marital status, family number, cohabitation status) and medical MATERIALS AND METHODS history were obtained directly inquired from patients and their family protectors. Study design We used self-reported structured questionnaires (A-VAS, APAIS, STAI-KYZ, SGDS) and questionnaire developed for This cross-sectional study was reviewed and approved by this study. the institutional review board (no. 19-0033), and written The contents of the questionnaires for older patients and informed consent was obtained prior to the interviews. family protectors were different. The questionnaires for the Study subjects consisted of one set of older patients and older patients were composed of a total of 8 questions, and family protectors. The patients included were 65 years of those for their family protectors consisted of a total of 6 age or older; inpatients undergoing elective surgery under questions. The questionnaire used in the study is shown in general or regional anesthesia; and individuals who could Supplementary Material. Commonly used tools for older understand the study questionnaire. The exclusion criteria patients and their family protectors are the A-VAS and the were as follows: (1) individuals with difficulty completing APAIS. As additional tools for the older patients only, we the survey and interviews; and (2) patients taking pre- selected the anxiety state version of the STAI-KYZ and the scribed sedatives and antidepressants or anxiolytics. Fami- SGDS. We also asked the individuals about their specific ly protectors included in the study were in the same room knowledge of anesthesia (Cronbach’s a [reliability coeffi- as the patient when the questionnaire was administered. cient] was 0.7 and 0.6 for older patients and their family Relationships between older patients and their family pro- protectors, respectively) and the concrete causes of anxiety tectors included spouse, child, daughter-in-law, son-in- regarding anesthesia and surgery (Cronbach’s a 0.7 and 0.6 law, or sibling. When there were two or more possible fam- for older patients and their family protectors, respectively) ily protectors, we selected the first applicants among these using the survey questions we designed. individuals. To calculate the number of samples we used G*Power Anxiety measuring tools 3.1.9.2 with the alpha error set at 5% and power set at 95%, effect size at 15%, number of predictors at 4 (number of key The A-VAS is a scale graded with a score from 1 (slightly

218 www.anesth-pain-med.org General ------]. 15 , 219 8 [ shows shows ) and their ) and their Fig. 1 Fig.

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RESULTS RESULTS -test, P -test, = a statistical was 0.115). There Fig. 1B Fig. t 3.3 compared to 4.9 to 3.3 compared ± of the SGDS 0.6 in this study. was a None of the older patients or family protectors withdrew withdrew protectors or family of the older patients None pro their family and patients older the of Characteristics (n Older patients = protec 114, 81.4%) and their family anxiety (A-VAS, of the anxiety values mean score The Statistical analysis was performed using MedCalc Software Software performed was analysis MedCalc using Statistical between environmental of the relationship Assessment older patients are shown in shown are patients older of the the anxiety subscore between the A-VAS, correlation for assessing an an instrument and the STAI-KYZ, APAIS, of analysis correlation the of results specific anxiety.The as follows:anxiety tools were assessment between A-VAS (r of APAIS and anxiety subscore = 0.684, P < 0.001); be (r and STAI-KYZ =tween A-VAS 0.681, P < 0.001); between from the present study. Finally, 140 older patients and 140 140 older patients Finally, study. the present from study. participated in our protectors family in presented tectors are (n tors = ‘‘are the question, to yes 114, 81.4 %) answered 103 older pa them, Among anxious of surgery?’’. ahead you equally. replied protectors and family tients ( distribution of the patients the A-VAS ( protectors family in older of the A-VAS value and the mean is 5 points, A-VAS 4.5 was patients (paired protectors (r correlation linear positive moderate significant ly = 0.383, P of the older patients < 0.001) between the A-VAS protectors. and their family and patients of older and STAI-KYZ) of APAIS subscores (SGDS) score of and the depression protectors their family 15, and a score 15, and a score > with a of depression, is suggestive 5 points score ≥ depression of indicative always almost 10 points Cronbach’s Statistical analysis and Belgium) Software, (Medcalc 17.1 for Windows Version Inc., Software (Graphpad 8 Version Prism Software Graphpad USA). A P value < significant. statistically considered 0.05 was performed was and anxietyfactors using or depression or coefficient correlation (Pearson analysis correlation one-way and correlation) rank of coefficient Spearman’s used medium 0.15 of ef We of variance (ANOVA). analysis cor and analysis used commonly f2 fectin regression size analysis. relation ------]. of 14 a [ Preoperative anxiety in older patients in older anxiety Preoperative of the 4 questions (1st, (1st, of the 4 questions a of the APAIS used in this used in this of the APAIS a ]. 11 [ ]. Cronbach’s ]. Cronbach’s 13 , 12 [ The SGDS contains 15 questions that are answered “yes” or “yes” answered are SGDS The that questions 15 contains The STAI-KYZ contains 20 questions each for anxiety for anxiety each 20 questions contains STAI-KYZ The The APAIS consists of 6 questions using a five-point a five-point using 6 questions of consists APAIS The www.anesth-pain-med.org or negatively (‘am happy’). That is, the 1st, 5th, 7th, 11th, 13th 11th, 7th, 5th, the 1st, is, That happy’). (‘am or negatively and happy’) loaded (‘am of the SGDSquestions negatively are to 0 SGDSfrom the on Scores range bereverse-scored. must “no”. In scoring the SGDS, each item is scored 0 or 1 depending 0 or 1 depending is scored item scoring each the SGDS, In “no”. depressive’) (‘am positively upon is worded whether the item Depression measuring tool Cronbach’s α of the STAI-KYZ was 0.7 in the present study. study. 0.7 in the present was α of the STAI-KYZ Cronbach’s tients and 0.8 for their family protectors. Cronbach’s Cronbach’s protectors. family and 0.8 for their tients tectors. In the APAIS, Cronbach’s Cronbach’s the APAIS, In tectors. anxiety representing of the APAIS) 5th questions 2nd, 4th, and surgery anesthesia to pa older 0.8 for with was respect would like to know as much as possible about anesthesia anesthesia about as possible as much know to like would or surgery pro for their family and 0.9 0.9 for older patients was study significant anxiety state. A score with respect to desire for for desire to with respect A score anxiety state. significant an individual that means or more points of 8 information tions of the APAIS) and desire for information related to to related for information desire and tions of the APAIS) of the APAIS). 6th questions surgery (3rd, and anesthesia a indicates or more points of 11 anxiety subscore An APAIS Likert scale (1: never, 2: low, 3: moderate, 4: strong, 5: ex 5: strong, 4: moderate, 3: low, 2: never, Likert(1: scale 5th ques 2nd, 4th, and assesses (1st, anxiety state treme) anxious) to 10 (extremely anxious). Values of A-VAS around around of A-VAS anxious). Values anxious) 10 (extremely to of level meaningful for a clinically threshold a reliable 5 are anxiety preoperative cally significant symptoms of anxiety for older adults symptoms significant cally tively loaded and must be reverse-scored to reduce the ef reduce to be reverse-scored loaded and must tively of point A cutoff happy’). ‘am fects of acquiescence (e.g., been detect to suggested clini has 54–55 on the STAI-KYZ indicate greater anxiety (e.g., ‘tense’). On the other hand, On ‘tense’). the other hand, anxiety (e.g., greater indicate 11th, 10th, 8th, 5th, 2nd, (1st, questions 10 remaining the nega are of the STAI-KYZ) 20th questions 19th, 16th, 15th, 4th, 6th, 7th, 9th, 12th, 13th, 14th, 17th, 18th questions of of 18th questions 17th, 14th, 13th, 12th, 9th, 7th, 6th, 4th, scores higher that such in a way worded are the STAI-KYZ) questions rated on a 4-point scale (1: not at all, 2: some (1: not at scale a 4-point on rated questions 4: very in so) for anxiety much 3: moderately, state what, (3rd, of the 20, 10 questions Out in this study. the STAI-KYZ state and trait, respectively (with 40 questions in total). (with in total). 40 questions respectively and trait, state by state emotional a situational represents Anxiety state used only the 20 We and tension. of fear feelings subjective 0.8 for their family protectors. protectors. 0.8 for their family the 2 questions (3rd, 6th questions of the APAIS) represent of the APAIS) questions 6th (3rd, the 2 questions and patients older 0.8 for was the need ing information for Anesth Pain Med Vol. 15 No. 2

Table 1. Characteristics of Participants Variable Older patients (n = 140) Family protectors (n = 140) Age (yr) 73.3 ± 6.2 59.8 ± 13.8 Sex (M/F) 56 (40)/84 (60) 59 (42.1)/81 (57.9) ASA class (II/III) 114 (81.4)/26 (18.6) Anesthetic experience (yes/no) 97 (69.3)/43 (30.7) 77 (55)/63 (45) Scheduled anesthetic type (general/regional) 116 (82.9)/24 (17.1) Number of families 1 36 (25.7) 2 81 (57.9) 3 17 (12.1) 4 or more 6 (4.3) Religion With 52 (37.1) 60 (42.9) Without 88 (62.9) 80 (57.1) Level of education Elementary school 48 (34.3) 14 (10) Middle school 45 (32.1) 33 (23.6) High school 31 (22.1) 49 (35) College 6 (4.3) 43 (30.7) Illiteracy 10 (7.1) 1 (0.7) Economic condition Low 1 (0.7) 7 (5) Middle 138 (98.6) 130 (92.9) High 1 (0.7) 1 (2.1) Living together (yes/no) 65 (4.4)/75 (53.6) Relationship with patient Spouse 60 (42.9) Child 60 (42.9) Daughter-in law 8 (5.7) Son-in-law 2 (1.4) Sibling 10 (7.1) Values are presented as mean ± SD or number (%). ASA class: American Society of Anesthesiologists physical status classification, Number of family: number of family members containing patients (If 1, the patient lives alone), Living together: currently living with the patient.

A 30 B 30

20 20 Number Number 10 10

0 0 0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10 A-VAS A-VAS

Fig. 1. Distribution of A-VAS in older patients (A) and family protectors (B). A-VAS: anxiety visual analogue scale.

anxiety subscore of APAIS and STAI-KYZ (r = 0.659, P < STAI-KYZ were 54.2 ± 11.3 and 40.1 ± 9.4 for the patients 0.001) in older patients, and between A-VAS and anxiety who answered that they were anxious and not anxious, re- subscore of APAIS (r = 0.644, P < 0.001) in family protec- spectively, and there was a significant difference (P < tors. The mean APAIS anxiety subscores were 12.5 ± 5.1 0.001). More than half of the patients (n = 80, 57.1%) and and 12.9 ± 4.7, respectively, in older patients and their their family protectors (n = 72, 51.4%) answered that they family protectors. In this study, the mean values of the had insufficient knowledge about the anesthesia adminis-

220 www.anesth-pain-med.org General - - - 221 3.3 6.9 4.8 2.5 3.7 3.8 ± ± ± ± ± ± 4.9 6.3 9.9 9.4 19.3 19.3 12.9 Family protectors Family 72 (51.4) 3.3 7.5 5.1 2.8 3.9 4.0 12.2 3.9 ± ± ± ± ± ± ± ± 6.1 6.1 9.1 4.5 9.5 4.4 Family protectors, n (%) Family protectors, 19 (13.6) 51.6 51.6 18.6 18.6 12.5 ). Older patients Older 49 (35) The A-VAS, anxiety subscore of APAIS, and STAI-KYZ and STAI-KYZ of APAIS, anxiety subscore A-VAS, The Fig. 3 Fig. rience with anesthesia, scheduledrience type with anesthetic (general anesthesia, or American Society anesthesia), of or regional anesthesia the classified We class. status physical Anesthesiologists as “minor” the differenc operations or “major” evaluate to the type to of according scores es in anxiety and depression surgery of invasive definedless as was surgery. ‘‘Minor’’ (

Anxiety and Depression Score before the Surgery the before Score Depression Anxiety and Degree of knowledge about anesthesia of older patient and family protectors. The answer to the 4th question in the questionnaire, questionnaire, in the 4th question the to answer The protectors. family and patient older of anesthesia about knowledge of Degree According to the SGDS scores, there were three groups: 0–5 three were there the SGDS to scores, According Depression Anxiety www.anesth-pain-med.org in each group was 98 (70%), 22 (15.7%), and 20 (14.2%), re was group in each spectively. SGDS divided by group by STAI-KYZ) of APAIS, subscore points (normal), 6–9 points (suggestive of depression), 10–15 10–15 of depression), (suggestive 6–9 points (normal), points of patients and the number of depression), (indicative points anxious about the possibility of failure to awaken following following awaken to of failure the possibility anxious about ( in order pain, surgery, and postoperative –0.065, P = in older pa of APAIS) 0.444 for anxiety subscore a significant that found it was the interviews, After tients. were protectors and their family of older patients number garding anesthesia was not correlated with previous anes with previous not correlated was anesthesia garding historythesia (rho = 0.074, P = no influence 0.386) and had (rho on anxiety scores = –0.102, P rho == 0.232 for A-VAS, tered during surgerytered Fig. 2. Fig. the blue: idea.”, no “I have answered persons (%) of number the orange: surgery?”, during done anesthesia about know you do much “How it well.” “I know answered persons (%) of number the gray: a little.”, “I know answered persons (%) of number surgery in APAIS (range from 2 to 10 points), Surgery: the degree to be afraid or want to know about surgery in APAIS (range from 3 to 15 15 3 to from (range in APAIS surgery about know to want or be afraid to degree the Surgery: points), 10 2 to from (range in APAIS surgery Trait State STAI-KYZ: points), 15 3 to from (range in APAIS anesthesia about know to want or afraid be to degree the Anesthesia: points), points). 15 0 to from (range Scale Depression Geriatric Short SGDS: Form points), 80 to 20 from (range YZ Form Korean Anxiety Inventory Values are presented as mean ± SD. A-VAS: anxiety visual analogue scale, a ten graded score from 1 (slightly anxious) to 10 (extremely (extremely 10 to anxious) 1 (slightly from score graded a ten scale, analogue anxiety visual SD. A-VAS: ± as mean presented are Values degree Anxiety: the points), 30 to 6 from (range APAIS of score total scale, information anxiety preoperative Amsterdam APAIS: anxious), and anesthesia about know to want desire: Information 20 points), 4 to from (range in APAIS anesthesia and surgery about be uneasy to Table 2. Table Anesth Pain Med Vol. 15 No. 2

Table 3. Concerns Related to Anesthesia and Surgery Question Older patients Family protectors I am anxious about whether a life-threatening situation will arise for anesthesia. 2.9 ± 1.5 3.2 ± 1.4 I am worried that anesthesia will affect my intellectual ability. 2.3 ± 1.6 2.4 ± 1.5 I am worried about loss of memory after anesthesia. 2.4 ± 1.6 2.5 ± 1.5 I am worried about waking up during surgery or being insufficient anesthesia. 2.4 ± 1.6 0.6 ± 0.8 I am worried about the pain after surgery. 3.5 ± 1.5 3.8 ± 3.8 I'm worried that there is no way for illness after surgery. 3.2 ± 1.5 3.5 ± 1.5 I am worried about postoperative complications. 3.3 ± 1.5 3.6 ± 1.4 I am anxious about whether a life-threatening situation will arise for surgery. 3.2 ± 1.5 3.4 ± 1.5 I'm worried I will not wake up from anesthesia. 3.6 ± 1.5 3.9 ± 1.5 Values are presented as mean ± SD. The question item consists of a total of 9 sentences. It was scored by a five-point Likert scale (1: never, 2: low, 3: moderate, 4: strong, 5: extreme) and the scores range from 9 to 45 points.

Table 4. Mean of A-VAS, APAIS, and STAI-KYZ for Each Group Divided by SGDS Score SGDS score Assessment tool 0–5 ( n = 98) 6–9 (n = 22) > 10 (n = 20) A-VAS 4.0 ± 3.3 5.4 ± 2.9* 5.8 ± 3.2* APAIS Sum 17.5 ± 7.6 21.1 ± 6.7* 21.3 ± 6.2* Anxiety subscore 11.7 ± 5.2 14.3 ± 4.4* 14.5 ± 4.2* STAI-KYZ 49.6 ± 12.4 52.7 ± 9.4 60.5 ± 10.3* Values are presented as mean ± SD. A-VAS: anxiety visual analogue scale, APAIS: Amsterdam preoperative anxiety information scale, Sum: total score of APAIS (range from 6 to 30 points), Anxiety subscore: the degree to be uneasy about surgery and anesthesia in APAIS (range from 4 to 20 points), STAI-KYZ: State Trait Anxiety Inventory Korean YZ Form, SGDS: Short Form Geriatric Depression Scale. *P < 0.05 vs. the group with SGDS score 0–5, one-way analysis of variance.

A 10 B 20 C 80

15 60

5 10 40 A-VAS STAI-KYZ

5 20 Anxiety subscore of APAIS 0 0 0 0 5 10 15 0 5 10 15 0 5 10 15 SGDS SGDS SGDS

Fig. 3. Association between the SGDS score and the A-VAS (A), anxiety subscore of APAIS (B) or STAI-KYZ (C). (A) The red solid line represents linear regression of SGDS vs. A-VAS (A-VAS = 0.2469 × SGDS + 3.392, P < 0.001) and red dotted lines represent 95% confidence interval (CI). Green filled circles show distribution of A-VAS score. (B) The red solid line represents linear regression of SGDS vs. Anxiety subscore of APAIS (Anxiety subscore of APAIS = 0.3743 × SGDS + 10.88, P = 0.001) and red dotted lines represent 95% CI. Blue filled circles show distribution of Anxiety subscore of APAIS score. (C) The red solid line represents linear regression of SGDS vs. STAI- KYZ (STAI-KYZ = 1.178 × SGDS + 46.40, P < 0.001) and red dotted lines represent 95% CI. Grey filled circles show distribution of STAI- KYZ. SGDS: Short Form Geriatric Depression Scale, A-VAS: anxiety visual analogue scale, Anxiety subscore of APAIS: Anxiety subscore of Amsterdam preoperative anxiety information scale, STAI-KYZ: State Trait Anxiety Inventory Korean YZ Form. pedic surgery, diagnostic procedure, arthroscopies, lapa- surgery, brain surgery, spine or hip surgery). There were roscopies, inguinal hernia). Operations classified as ‘‘ma- no significant differences in the A-VAS, APAIS, STAI-KYZ, jor’’ were extensive operations with a high impact and long and SGDS scores of older patients according to major or duration (≥ 2 h) (cancer surgery, laryngectomy, cardiac minor surgery. In contrast, the A-VAS of family protectors

222 www.anesth-pain-med.org General ------223 ]. However, we ]. However, 22 [ ]. These results suggest that that suggest results ]. These 19 ]. The authors of the current study study of the current authors ]. The 21 , ]. The more educated individuals were individuals were educated more ]. The 20 23 [ [ ]. Contrary to expectations, however, religion was not not was religion however, ]. Contrary expectations, to 23 [ The present study revealed that older female patients patients older female that revealed study present The education with more patients that suggested Another study Most of the older patients and their family protectors protectors their family and older patients of the Most (SGDS) positive scores showed a significant Depression sire to know about anesthesia was greater than that in patients in patients that than greater was anesthesia about know to sire that anticipated elementary school. We from graduated who nervous would be more without religion the older patients religion. had those who period than preoperative the during support to this presump study a previous was there Indeed, tion in the present in anxiety scores withassociated difference any pression and anxiety are two common mental health con health two common mental and anxiety are pression [ older patients cerns among interventions to in attention greater pay to it is important during the in older patients both anxiety and depression period. preoperative There patients. older male than anxiety higher scores have the re corroborate that in the literature studies many are study of our sults patients the male in anxiety scores the low that believe their feel of a tendency reveal not easily to the results were experience of previous that reported study An earlier ings. of anxietysurgery the degree decreases experience anesthetic and anxiety lev previous that found of the participants many although not correlated, els were (n = experienced 97, 69.3%) had before. anesthesia anxious more are of anxiety. Howev in their expression be to active likely more with anxi of education no correlation study, in the present er, observed was pro and their family ety score in older patients de the college, from who graduated patients older In tectors. surveyed responded that they had not received enough enough not received theysurveyed had that responded prior anesthesia surgery. to older pa about In knowledge seen for sur was in the anxiety scores no difference tients, protectors family but gery in the APAIS, and anesthesia worried surgery more about anes than significantly were (n patients older Interestingly, thesia. = 18.6%) and 26, (n protectors their family = they that 26, 18.6%) responded surgery. might finding This before not anxious even were low, of surgery fear really was the individuals’ that indicate staff. of faith in the medical deal they placed a great or that patients. older in with anxiety scores correlation linear between 0 and 5 had scores withOlder depression patients those to with depression compared anxiety scores different with a de older patients other words, In 6 or higher. scores anxiety a higher score had of 6 or higher score pression 5. De than less score those to with a depression compared ------]. 18 [ Preoperative anxiety in older patients in older anxiety Preoperative 2.7). However, there were were there 2.7). However, ± 0.9) had a stronger desire to to desire stronger a 0.9) had ± DISCUSSION 4.6, while that of patients living with living a fam of patients 4.6, while that ]. High levels of preoperative anxiety are anxiety are preoperative of levels High ]. ± 17 , 3.6. ± 16 , 1 [ Our findings indicated the presence of a statistically sig of a statistically the presence indicated findings Our The aim of the current study was to investigate the de investigate to was study of the current aim The A significant difference in the desire for information in in information for in the desire difference A significant Anxiety scores (A-VAS, anxiety subscore of APAIS, STAI- of APAIS, anxiety subscore (A-VAS, Anxiety scores www.anesth-pain-med.org However, unlike our predictions, we did not find significant we did not find significant predictions, our unlike However, and their of older patients in the anxiety scores differences study. in the present protectors family porting the idea that family members feel members family anxiety porting during that the idea anxiety-state their STAI period and that the preoperative patients those of the surgical than higher are scores that the degree of anxiety of family protectors might be be might of anxiety protectors of family the degree that sup is research There of older patients. that than higher Most of the family protectors of older patients present present of older patients protectors of the family Most Based on during the interview spouses or children. were assumed authors our describedthe information above, nificant correlation (r (r correlation nificant = P 0.383, 70 years under- Supplementary data (survey questionnaire for older patients) going cardiac surgery. Am J Cardiol 2013; 111: 137-42. are available at https://doi.org/10.17085/apm.2020.15.2.217. 7. Celik F, Edipoglu IS. Evaluation of preoperative anxiety and fear of anesthesia using APAIS score. Eur J Med Res 2018; 23: CONFLICTS OF INTEREST 41. 8. Conradsson M, Rosendahl E, Littbrand H, Gustafson Y, Olofs- No potential conflict of interest relevant to this article son B, Lövheim H. Usefulness of the Geriatric Depression was reported. Scale 15-item version among very old people with and without cognitive impairment. Aging Ment Health 2013; 17: 638- AUTHOR CONTRIBUTIONS 45. 9. Takagi H, Ando T, Umemoto T. Perioperative depression or Conceptualization: Seunghee Ki. Data acquisition: Youn- anxiety and postoperative mortality in cardiac surgery: a sys- mi Oh, Sungho Moon, Kwangrae Cho, Myoung-hun Kim. tematic review and meta-analysis. Heart Vessels 2017; 32: 1458-68. Formal analysis: Seunghee Ki. Supervision: Sehun Lim.

224 www.anesth-pain-med.org General - - - - - 225 . rg CB. Anx rg . .

. . . . xen A,xen K, Engedal Hartbe Selbæk G, adults. Acta Anaesthesiol Scand 2001; 45: 298-307 Anaesthesiol Acta adults. 69: 763-7. 1989; Analg Anesth entity? predictable 1990; 45: 153-5 Anaesthesia Hospital, Sialkot. J Pak Med Assoc 2017; 67: 884-8 Med J Pak Sialkot. Hospital, Can anxiety: factors. detection and contributing Preoperative 1990; 37(4 Pt 1): 444-7 J Anaesth bers: characteris between family anxiety levels, relationship 1996; 16: 43-5 Nurs Surg Plast tics. associated are in older adults with depression iety symptoms with Geriatr 2018; 45: 180-9. Dement suicidality. Cogn Disord anxiety of anesthesia: fear and effect of Patient’s G. dopoulos experience anesthe of previous and education, age, gender, 104-8 2013; 27: J Anesth A surveysia. of 400 patients. 1999; ClinJ Psychiatry socialof anxiety disorder. management 9: 9-13 60 Suppl anxiety in for preoperative et al. Risk factors D, CW, Bandeira Weinstock LS. Gender differences in the presentation and and in the presentation Gender differences LS. Weinstock Badner NH, Nielson WR, Munk S, Kwiatkowska C, Gelb AW. C, Gelb AW. Kwiatkowska S, WR, Munk Nielson NH, Badner Caumo W, Schmidt AP, Schneider CN, Bergmann J, Iwamoto Iwamoto J, Bergmann Schneider CN, W, Schmidt AP, Caumo Mavridou P, Dimitriou V, Manataki A, E, Papa Arnaoutoglou Manataki Dimitriou V, P, Mavridou McCleane GJ, Cooper R. The nature of pre-operative anxiety. pre-operative of Cooper nature R. The GJ, McCleane Domar AD, Everett LL, Keller MG. Preoperative anxiety: is it a Preoperative LL, MG. Keller Everett AD, Domar Hinojosa RJ. Anxiety of elective surgical patients’ family mem family patients’ Anxiety elective surgical of RJ. Hinojosa Bakkane Bendi Bakkane ...... 23. 24 17 18 19. 20 21 22 ------. Preoperative anxiety in older patients in older anxiety Preoperative . . . . . cross-sectional study from Allama Iqbal Memorial Teaching Teaching Memorial Iqbal Allama from study cross-sectional 37-49 and emergency elective undergoing surgery: in patients al. Development and validation of a geriatric depression of a geriatric depression and validation al. Development 1982; 17: Res J Psychiatr report. a preliminary scale: screening ing mental disorders in geriatric patients. Int J Geriatr Psychi Int in geriatric patients. disorders mental ing atry 2005; 20: 629-34 tive observational study. Eur J Anaesthesiol 2013; 30: 758-63 J Anaesthesiol observational Eur tive study. in detect scale the state Anxiety (STAI): Inventory State-Trait Anesth Analg 1996; 82: 445-51 Analg Anesth a prospec rating: and clinical anxiety a questionnaire using 95 Scale (APAIS). Anxiety and Information Preoperative dam al. Validation of visual analogue scale for anxiety (VAS-A) in in anxiety for (VAS-A) scale analogue visual of Validation al. 2013; 79: 1389- Minerva Anestesiol evaluation. preanesthesia mation in relieving anxiety in oral surgery patients. Commu surgery anxietyoral in patients. in relieving mation 2004; 32: 227-35 Epidemiol Oral nity Dent Laufenberg-Feldmann R, Kappis B. Assessing preoperative preoperative B. Assessing R, Kappis Laufenberg-Feldmann Kvaal K, Ulstein I, Nordhus IH, Engedal K. The Spielberger K.Engedal IH, Spielberger The K, UlsteinNordhus I, Kvaal Yesavage JA, Brink TL, Rose TL, Lum O, Huang V, Adey M, et M, et Adey JA, V, Brink TL, Huang TL, Rose O, Lum Yesavage Facco E, Stellini E, Bacci C, Manani G, Pavan C, Cavallin F, et et F, C, Cavallin Pavan G, C, E, Bacci E, Stellini Manani Facco Moerman N, van Dam FS, Muller MJ, Oosting H. The Amster H. The Oosting MJ, Muller FS, Dam van N, Moerman Ng SK, Chau AW, Leung WK. The effect of pre-operative infor Leung WK. effect of pre-operative The SK, AW, Ng Chau Latif A, Shamsher Khan RM, Nawaz K. and anxiety Depression A,Latif RM, Nawaz Khan Shamsher ...... www.anesth-pain-med.org 16 15 14 13 12 11 10 Anesth Pain Med 2020;15:226-232 https://doi.org/10.17085/apm.2020.15.2.226 Clinical Research pISSN 1975-5171 • eISSN 2383-7977

Vocal cord paralysis following general anesthesia with endotracheal intubation: a clinical review on 43 cases

Sehun Lim, Dong-chun Kim, Kwangrae Cho, Myoung-hun Kim, Sungho Moon, Hakmoo Cho, and Seunghee Ki Received August 6, 2019 Revised October 28, 2019 Department of Anesthesiology and Pain Medicine, Busan Paik Hospital, Inje University Accepted October 28, 2019 College of Medicine, Busan, Korea

Background: Vocal cord paralysis (VCP) is one of the most stressful experiences for patients undergoing general anesthesia. Moreover, it is a risk factor for aspiration pneumonia and may increase morbidity and mortality. We examined several clinical features of the condition by reviewing the medical records of patients who experienced VCP following general anesthesia. Methods: We reviewed the medical records of 321 patients who consulted an otolaryngologist owing to hoarseness, sore throat, throat discomfort, or dysphagia after general anesthesia. Among these, we included in the present study 43 patients who were diagnosed with VCP by laryngoscopy, who did not have symptoms of suspected VCP before surgery, who had no past history of VCP, and for whom endotracheal intubation was not continued after surgery. Results: The mean age of patients with VCP was 51.28 years. With respect to surgical site, the most common was upper limb surgery, performed in 12 cases (9 cases were performed in sitting posture. With respect to surgical duration, only 11 cases lasted less than 3 h, Corresponding author whereas 32 cases required a surgical duration longer than 3 h. The most common symptom Seunghee Ki, M.D. of VCP was hoarseness. Nine of the patients with VCP recovered spontaneously, but VCP Department of Anesthesiology and persisted in 13 cases until the final follow-up examination. Pain Medicine, Busan Paik Hospital, Inje University College of Medicine, 75 Conclusions: We hope that this study might call attention to the occurrence of VCP following Bokji-ro, Busanjin-gu, Busan 47392, general anesthesia. Moreover, it is necessary to further evaluate the reasons for the higher Korea incidence of VCP in upper limb surgery performed in sitting posture. Tel: 82-51-890-6520 Fax: 82-51-898-4216 E-mail: [email protected] Keywords: Endotracheal intubation; General anesthesia; Vocal cord paralysis.

INTRODUCTION mortality [6–8]. VCP may be caused by neurogenic injury or by limitation Although vocal cord paralysis (VCP) is a rare complica- of vocal cord movement. Neurogenic injuries are usually tion associated with endotracheal intubation during sur- caused by damage to the vagal or recurrent laryngeal nerve gery [1–3], it could be a stressful experience for patients resulting from surgery or neoplastic infiltration [5,9,10]. following anesthesia [4,5]. Moreover, it is a risk factor for During surgery, the cuff pressure of the endotracheal tube aspiration pneumonia and could increase morbidity and may be related to nerve paralysis and neuropraxia [11].

226 General - - - - 227 , no. KCT0002717). KCT0002717). , no. RESULTS RESULTS (http://cris.nih.go.kr shows basic patient data. The number of surger number The data. patient basic shows Laryngoscopic views of vocal cord paralysis (VCP). (A) (VCP). (A) paralysis cord vocal of views Laryngoscopic B A This study protocol was reviewed and approved by the the by and approved reviewed was protocol study This 1 Table Fig. 1.Fig. VCP of are pictures VCP. Above VCP, (B) bilateral (right) Unilateral hospital. our at occurred who patients ation); and anesthetic factors (Cormack-Lehane grade, size size grade, (Cormack-Lehane factors and anesthetic ation); and tube, typeof endotracheal tube, of endotracheal used was for anesthesia). gas oxide whether nitrous 16-0249) and (no. hospital of our board review institutional infor research the clinical at registered was the protocol servicemation October 2007 to 2016 was ies performed January from to referred surgery, were patients 321 100,921. Following di 43 were an otolaryngologist. these Among 321 patients, VCP unilateral the 43 patients, Among agnosed with VCP. [55%] with left VCP and 18 pa in 40 (22 patients occurred ------]. It is also is also ]. It Vocal cord palsy after anesthesia after palsy cord Vocal 18 – ]. Carotid end ]. Carotid 16 [ 15 ]. 8 ]. Mechanical larynge ]. Mechanical ]. The most common common most The ]. 14 14 , – 12 [ 12 [ ]. The most common cause of VCP in the of VCP in the cause common most ]. The 13 , 8 , 5 [ MATERIALS AND METHODS MATERIALS ); (2) Patients who did not have symptoms of sus of symptoms have not did who Patients (2) ); Fig. 1 Fig. ( We reviewed the medical record of 321 patients who con of 321 patients record the medical reviewed We In the present study, we analyzed 43 cases of VCP 43 cases follow we analyzed study, the present In www.anesth-pain-med.org height, weight, body mass index, body mass weight, sur and comorbidities); height, of surgery, (type of surgery, factors gical surgical duration during the oper changed and whether the posture posture study). The analyzed factors were the following: otolaryn the following: were factors analyzed The study). con receive time to (symptoms, factors medical gological sex, (age, profiles patient recovery); and time to sultation, tained after surgery (for this reason, patients who under tained surgery after patients (for this reason, the current open-heartwent surgery from excluded were pected VCP before surgery; (3) Patients without a past his without past a surgery; pected VCP before Patients (3) tory in whom en of VCP prior the surgery; to (4) Patients not main was or ventilatory care intubation dotracheal criteria were as follows: (1) Patients diagnosed with VCP diagnosed with VCP as follows:criteria were (1) Patients laryngosco by or bilateral) unilateral (partial or complete, py general anesthesia from January 2007 to October 2016. October 2007 to 2016. January from anesthesia general diagnosed with postopera were 43 patients these, Among inclusion The study. VCP and includedtive current in the sulted an otolaryngologist owing to sore throat, throat dis throat throat, an otolaryngologist sulted sore to owing following change or voice in swallowing, comfort, difficulty period of 10 years to investigate the clinical features (symp features the clinical period investigate to of 10 years of VCP. and prognosis) progress, toms, ing general anesthesia that occurred in our hospital over a over hospital in our occurred that anesthesia general ing known that ischemic nerveknown that of the laryngeal damage nerve to VCP owing of postoperative be a cause may cords and vocal [ placement tube endotracheal prolonged placed in an improper position and maintained for an ex position and maintained placed in an improper carti arytenoid of tended period, and dislocation damage result cartilage may and cricothyroid lage al injuries such as dislocation and subluxation of the cricothe of subluxation and dislocation as such injuries al or cricoarytenoid endotra occur after can joints thyroid is tube if the endotracheal addition, In intubation. cheal absence of iatrogenic nerve injury of iatrogenic absence damage is mechanical intubation endotracheal from vical spine decompression, open-heart surgery, decompression, spine vical and tho postopera cause to also been revealed surgeryracic have VCP tive cause of postoperative VCP is iatrogenic recurrent larynge recurrent VCP is iatrogenic of postoperative cause al nerve surgery [ injury thyroid following artery, of the carotid for stenosis cer anterior arterectomy Mechanical fixation of the vocal cords might result from from result might cords of the vocal fixation Mechanical glot of the arytenoid or inflammation edema dislocation, invasion neoplastic or tis, Anesth Pain Med Vol. 15 No. 2 tients [45%] with right VCP), and bilateral VCP occurred in to 11 h (Fig. 2). VCP occurred in 11 patients (25.6%) whose 3 patients. All patients with bilateral VCP underwent total operation time was less than 3 h, in 22 patients (51.2%) thyroidectomy with lymph node dissection, and one un- whose operation time was between 3 h and 6 h, and in 10 derwent nasotracheal intubation owing to difficulty in patients (23.3%) whose operation time was 6 h or more. breathing 1 day after surgery. The number of patients with Cormack-Lehane grade 3 was 5. The types of surgery and characteristics of VCP are In two of these patients, we failed to perform intubation with a shown in Table 2. The most common type of surgery pre- laryngoscope blade and reattempted the intubation using a fi- ceding VCP was upper limb surgery including the clavicle (n = 12, 27.9%). The next most common types of surgery were cervical spine surgery (n = 8, 18.6%) and abdominal Table 2. The Types of Surgery and Characteristics of VCP surgery (n = 8, 18.6%). Thoracic surgery (n = 6, 14.0%) and thyroid surgery (n = 5, 11.6%) were next in frequency. Ta- Unilateral (n = 40) Bilateral Surgery (n = 3) ble 3 depicts the most common positions of patients during Right (n = 18) Left (n = 22) surgery. Nine of the 10 patients who underwent surgery in Brain 1 3 Neck sitting position received orthopedic upper limb surgery Cervical spine (anterior 6 2 and 1 underwent laparoscopic cholecystectomy. approach) The surgical procedures varied in duration from 65 min Total thyroidectomy 1 3 Right parathyroidecto- 1 my Thorax Table 1. Basic Data of Patients Esophageal cancer 1 Variable VCP (n = 43) Right Mediastinal 1 mass Age (yr) 51.3 ± 14.9 Left Mediastinal mass 1 20s 3 (7.0) Left pneumothorax 1 30s 7 (16.3) Left pneumonectomy 1 40s 6 (14.0) Thoracic spine (poste- 1 50s 13 (30.2) rior approach) 60s 10 (23.3) Upper limbs 70s 4 (9.3) Right clavicle 3 Gender Left clavicle 1 Female 18 (41.9) Right upper arm 3 Male 25 (58.1) Left upper arm 3 1 ± Weight (kg) 64.6 12.7 Right lower arm 1 ± Height (cm) 166.3 9.0 Abdomen 2 ± BMI (kg/m ) 23.4 3.3 Laparoscopic surgery 1 BMI < 18.5 2 (4.7) Open surgery 4 3 18.5 ≤ BMI < 23 18 (41.9) Values are presented as number. VCP: vocal cord paralysis, 23 ≤ BMI < 25 10 (23.3) Unilateral: one-sided VCP, Bilateral: both sides VCP, Right: right 25 ≤ BMI < 30 10 (23.3) 30 ≤ BMI < 40 1 (2.3) Unmeasured 2 (4.7) Comorbidity Table 3. Main Position during Surgery and Characteristics of VCP Hypertension 5 (11.6) Unilateral (n = 40) Bilateral Diabetes mellitus 6 (14.0) Position Right (n = 18) Left (n = 22) (n = 3) CVA 0 (0.0) Supine 11 8 3 Cardiovascular 1 (2.3) Prone 1 Values are presented as mean ± SD or number (%). VCP: vocal Right lateral 2 3 cord paralysis, BMI: body mass index (kg/m2), Classification of BMI Left lateral 2 1 according to Korean Society for the Study of Obesity; Underweight: BMI < 18.5, Normal: 18.5 ≤ BMI < 23, Overweight: 23 ≤ BMI < Sitting 2 8 25, Mild obesity: 25 ≤ BMI < 30, Severe obesity: 30 ≤ BMI < 40, Trandelenburg 1 1 Unmeasured: two patients were missing weight data, Comorbidity: Values are presented as number. VCP: vocal cord paralysis, patient accompanying the disease, CVA: cerebrovascular accident, Position: the main posture during the operation, Supine: including Cardiovascular: cardiovascular disease. supine with lithotomy, Sitting: including reverse trandelenburg.

228 www.anesth-pain-med.org General - 229 Dyspnea . Fifteen patients patients . Fifteen Dysphagia Fig. 4 Fig.

15 (34.9) in throat Discomfort 9 (20.9) Patient, n (%) Sore throat 13 (30.2) 6 (14.0) Hoarseness Distribution of vocal cord paralysis (VCP) patients by by (VCP) patients paralysis cord vocal of Distribution Symptoms complained by vocal cord paralysis patients. patients. paralysis cord by vocal complained Symptoms

30 20 10 40 Patient (n) Patient The course of VCP course is shown in The Fig. 4. Fig. follow- have not did who patients Grey: progress. and prognosis once, only examination otolaryngology seeing after observation up had patients Blue: spontaneously, recovered patients Green: VCP until had patients Orange: injection, cord with vocal treatment examination. laryngoscopic last the Fig. 3. Fig. in duplicate. counted were symptoms complaining The time required for patients to see to an otolaryngologist for patients after time required surgery 13 days. was Otolaryngol the to visit a single after follow-up to lost were spontaneously recovered patients Nine ogy Department. VCP), (with laryngoscopic from of recovery confirmation change. of voice symptoms 3 experiencedbut continuing between VCP varied 20 to from from recover time to The vocal received patients Six 58 days). (average: 113 days report to 2 of these continued but injection therapy, cord to continued Thirteen patients treatment. after symptoms experience laryngoscopic the last VCP until examination of VCP last the to occurrence period(the longest from within 2–6 improved while symptoms 449 days), exam was 11 . 10 Vocal cord palsy after anesthesia after palsy cord Vocal Table 4 Table

5 (11.6) 5 (11.6) 0 (0.0) 5 (11.6) 4 (9.3) 1 (2.3) 1 (2.3) VCP (n = 43) 21 (48.8) 21 19 (44.2) 19 13 (30.2) 13 23 (53.5) 22 (51.2) 38 (88.4) Operation time (h) ). The number of patients who reported reported who patients of number The ). Fig. 3 Fig. ( Factor 23456789 Distribution of VCP Patients by Factors associated with with associated by Factors Patients VCP of Distribution Distribution of vocal cord paralysis patients by operation by operation patients paralysis cord vocal of Distribution

0 5

10 15 Patient (n) Patient SLT ID 7.0 mm 7.0 ID SLT 6.5 mm ID SLT DLT 37 fr 37 DLT 35 fr DLT mm 7.5 ID SLT The most frequent symptom of patients with VCP was withVCP was of patients symptom frequent most The Nitro Yes No 2 3 4 grade Cormack 1

SLT DLT ETT of Size Type of ETT of Type www.anesth-pain-med.org of endotracheal tube used for intubation, ID: Inner diameter, diameter, Inner ID: intubation, for used tube endotracheal of missing were patients 10 grade, Cormack-Lehane grade: Cormack gas was oxide nitro whether Nitro: data, grade Cormack-Lehane anesthesia. general used during Values are presented as number (%). VCP: patient diagnosed diagnosed (%). VCP: patient as number presented are Values ETT: of types endotracheal of Type paralysis, cord with vocal endotracheal cuffed lumen single SLT: intubation, used for tubes ETT: of size Size tube, endotracheal lumen double DLT: tube, Anesthesia Table 4. Table Fig. 2. Fig. n” = time “operation operation, of length time: Operation time. less ‘n’ and than more is ‘n – 1’ h or operation of length that means < 3 h). time 3: 2 h ≤ operation (e.g., hoarseness hoarseness without discomfort, any or dyspnea throat throat, sore only average The respectively. 6, 2, and 1, were other symptoms beroptic bronchoscope. The types and sizes of endotracheal types of endotracheal and sizes The bronchoscope. beroptic in shown are gas oxide of nitrous and usage tubes Anesth Pain Med Vol. 15 No. 2 months in 4 of the patients. Additionally, one patient con- also occurs in head and neck surgery, thoracic surgery, tinued to report symptoms (voice change and throat dis- cervical spine surgery, and open-heart surgery [5,8,13]. comfort) for more than 3 years, regardless of recovery from However, in our study, the most common surgery associat- VCP. ed with VCP was upper limb surgery including the clavicle (12/43 patients, 27.9%). While upper limb surgery includ- DISCUSSION ing the clavicle constituted 27.9% of all VCP cases in the present study, the proportion occupied by thyroid and In this study, among 100,941 cases of general anesthesia, 43 parathyroid surgery was only 11.6% (5/43 patients). This patients experienced postoperative VCP (the incidence was finding seems to be the result of the decrease in iatrogenic 0.043%). Risk factors for VCP included long operation time, nerve injury owing to developments in surgical techniques sitting posture during surgery, and whether the posture and nerve monitoring devices in thyroid surgery. In the changed during surgery. above 5 patients, no device for monitoring laryngeal nerve A previous study by Kikura et al. [8], which investigated damage was used, but in 4 patients the symptoms resolved risk factors for VCP with endotracheal intubation, reported spontaneously, and one patients was lost to follow-up that the incidence of VCP following general anesthesia was without further evaluation. However, in the course of up- 0.077%. In their study, patients undergoing brain surgery, per limb surgery, it is likely that the hyperextension of neck thyroid surgery, carotid endarterectomy, panendoscopy, to obtain a better surgical view, as well as surgical manipu- laryngeal or pharyngeal surgery, anterior cervical surgery, lation such as pressing and pulling, resulted in more severe thoracic surgery, or cardiac surgery were excluded to rule vocal cord damage. Moreover, most of the upper limb sur- out iatrogenic VCP. In our study, however, we did not ex- geries were performed in a sitting position. We expect that clude types of surgery in which the vocal cords could be a sudden migration of the endotracheal tube followed by susceptible to iatrogenic damage. Moreover, we reviewed posture change caused damage to the vocal cords. In addi- only the charts of patients who reported symptoms such as tion, Kikura et al. [8] hypothesized that ischemic neuronal hoarseness, pain or discomfort in the throat, dysphagia, or damage to the recurrent laryngeal nerve and its peripheral dyspnea following surgery. Thus, asymptomatic patients branches in the larynx can be caused by a decrease in mi- with VCP may have been excluded in the present study. crocirculatory supply owing to cuff pressure. In upper limb There are several known risk factors for VCP associated surgery with posture change, the cuff may move to a place with endotracheal intubation. Gupta et al. [19] reported vulnerable to these injuries and cause VCP. that the incidence of VCP increased with age and peaked VCP with nerve injury has a low rate of spontaneous re- in the fifth decade. Kikura et al. [8] reported that patient covery, while idiopathic VCP without nerve injury has a comorbidities (arterial hypertension, diabetes mellitus) spontaneously recovery rate from 13% to 85%. Most pa- and the duration of intubation, as well as age, were risk fac- tients with idiopathic VCP spontaneously recover within tors for VCP associated with endotracheal intubation. The one year. However, the cure rate of patients experiencing authors reported that the risk of VCP increased three-fold idiopathic VCP longer than one year is very low [20,21]. In in patients aged 50 or older, increased two-fold in patients our study, spontaneous recovery was observed in 20.9% with diabetes mellitus and hypertension, and also in- (9/43) of patients with VCP following general anesthesia. creased with duration of intubation (the risk doubled in The recovery time was about two months on average. Ha- patients with an intubation duration of more than 3 h and vas et al. [20] recommend early surgical treatment or re-in- less than 6 h). The results of our study show a similar ten- nervation if aspiration or other symptoms are present or dency. While VCP occurred in 27 patients (62.8%) more the possibility of nerve injury is high. Therefore, it is im- than 50 years old, it occurred in only 16 patients (37.2%) portant to identify the exact cause and etiology of the VCP less than 50 years old. Moreover, VCP occurred in only 11 [20–22]. Radiological examination such as X-rays, and patients (25.6%) whose operation time was less than 3 h, computed tomography with and/or without contrast, and whereas it occurred in 32 patients (74.4%) with operations laryngeal electromyography can be helpful to establish the lasting longer than 3 h. prognosis of VCP [23,24]. The most common surgery associated with iatrogenic There are potential limitations in our study. VCP is thyroid surgery. It is also known that iatrogenic VCP First, because the incidence of postoperative VCP itself is

230 www.anesth-pain-med.org General - - - - - 231

y FW. Airway injury a M, Tayama N. Single in Single N. a M, Tayama

ORCID original draft: Hakmoo Cho, Dong- draft: original Cho, Hakmoo review&editing: Seunghee Ki. review&editing: — REFERENCES

— CONFLICTS OF INTEREST OF INTEREST CONFLICTS AUTHOR CONTRIBUTIONS y HS, Gildea JE. Vocal cord paralysis after tracheal intuba tracheal after paralysis cord JE. Vocal Gildea y HS, David DS, Shah M. Vocal cord paralysis following intubation. intubation. following paralysis cord M. Vocal Shah DS, David tion. JAMA 1971; 215: 281-4. tion. JAMA otolaryngology: surgery. and neck head et al. Cummings 6th 2015. Elsevier. ed. Philadelphia, in etiology 45 years of vocal over of trends analysis stitutional Larynx 2012; 39: 597-600. Nasus Auris fold paralysis. JAMA 1971; 216: 1645-6. JAMA Anesthesiology anesthesia: during analysis. closed a claims 1999; 91: 1703-11. Takano S, Nito T, Tamaruya N, Kimur N, Tamaruya T, Nito S, Takano Domino KB, Posner KL,Domino KB, RA, Posner Caplan Chene Holle Particularly based on the results of this study, it is neces of this study, based on the results Particularly this article to relevant of interest conflict potential No acqui Data Lim. Sehun Seunghee Ki, Conceptualization: 4. Flint P, Haughey B, Lund V, Niparko J, Robbins K, Robbins JR, Thomas J, Niparko V, B, Lund Haughey P, 4. Flint 5. 1. 2. 3. Formal analysis: Sungho Moon, Seunghee Ki. Supervision: Seunghee analysis: Ki. Moon, Sungho Formal Writing Lim. Sehun Writing Kim. chun https://orcid.org/0000-0001-8450-0595 Lim, Sehun https://orcid.org/0000-0002-0661-3129 Kim, Dong-chun https://orcid.org/0000-0002-9805-9582 Cho, Kwangrae https://orcid.org/0000-0002-4350-0078 Kim, Myoung-hun https://orcid.org/0000-0002-3602-9441 Moon, Sungho https://orcid.org/0000-0002-3914-7865 Cho, Hakmoo https://orcid.org/0000-0002-1792-3771 Seunghee Ki, patients undergoing surgery undergoing under these conditions. patients incidence higher for the sary the reasons further to explore surgery of VCP in upper limb performed posture. in sitting provide may study the present we hope that Furthermore, and VCP regarding anesthesiologists to awareness greater in pa discomfort cause it can and danger the significant tients. reported. was Kim. Dong-chun Kim, Myoung-hun Cho, Kwangrae sition: ------], the in 25 [ Vocal cord palsy after anesthesia after palsy cord Vocal ]. In most cases, however, no further examina however, cases, most ]. In 24 , 23 ]. However, we excluded patients who were main who were we patients excluded ]. However, [ 26 Finally, since our study performed only clinical review of performed study our since review clinical only Finally, Fourthly, the exclusion criteria for this study included included criteria study this for exclusion the Fourthly, Thirdly, as we reviewed charts of patients who received who received charts of patients as we reviewed Thirdly, Secondly, during the time period covered in the present in the present Secondly, during period the time covered , 6 www.anesth-pain-med.org during a particular type of surgery surgery) (upper limb is locate to be taken should care believe that We meaningful. in circulation and maintain properly tube the endotracheal complete enumeration survey, risk and failed identify to enumeration complete our with associated factors type of surgery. Nevertheless, of VCP of cases occurred proportion a large discovery that VCP through analysis of 43 cases, we did not investigate the the investigate wenot did cases, 43 of analysis VCPthrough a the type to of surgery through exact incidence according tained on ventilator care, so patients who developed VCP who developed VCP so patients care, tained on ventilator open-heartfollowing surgery not investigated. were after surgery. Previous studies have shown that the risk of shown that have studies surgery.after Previous open-heart undergoing surgery in patients VCP is high [ to investigate these asymptomatic cases. cases. these asymptomatic investigate to maintained was intubation in whom endotracheal patients cidence of asymptomatic VCP was reported to be to twice reported the VCP was asymptomatic of cidence unable VCPwe and (8.3%), were incidence of symptomatic an otolaryngology consultation for symptoms such as an otolaryngology as such for symptoms consultation VCP were surgery,hoarseness after of asymptomatic cases et al. Jung to according not included. However, tion was performed and only symptomatic treatment was was performed treatment tion was symptomatic and only performed. raphy should be performed to identify the exact cause of be performed should of exact cause the identify to raphy VCP the paralyzed vocal cord. Also, as mentioned above, radio above, as mentioned Also, cord. vocal the paralyzed tomography computed as X-rays, such examination logical and laryngeal electromyog with and/or without contrast, physical findings such as the area of paralyzed vocal cord cord vocal of paralyzed as the area such findings physical and atrophy, cord vocal or the existence of paralyzed of the arytenoid dislocation was of cartilage whether there in the otolaryngology medical records, and this informa and this in the otolaryngology records, medical description of allow to of the degree not sufficient tion was or possible, was and whether vocalization hoarseness cases, detailed evaluation of VCP was not performed. not performed. VCP of was detailed evaluation cases, the laryngoscopic only described were findings Moreover, garding the course of the VCP. Of the 43 patients with VCP Of the 43 patients of the VCP. the course garding an otolaryngologist 15 saw study, in the present identified these In follow-up. to lost subsequently and were once only study, the medical records of patients diagnosed with VCP of patients records the medical study, details re lacked frequently anesthesia general following very low, despite a review of the medical records of the past past of the records of the medical very review a despite low, diagnosed with patients 43 we only identified 10 years, hospital. VCP in our postoperative Anesth Pain Med Vol. 15 No. 2

6. Hamdan AL, Moukarbel RV, Farhat F, Obeid M. Vocal cord pa- 17. Santos PM, Afrassiabi A, Weymuller EA Jr. Risk factors associ- ralysis after open-heart surgery. Eur J Cardiothorac Surg 2002; ated with prolonged intubation and laryngeal injury. Otolar- 21: 671-4. yngol Head Neck Surg 1994; 111: 453-9. 7. Hulscher JB, van Sandick JW, Devriese PP, van Lanschot JJ, 18. Weymuller EA Jr. Laryngeal injury from prolonged endotra- Obertop H. Vocal cord paralysis after subtotal oesophagecto- cheal intubation. Laryngoscope 1988; 98(8 Pt 2 Suppl 45): my. Br J Surg 1999; 86: 1583-7. 1-15. 8. Kikura M, Suzuki K, Itagaki T, Takada T, Sato S. Age and co- 19. Gupta J, Varshney S, Bist SS, Bhagat S. Clinico-etiolological morbidity as risk factors for vocal cord paralysis associated study of vocal cord paralysis. Indian J Otolaryngol Head Neck with tracheal intubation. Br J Anaesth 2007; 98: 524-30. Surg 2013; 65: 16-9. 9. Feierabend RH, Shahram MN. Hoarseness in adults. Am Fam 20. Havas T, Lowinger D, Priestley J. Unilateral vocal fold paralysis: Physician 2009; 80: 363-70. causes, options and outcomes. Aust N Z J Surg 1999; 69: 509- 10. Mau T. Diagnostic evaluation and management of hoarseness. 13. Med Clin North Am 2010; 94: 945-60. 21. Sulica L. The natural history of idiopathic unilateral vocal fold 11. Tasar A, Yanturali S, Topacoglu H, Ersoy G, Unverir P, Sarikaya paralysis: evidence and problems. Laryngoscope 2008; 118: S. Clinical efficacy of dexamethasone for acute exudative 1303-7. pharyngitis. J Emerg Med 2008; 35: 363-7. 22. Woodson GE, Miller RH. The timing of surgical intervention in 12. Quick CA, Merwin GE. Arytenoid dislocation. Arch Otolaryn- vocal cord paralysis. Otolaryngol Head Neck Surg 1981; 89: gol 1978; 104: 267-70. 264-7. 13. Rosenthal LH, Benninger MS, Deeb RH. Vocal fold immobility: 23. Hoffman HT, McCulloch TM. Anatomic considerations in the a longitudinal analysis of etiology over 20 years. Laryngoscope surgical treatment of unilateral laryngeal paralysis. Head Neck 2007; 117: 1864-70. 1996; 18: 174-87. 14. Rudert H. [Uncommon injuries of the larynx following intuba- 24. Yin SS, Qiu WW, Stucker FJ. Major patterns of laryngeal elec- tion. Recurrent paralysis, torsion and luxation of the cricoary- tromyography and their clinical application. Laryngoscope tenoid joints]. HNO 1984 32: 393-8. German. 1997; 107: 126-36. 15. Younes N, Robinson B, Delbridge L. The aetiology, investiga- 25. Jung A, Schramm J, Lehnerdt K, Herberhold C. Recurrent lation and management of surgical disorders of the thyroid ryngeal nerve palsy during anterior cervical spine surgery: a gland. Aust N Z J Surg 1996; 66: 481-90. prospective study. J Neurosurg Spine 2005; 2: 123-7. 16. Colton House J, Noordzij JP, Murgia B, Langmore S. Laryngeal 26. Hahn FW Jr, Martin JT, Lillie JC. Vocal-cord paralysis with en- injury from prolonged intubation: a prospective analysis of dotracheal intubation. Arch Otolaryngol 1970; 92: 226-9. contributing factors. Laryngoscope 2011; 121: 596-600.

232 www.anesth-pain-med.org General - - - ] - - - - - ). 1 [ Fig. 1 Fig. ( Clinical Research Clinical MATERIALS AND METHODS MATERIALS ]. Furthermore, previous studies have focused on focused on have studies previous ]. Furthermore, 6 [ After receiving Institutional Review Board approval (no. (no. approval Board Review Institutional receiving After

HIRB-2019-0717-070), we retrospectively analyzed all consec analyzed HIRB-2019-0717-070), we retrospectively aged patients utive ≥ who underwent 16 years emergency op December 1, 2017, to 31, 2017 January from erations tion and there is a tendency to refrain from reporting such such reporting from is a tendency refrain to tion and there cases surgical individual carried by out emergency reoperations been extensively studied have reoperations Few specialties. physi general The perspective. an anesthesiologist’s from is not as good as anticipated condition of the patient cal operation the previous periodduring the recovery from would also be differ characteristics and the intraoperative the we analyzed Therefore, the other operation. from ent an anesthesiol from risk of emergency factors reoperation perspective in this study. ogist’s 233 - - - - eISSN 2383-7977 • The type of surgery, hemodynamics, hemoglobin values, the duration of sur of duration the values, hemoglobin hemodynamics, type surgery, The of Emergency reoperation is considered to be a quality indicator in surgery. We We in surgery. indicator quality be a to considered is reoperation Emergency ]. Thus, it ]. Thus, 1 Anesthesia; Emergency operation; Emergency reoperation; Risk factors. Risk reoperation; Emergency operation; Emergency Anesthesia; [ Patients who underwent emergency operations from January 1, 2017, to Decem to 2017, 1, January from operations emergency underwent who Patients A total of 1,481 patients underwent emergency operations during the study period. period. study the during operations emergency underwent patients 1,481 of A total ]. ]. ] because they are they are ] because 4 5 , , 3 2 Methods: logistic Multivariate study. retrospective this in reviewed were hospital our at 2017, 31, ber reoperation. emergency for factors risk perioperative the for performed was regression Results: emer to related variables The reoperations. emergency received 79 patients them, Among highest lesions, intraoral and intracranial involving surgeries included reoperation gency duration anemia, beats/min, 100 ≥ heart highest mmHg, rate ≥ 110 pressure arterial mean unit (ICU). care intensive the from arrival and min, > 120 operation of Conclusions: reoperations. with emergency associated were ICU from arrival and gery, Keywords: Risk factors of emergency reoperations reoperations of emergency Risk factors Kyoung Na Choi, Ui Jin Park, Yu Kwan Kim, Jun Rho Yoon, Tae Kim Rim Kim, and Taehee College Hospital, Mary’s St. Bucheon Medicine, Pain and Anesthesiology of Department University of Korea, Bucheon, Korea of Medicine, The Catholic Background: reoperations. emergency for factors risk the analyzed Anesth Pain Med 2020;15:233-240 Med Pain Anesth https://doi.org/10.17085/apm.2020.15.2.233 pISSN 1975-5171 3 [ ]. Therefore, emergen ]. Therefore, [ 2 [ ]. In spite of early diagno early of spite In ]. 3 , 2 INTRODUCTION August 7, 2019 2019 7, August October 10, 2019 2019 10, October October 10, 2019 2019 10, October However, reports of emergency reoperations tend to be be to tend of emergency reports reoperations However, Emergency reoperation is an important index of quality index of quality is an important Emergency reoperation Complications after surgical procedures are frequently frequently are procedures surgical after Complications 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 permits which (http://creativecommons.org/licenses/by-nc/4.0) License Non-Commercial Attribution Commons Creative the of terms the under Access article is an Open This distributed cited. is properly work original the provided in any medium, reproduction and distribution, use, non-commercial unrestricted 2020 Anesthesiologists, Society of Korean © the Copyright infrequent, brief, and fragmented [ and fragmented brief, infrequent, of the primary be to a failure opera sometimes considered indicators in healthcare institutions institutions in healthcare indicators as “final-choice operations” [ operations” “final-choice as following the mortality rates progress, ses and therapeutic high still are emergency reoperation emergency intervention via reoperation may prevent the the prevent may emergency intervention reoperation via lives risk save and even increased known surgeries are complicated following cy reoperations is imperative to do everything possible to minimize the everything do to the minimize to possible is imperative com of fatal in the case However, of complications. chance and of complications diagnosis the prompt plications, associated with poor outcomes and high costs with costs associated and high poor outcomes Fax: 82-32-340-2255 Fax: [email protected] E-mail: Sosa-ro, Wonmi-gu, Bucheon 14647, 14647, Bucheon Wonmi-gu, Sosa-ro, Korea 82-32-340-7075 Tel: Department of Anesthesiology and and Anesthesiology of Department St. Mary’s Bucheon Medicine, Pain The Medicine, of College Hospital, 327 Korea, of University Catholic Corresponding author author Corresponding M.D.,Ph.D. Yoon, Rho Jun Received Received Revised Accepted Anesth Pain Med Vol. 15 No. 2

Emergency reoperation was defined as any unscheduled sur- gency reoperations following a previous operation within 60 gery after the initial operation within the postoperative 60 days). Age was categorized as patients older or younger than days [3,6]. Interventional radiology procedures conducted in 65 years. The medical specialties included general surgery, collaboration with anesthesiologists, such as coiling and orthopedic surgery, neurosurgery, and others. The operative stenting, were also included. The following data were collect- lesions were grouped into intracranial, intraoral, cervical, in- ed from the electronic medical record database; sex; age; trathoracic, intra-abdominal, and other categories. Abnormal American Society of Anesthesiology classification; medical pre-induction blood pressure and heart rate were categorized specialties; the operative lesion; the complexity of the surgery, as pre-induction systolic blood pressure (SBP) ≥ 180 mmHg, categorized as minor, moderate, major, and major + blood pre-induction mean arterial pressure (MAP) ≥ 110 mmHg, loss of ≤ 100, 101–500, 501–999, or 1,000 ml [7–9]; hemody- and pre-induction heart rate (HR) < 40 or ≥ 100 beats/min. namic values; hemoglobin (Hgb) and hematocrit values; the Based on abnormality in the highest SBP, MAP, and HR during anesthetic method and main anesthetic agents; the duration the operation, the patients were categorized as follows: SBP ≥ of anesthesia; the net fluid balance; blood transfusions; the 180 mmHg, MAP ≥ 110 mmHg, and HR ≥ 100 beats/min. use of inotropics; patient-controlled analgesia (PCA); the time Based on abnormality in the lowest SBP, MAP, and HR values the operation commenced, and hospital places of origin and during surgery, the following categories were created: SBP ≤ destination. We excluded operations due to unrelated pathol- 80 mmHg, MAP ≤ 60 mmHg, and HR ≤ 40 beats/min. Ane- ogy that occurred during the period of recovery from the first mia was defined by Hgb levels < 13 g/dl and < 40% in males operation. and < 12 g/dl and < 36%, respectively, in females according The cases were divided into Group O (emergency opera- to our laboratory guidelines. The duration of anesthesia was tions without a previous operation) and Group R (emer- categorized as ≤ 120 min or longer. Based on the time surgery commenced, the surgeries were categorized as regular working time (from 8:00 am to 5:00 pm) on weekdays or non-holi- days and outside of working time. Postoperative mortality was 17,345 cases surgery performed defined as death within 30 days postoperatively [9]. The data are expressed as frequencies (%) and median Exclusion criteria: local anesthesia (n = 7,578) (range), as appropriate for comparison between the groups. The chi-squared test or Fisher’s exact test was used 9,767 cases general anesthesia performed for categorical variables and the Wilcoxon rank-sum test was applied for continuous variables. Univariate and mul- Duplicate (n = 229) tivariate logistic regression analysis was used to identify

9,538 patients general the independent predictors of emergency reoperation. A anesthesia performed multivariate logistic regression model was constructed using stepwise selection with entry criteria of P < 0.1 and sig- Elective operation (n = 7,911) nificant criteria of P < 0.05. We applied Firth’s penalized maximum likelihood estimation to reduce bias in the pa- 1,627 patients rameter estimates in the multivariate analyses with few < 16 years (n = 146) events, leading to non-estimable coefficients or 95% confidence intervals. A P value of < 0.05 was statistically consid- 1,481 patients ered significant. All statistical analyses were performed using SAS software ver. 9.4 (SAS Institute Inc., USA).

RESULTS Emergency operation Emergency reoperation (n = 1,402) (n = 79) During the study period, 1,481 emergency operations were performed with anesthesiologist involvement (Fig. 1). Fig. 1. Flow diagram of patient selection process for this study. Comparisons of the baseline demographic characteristics Any patient who has received multiple operations is counted as one patient and his or her last operation is selected. between Group O and Group R are summarized in Table 1.

234 www.anesth-pain-med.org General 235 0.751 0.123 0.712 0.005 0.582 0.004 P value < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 (Continued to the next page) next the to (Continued 5.0 19.0 95.0 ± ± ± 0 (0.0) 2 (2.5) 0 (0.0) 4 (5.1) 7 (8.9) 6 (7.6) 7 (8.9) 0 (0.0) 17 (21.5) 17 41 (51.9) 41 41 (51.9) 41 47 (59.5) 47 51 (64.6) 51 37 (46.8) 37 (46.8) 37 27 (34.2) 27 61 (77.2) 61 21 (26.6) 21 14 (17.7) 14 77 (97.5) 77 4.3 15 (19.0) 15 13 (16.5) 13 18 (22.8) 18 58 (73.4) 45 (57.0) 34 (43.0) 22 (27.8) 38 (48.1) 42 (53.2) 43 (54.4) 36 (45.6) 32 (40.5) 36 (45.6) 23 (29.1) 35 (44.3) 38 (48.1) 57.0 57.0 Group R (n R (n Group = 79) 148.0 148.0 19.0 57.3 95.0 ± ± ± 8 (0.6) 4 (0.3) 47 (3.4) 47 31 (2.2) 31 15 (1.1) 15 15 (1.1) 15 35 (2.5) 93 (6.6) 6.1 6.1 376 (26.8) 376 276 (19.7) 276 216 (15.4) 216 (15.4) 216 51.0 51.0 547 (39.0) 547 597 (42.6) 597 401 (28.6) 401 387 (27.6) 387 773 (55.1) 773 779 (55.6) 779 772 (55.1) 772 188 (13.4) 188 (13.3) 186 805 (57.4) 629 (44.9) 962 (68.6) 758 (54.1) 268 (19.1) 630 (44.9) 334 (23.8) 599 (42.7) 339 (24.2) 1,134 (80.9) 1,134 1,001 (71.4) 1,001 1,352 (96.4) 1,352 (93.4) 1,309 1,026 (73.2) 1,026 (76.2) 1,068 114.0 114.0 Group O (n O (n Group = 1,402) 19.2 55.8 96.0 ± ± Emergency reoperation Emergency ± 8 (0.5) 51 (3.4) 51 31 (2.1) 31 37 (2.5) 37 10 (0.7) 10 15 (1.0) 15 22 (1.5) 6.0 221(14.9) 412 (27.8) 412 51.0 51.0 813 (54.9) 813 618 (41.7) 618 818 (55.2) 818 231 (15.6) 231 224 (15.1) 224 612 (41.3) 612 381 (25.7) 381 111 (7.5) 111 305 (20.6) 863 (58.3) 663 (44.8) 780 (52.7) 598 (40.4) 439 (29.6) 362 (24.4) 793 (53.5) 404 (27.3) 253 (17.1) 989 (66.8) 668 (45.1) 283 (19.1) 1,176 (79.4) 1,176 1,100 (74.3) 1,100 1,370 (92.5) 1,370 1,429 (96.5) 1,429 (70.4) 1,042 1,069 (72.2) 1,069 116.0 116.0 Overall (n Overall = 1,481) Variable Patient Characteristics Patient ≤ 120 > 120 < 65 ≥ 65 Working time Working General anesthesia General anesthesia Regional Major + Other regions Other Orthopedic surgery 3–6 surgery General 1–2 Commencement of operation of Commencement Other PCA No Yes Yes Inotropics No Yes Net fluid balance (ml/min) balance fluid Net Transfusion No Duration (min) Duration Desflurane Sevoflurane Propofol MAC anesthesia in general agent anesthetic Main Major anesthesia of Type Surgical complexity* Surgical Minor Moderate Cervical Intrathoracic Intra-abdominal Lesion Intracranial Intraoral Neurosurgery Others Operator ASA Male Female (yr) Age Sex www.anesth-pain-med.org Table 1. Table Anesth Pain Med Vol. 15 No. 2

Table 1. Continued Variable Overall (n = 1,481) Group O (n = 1,402) Group R (n = 79) P value Origin < 0.001 ER 603 (40.7) 588 (41.9) 15 (19.0) ICU 117 (7.9) 85 (6.1) 32 (40.5) Ward 761 (51.4) 729 (52.0) 32 (40.5) Destination < 0.001 ICU 383 (25.9) 335 (23.9) 48 (60.8) Ward 1,098 (74.1) 1,067 (76.1) 31 (39.2) Values are presented as number (%) or mean ± SD. Group O: patients who underwent emergency operations without a previous operation, Group R: patients who underwent emergency reoperations following a previous operation within 60 days. ASA: American Society of Anesthesiologists, MAC: monitoring anesthesia care, PCA: patient-controlled analgesia, ER: emergency room, ICU: intensive care unit. *Surgical complexity: minor, moderate, major, and major. + blood loss ≤ 100, 101–500, 501–999, and 1,000 ml. P values for differences were determined by using the chi-squares, Fisher’s exact test, t-test, or the Wilcoxon rank-sum test.

Table 2. Top 10 Primary Diagnoses in Emergency Operations and Reoperations Group O* (n = 1,402) Group R† (n = 79) No. Diagnosis Number (%) Diagnosis Number (%) 1 Appendicitis 249 (17.8) SAH 10 (12.7) 2 Cholecystitis 219 (15.6) ICH 9 (11.4) 3 Fracture 212 (15.1) SDH 7 (8.9) 4 Pregnancy 119 (8.5) EDH 5 (6.3) 5 SDH 79 (5.6) Tonsillitis 5 (6.3) 6 Ovary cyst torsion 42 (3.0) Deep neck infection 3 (3.8) 7 ICH 41 (2.9) Pyogenic arthritis 3 (3.8) 8 SAH 29 (2.1) Uterine cancer 3 (3.8) 9 Cerebral infarct 28 (2.0) Thyroid cancer 2 (2.5) 10 Pneumothorax 24 (1.7) Ectopic pregnancy 2 (2.5) SDH: subdural hematoma, ICH: intracerebral hemorrhage, SAH: subarachnoidal hemorrhage, EDH: epidural hematoma. *Patients who underwent emergency operations without a previous operation, †Patients who underwent emergency reoperations following a previous operation within 60 days.

The mean age of the study subjects was 51.0 ± 19.2 years tomy (11 [13.9%]), tonsillectomy (6 [7.6%]), and craniotomy (4 and 668 (45.1%) were male. Age, American Society of Anes- [5.1%]) (Table 3). thesiology classification, operator, lesion, surgical com- The most common cause of emergency reoperation was plexity, the main anesthetic agent in general anesthesia, hemorrhage in 42 (53.2%) cases, followed by infection or the duration of anesthesia, transfusions, inotropics, PCA, sepsis in 11 (13.9%) cases, wound dehiscence in seven origin, and destination were significantly different between (8.8%), and increased intracranial pressure in four (5.1%) Group O and Group R (Table 1). patients. Sixty-four (4.3%) of the 1,481 patients died within The diagnoses in Group O were appendicitis (249 [17.8%]), 30 days postoperatively. Mortality was observed in 16.5% followed by cholecystitis (219 [15.6%]), fracture (212 [15.1%]), (13/79) in Group R. Death occurred in 11 patients after and pregnancy (119 [8.5%]) (Table 2). The most common dis- neurosurgery and in two patients after general surgery in ease categories in Group R were subarachnoidal hemorrhage Group R. The fatality rate associated with each cause of re- (10 [12.7%]), followed by intracerebral hemorrhage (9 [11.4%]), operation ranged from 0% to 36.4% (Table 4). and subdural hematoma (7 [8.9%]) (Table 2). The most com- Multivariate analysis revealed that intracranial (odds ra- mon surgeries performed in Group O were appendectomy tio [OR] = 6.32, P < 0.001) and intraoral (OR = 28.37, P < (251 [17.9%]), followed by cholecystectomy (222 [15.8%]), 0.001) lesions were significantly associated with emergency open reduction and internal fixation (130 [9.3%]), and Cesare- reoperation. The highest MAP ≥ 110 mmHg was signifi- an section (119 [8.5%]) (Table 3). The previous surgeries in cantly correlated with emergency reoperation compared to Group R were extraventricular drainage (14 [17.7%]), craniec- MAP < 110 mmHg (OR = 1.76, P = 0.040). The highest HR

236 www.anesth-pain-med.org General ------– 11 , 237 3 , 1 ]. In con ]. In 6 ]. The term The ]. [ 6 (7.6) 4 (5.1) 4 (5.1) 2 (2.5) 2 (2.5) 2 (2.5) 2 (2.5) 2 (2.5) 14 (17.7) 14 11 (13.9) 11 10 [ Number (%) Number ]. The incidence of incidence of ]. The 11 [ (n = 79) † ] reported that 2% of all emergency that ] reported 14 [ ]. Significant associations between associations emer ]. Significant Group R ]. In a previous study, reoperations were were reoperations study, a previous ]. In 15 , 6 [ 5 , 4 Surgery , 2 ], although most commonly they were conducted they commonly were most although ], [ 2 [ ]. The incidence of emergency reoperations in this study in this study incidence of emergency]. The reoperations Emergency reoperation was defined as surgery was per Emergency reoperation of reoperation the incidence to related data Published operations required emergency reoperation within a week, emergency reoperation required operations vascu in rate reoperation The report. present the to similar surgerylar be to 12% reported was re was emergency requiring re-laparotomy complications who underwentported 1–4.4% in patients abdominal at surgeries been established sex have and male gency reoperations reoperation were intracranial and intraoral lesions, MAP lesions, and intraoral intracranial were reoperation ≥ HR and 110 mmHg ≥ surgery, before anemia, 100 beats/min of operation duration > the opera before and ICU stay 2 h, tion. formedprimarya to due condition surgical performed within two operations to refers “reoperation” initial the to of the primary and related months operation surgery earlier much 24 day 1 to day postoperative conducted from period ranged the reoperation investigation, in our trast, 29 days. 0 to from with rates reported vary populations, between different the definition used, to 21% according to 2% from ranging opera and pathology departments, the bias, institutional [ of coexisting problems and the presence tion type, 13 study our because reports previous than lower (0.83%) was re for potential with low included a variety of operations Lee et al. operation. clinical features, as well as anesthetic considerations, of emer of wellconsiderations, as anesthetic as features, clinical emergency ordinary to opera compared gency reoperation emergency to related the factors study, the present In tions. IF Patients who underwent emergency reoperations following a previous previous a following reoperations emergency underwent who Patients & † - - EVD Craniectomy Tonsillectomy Craniotomy Debridement OR trephination hole Burr hematoma intracranial of removal guided Navigation Oophorectomy Salpingectomy Emergency reoperation Emergency 4 (36.4) 6 (14.3) 1 (9.1) 1 (14.3) 1 (25.0) 0 (0) 0 (0) Mortality rate* IF: closed reduction and internal fixation, EVD: extraventricular drainage. *Patients who who *Patients drainage. EVD: extraventricular fixation, internal and reduction closed IF: & 41 (2.9) 41 59 (4.2) 45 (3.2) 42 (3.0) 40 (2.9) 32 (2.3) Number (%) Number 251 (17.9) 251 119 (8.5) 119 130 (9.3) 130 222 (15.8) Others include airway airway Others include † 7 (8.8) 4 (5.1) 2 (2.5) 2 (2.5) (n = 79) 11 (14.0) 11 11 (13.9) 11 42 (53.2) Emergency reoperation ). Table 5 Table ( Group O* (n O* (n Group = 1,402) DISCUSSION Surgery IF IF & & Craniectomy Tenorrhaphy OR Cesarean section CR cystectomy Ovary trephination hole Burr EVD Appendectomy Cholecystectomy Causes of Emergency Reoperation and Mortality and Rates Reoperation Emergency of Causes Surgical Procedures in Group O and Previous Operations in Group R in Group Operations Previous O and in Group Procedures Surgical † IF: open reduction and internal fixation, CR fixation, internal and reduction open IF: 7 8 9 10 4 5 6 1 2 3 No. & Emergency reoperation has been reported to have distin been have to reported has Emergency reoperation Thrombotic arteryocclusion Thrombotic Ileus Others Infection or Sepsis or Infection dehiscence Wound pressure intracranial Increased Causes Hemorrhage = 1.94, P = in the treated of patients number 0.025). The ≥ with emer correlated significantly was 100 beats/min = P 2.87, < levels Hemoglobin 0.001). < males in g/dl 13 www.anesth-pain-med.org guishing features and risks. Therefore, we investigated the the we investigated Therefore, risks. and features guishing statistically significant significant statistically intensive care unit (ICU) (OR care intensive = 2.89, P = 0.007) remained and < with correlated significantly were 12 g/dl in females (OR reoperation = 2.47, P = of surgery 0.001). Duration (OR reoperation to related significantly two was hours over gency reoperation compared to HR to compared gency reoperation < (OR 100 beats/min anastomosis leakage resulted in death. resulted leakage anastomosis hardware loosening, hygroma, intestinal anastomosis leakage, leakage, anastomosis intestinal hygroma, loosening, hardware tracheostoma, fistula, pharyngocutaneous nonunion, injury, nerve obstruction, airway causes, other the Among injury. ureteral and intestinal and leakage, fluid cerebrospinal infarction, cerebellar Values are presented as number (%) of categorical variables. *The *The variables. categorical (%) of as number presented are Values from calculated mortality the percentage include parentheses reoperation, emergency of cause each leakage, fluid cerebrospinal infarction, cerebellar obstruction, Table 4. Table OR operation, previous a without operations emergency underwent within 60 days. operation Table 3. Table Anesth Pain Med Vol. 15 No. 2

Table 5. Multivariate Logistic Regression Analyses of Factors Associated with Reoperations (n = 1,481) Variable Crude odds ratios (95% CI) P value Adjusted odds ratios (95% CI) P value Lesion Intracranial 4.22 (2.31–7.68) < 0.001 6.32 (2.41–16.58) < 0.001 Intraoral 31.98 (8.30–123.20) < 0.001 28.37 (6.26–128.62) < 0.001 Cervical 10.71 (3.89–29.48) < 0.001 2.07 (0.62–6.93) 0.238 Intrathoracic 0.35 (0.02–6.25) 0.477 1.06 (0.05–22.83) 0.920 Intra-abdominal 0.41 (0.20–0.84) 0.014 1.50 (0.64–3.56) 0.354 Others Reference Reference Surgical complexity Minor 2.95 (0.14–61.87) 0.487 17.23 (0.72–413.69) 0.079 Moderate 0.49 (0.02–10.24) 0.643 2.71 (0.12–61.46) 0.531 Major 1.22 (0.06–26.19) 0.900 1.57 (0.07–36.91) 0.779 Major + Reference Reference Highest MAP < 110 Reference Reference ≥ 110 3.19 (2.01–5.04) < 0.001 1.76 (1.03–3.03) 0.040 Highest HR < 100 Reference Reference ≥ 100 6.21 (3.91–9.87) < 0.001 2.87 (1.64–5.02) < 0.001 Hgb (g/dl) Male < 13, female < 12 3.18 (1.99–5.07) < 0.001 Reference Male ≥ 13, female ≥ 12 Reference 2.47 (1.44–4.27) 0.001 Duration (min) ≤ 120 Reference Reference > 120 2.31 (1.47–3.64) < 0.001 1.94 (1.09–3.46) 0.025 Origin ER 0.59 (0.32–1.09) 0.094 0.48 (0.23–1.01) 0.052 ICU 8.53 (4.99–14.59) < 0.001 2.89 (1.34–6.23) 0.007 Ward Reference Reference A multivariate logistic regression model was constructed using stepwise selection (with entry criteria of P < 0.1 and significant criteria of P < 0.05). CI: confidence interval, MAP: mean arterial pressure, HR: heart rate, Hgb: hemoglobin, ER: emergency room, ICU: intensive care unit.

[3,12]. The relative paucity of males in our study differs medical treatment [2]. Other risk factors for mortality re- from other studies and suggests the inherent effects of the ported in a previous study included hypoproteinemia, a de- hospital and region. lay in diagnosis, and intestinal obstruction [1]. One of the most important factors affecting mortality Causes of urgent abdominal re-explorations were known rates in emergency reoperations is the cause, lesion, and to involve leakage from the intestinal repair site, hemor- organ involved in the reoperation [2]. The 30-day mortality rhage, intestinal perforation, intra-abdominal infection or rate for emergency abdominal reoperations was reported to sepsis, mechanical obstruction, intestinal necrosis, enteral range from 5.5% to 48% [1,3,6]. Hemorrhage and infection, anastomosis failure, stomal complications, surgical wound as well as leakage from intestinal repair sites, were associat- dehiscence, fistulas, and ileus [1,2]. Intracranial lesions ed with low, mid, and high mortality risks in intra-abdomi- show an increased tendency for emergency reoperation [7], nal operations, respectively [2]. The overall mortality rate in consistent with our findings. The fact that six patients died patients undergoing vascular surgery was 16% [11]. In con- from intracranial hemorrhage also suggests the importance trast, in our study, the mortality among re-operated patients of brain lesions in the increased risk of reoperation. Neuro- was 16.5% (13/79). A comparison of the incidence with pre- surgical reoperations tend to be performed frequently fol- vious reports was difficult because of the different method- lowing the initial operation [2,10]. Surgical complexity was ologies used to calculate the incidence and variation in the reportedly associated with emergency reoperations [3], populations included. Reoperation is riskier, even though which was not shown in our findings. patients are likely to respond positively to perioperative In our study, the highest MAP ≥ 110 mmHg and the

238 www.anesth-pain-med.org General ------239 ORCID REFERENCES CONFLICTS OF INTEREST CONFLICTS AUTHOR CONTRIBUTIONS district general hospital. Ann R Coll Surg Engl 1987; 69: 169-74. Engl Surg Ann R Coll hospital. district general Wain MO, Sykes PA. Emergency abdominal re-exploration in a re-exploration Emergency abdominal PA. Sykes MO, Wain No potential conflict of interest relevant to this article this article to relevant conflict of interest potential No Jun acquisition: Data Rho Yoon. Jun Conceptualization: In summary, our results described the clinical features of described features summary, the clinical results In our 1. Kyoung Rim Kim, https://orcid.org/0000-0001-5442-8705 Rim Kim, Kyoung https://orcid.org/0000-0002-0476-3254 Kim, Taehee quired to redefine the clinical features of emergency reop features the clinical redefine to quired eration. reported. was analysis: Formal Kim. Taehee RimKim, Kyoung Rho Yoon, Rho Supervision: Jun Park. Jin Ui Funding: Kim. Kwan Tae Writing—re Writing—original draft: Rho Yoon. Jun Yoon. Kim. Kwan Tae Choi, Na Yu view & editing: https://orcid.org/0000-0002-0635-3304 Kim, Kwan Tae https://orcid.org/0000-0001-7457-7433 Rho Yoon, Jun https://orcid.org/0000-0001-9111-8298 Choi, Na Yu https://orcid.org/0000-0003-2114-0195 Park, Jin Ui future. The selection of abnormal variables, including vital including selection variables, The of abnormal future. have and these defined aspects arbitrarily was may signs, anes the we not analyze could Third, affected results. our mortalityend as an postoperative for thetic implications varia Lastly, of mortalities. number the small due to point experi the surgeon’s due to procedures tions in surgical not beana and methods could devices, operative ence, beyond the scope of and were way in a meaningful lyzed the study. withassociated a factors The emergencyreoperations. intra were of emergency proportion higher reoperations MAP highest lesions, and intraoral cranial ≥ 110 mmHg HR and ≥ the arrival and from anemia, beats/min, 100 Emergency of segment is an important anesthesia ICU. af care in anesthetic anesthesiology and advances clinical emer be to paid must attention fect mortality. Particular re are time and resources and more gency reoperation ------]. A 1 [ Emergency reoperation Emergency ]. There ]. For ex ]. For 2 1 , [ 1 [ ]. Tachycardia is is ]. Tachycardia 9 [ ], consistent with our findings, in with findings, our ], consistent ]. Half of the reoperations were mi were of the reoperations ]. Half 10 [ 16 [ ]. These patients are usually anemic usually are patients ]. These 6 , 1 [ ]. Surgical challenges include inappropriate inappropriate include challenges Surgical ]. 2 [ ]. 16 [ This study had several limitations. First, our research was was research our First, limitations. several had study This The possibility of effectively lowering the mortality rate lowering possibility the mortality of effectively The rate www.anesth-pain-med.org clear distinction between the effects of reoperation on pa between distinction clear the effects of reoperation be based should on analyses results The outcomes. tient in the and procedures individual departments to according gation may be too diverse to perform a comprehensive be too diverse perform to may a comprehensive gation The variables. of unmeasured the role and exclude analysis a included did not allow variety of diseases and operations ty-affiliated community hospital. Institutional factors may may factors Institutional hospital. community ty-affiliated Second, investi in our the variables limit generalizability. Therefore, the results may differ from those involving larg those involving differ from may the results Therefore, regional as such institutions, multiple and populations er a universi is institution Our centers. emergency trauma based on data obtained from a single institution and sur institution a single obtainedbased from on data two hours) than less (70.0% were geries of short duration types of surgery (83.9%). minor-to-moderate and involved tients. tients. was study This groups. study of the the size limited by transferred from the ICU. This reflects the urgency reflects of most This the ICU. from transferred of these pa status physical and the grave cases reoperation nor surgeries in the present study, suggesting possible possible suggesting study, nor surgeries in the present study, our In during operation. initial the errors technical mostly were emergency undergoing reoperations patients operation operation handling and incorrect poorly developed skills, judgment, devices of surgical ample, a majority of the hemorrhages were caused by tech by caused were of the hemorrhages a majority ample, during first the hemostasis as inadequate such errors, nical fore, a number of these problems can be avoided by taking taking by be avoided can theseof problems number a fore, operation time of the initial the at possible all precautions of complications the occurrence minimize to ately ately operation of the first depends on the success directly suggesting coagulation deficiencycoagulation and poor nutri suggesting directly seor anemia with associated is severe hemorrhage If tion. proportion increases the mortality rate hypotension, vere lower hemoglobin concentration is associated with is associated a high hemoglobin concentration lower er risk of reoperation tive mortalitytive in emergency surgeries intravas unstable and suggests common in these patients volume cular intracranial problems, the use of inotropics, and psycho and use the inotropics, of problems, intracranial blood requiring and hemorrhage Shock stress. logical postopera susceptibility to patients’ increase transfusion highest HR highest ≥ emergency to re related were 100 beats/min hemodynamic high reflected indirectly which operations, in reflex be Cushing due to may Hypertension instability. Anesth Pain Med Vol. 15 No. 2

2. Unalp HR, Kamer E, Kar H, Bal A, Peskersoy M, Ali Onal M. Ur- Polak J, et al. Emergency reoperations in cranial neurosurgery. gent abdominal re-explorations. World J Emerg Surg 2006; 1: 10. World Neurosurg 2017; 105: 749-54. 3. Guevara OA, Rubio-Romero JA, Ruiz-Parra AI. Unplanned re- 11. Davies AH, Pope I, Collin J, Morris PJ. Early reoperation after operations: is emergency surgery a risk factor? A cohort study. J major vascular surgery: a four-year prospective analysis. Br J Surg Res 2013; 182: 11-6. Surg 1992; 79: 76-8. 4. Tera H, Aberg C. Relaparotomy. A ten-year series. Acta Chir 12. Brant JA, Bur AM, Chai R, Hatten K, Nicolli EA, Fischer JP, et al. Scand 1975; 141: 637-44. Reoperation following adult tonsillectomy: review of the Ameri- 5. O’Leary DP, Hardwick RH, Cosford E, Knox AJ. Does hospital can College of Surgeons National Surgical Quality Improvement mortality rate reflect quality of care on a surgical unit? Ann R Program. Otolaryngol Head Neck Surg 2016; 154: 779-84. Coll Surg Engl 1997; 79: 46-8. 13. Ramachandran R, Hegde T. Chronic subdural hemato- 6. Harbrecht PJ, Garrison RN, Fry DE. Early urgent relaparotomy. mas--causes of morbidity and mortality. Surg Neurol 2007; 67: Arch Surg 1984; 119: 369-74. 367-72. 7. Copeland GP. The POSSUM system of surgical audit. Arch Surg 14. Lee DI, Lee MH, Shin OY, Shin KY. A clinical study of anesthesia 2002; 137: 15-9. for emergency surgery. Korean J Anesthesiol 1979; 12: 252-60. 8. Donati A, Ruzzi M, Adrario E, Pelaia P, Coluzzi F, Gabbanelli V, 15. Ching SS, Muralikrishnan VP, Whiteley GS. Relaparotomy: a five- et al. A new and feasible model for predicting operative risk. Br year review of indications and outcome. Int J Clin Pract 2003; J Anaesth 2004; 93: 393-9. 57: 333-7. 9. Matsuyama T, Iranami H, Fujii K, Inoue M, Nakagawa R, 16. Irita K. Risk and crisis management in intraoperative hemor- Kawashima K. Risk factors for postoperative mortality and mor- rhage: human factors in hemorrhagic critical events. Korean J bidities in emergency surgeries. J Anesth 2013; 27: 838-43. Anesthesiol 2011; 60: 151-60. 10. Kwinta BM, Krzyżewski RM, Kliś KM, Donicz P, Gackowska M,

240 www.anesth-pain-med.org General ------]. Several ]. Several 3 [ ]. 5 , 4 [ ]. To screen patients with de patients screen ]. To 6 [ Clinical Research Clinical The prevalence of depression is increasing in most coun in most is increasing of depression prevalence The tries, including Korea, where the lifetime and annual prev and annual the lifetime where Korea, including tries, 6.7% and 3.0% alence are Ques Health as the Patient such measures, many pression, shortens hospitalization and convalescence and convalescence shortens hospitalization may depression but pain, influence postoperative factors its intensity heighten significantly 241 - eISSN 2383-7977 • Postoperative pain is affected by preoperative depression. If the risk of post of risk If the depression. by preoperative pain is affected Postoperative We observed a correlation between the PHQ-2 score and postoperative pain. pain. postoperative and score PHQ-2 the between a correlation observed We Analgesics; Depression; Patient health questionnaire; Postoperative pain. Postoperative questionnaire; health Patient Depression; Analgesics; A total of 50 patients scheduled for elective laparoscopic cholecystectomy with with cholecystectomy laparoscopic elective for scheduled 50 patients of A total The NRS score in PACU was not significantly associated with the PHQ-2 score (cor score PHQ-2 with the associated significantly not was in PACU score NRS The and 72 postoperative hours. At 72 h, the IV-PCA device was removed and the final dosage dosage final the and removed was device IV-PCA the 72 h, At hours. postoperative 72 and recorded. was Results: was surgery after analgesics use of the However, [P = 0.367]). 0.13 coefficients: relation 0.33 [P = 0.018]). coefficients: (correlation more 3 or of score with PHQ-2 in patients higher Conclusions: Particular depression. preoperative for test screening a as useful be could PHQ-2 Therefore, with the associated was score PHQ-2 the score, cut-off used as the were 3 points when ly, higher with high be to expected be could demand analgesic the and analgesics, of dosage scores. PHQ-2 Keywords: Background: anesthesiolo preoperatively, can be predicted with depression pain associated operative this of objective The care. it with personalized manage can better surgeons gists and/or depression (PHQ-2) Questionnaire-2 Health Patient of efficacy the determine to was study pain. postoperative of as a predictor tool screening Methods: an They enrolled. 2 were 1 or status physical Anesthesiologists of Society an American a researcher of supervision the under questions, two of consists which PHQ-2, the swered assessed were at scores (NRS) scale rating numerical The surgery. the before day the on in of amount the and hours, 48 postoperative and 24, at unit (PACU), care post-anesthesia 48, 24, at documented was administered (IV-PCA) analgesia patient-controlled travenous Correlation between patient health patient between Correlation pain in and postoperative questionnaire-2 cholecystectomy laparoscopic Dong-jin Shim, Huiyoung Kim, Park, Woo Shin, Tae Yusom Kim, and Donghee Kang Hochul Lee, Joo-Duck Medicine, Medicine, Kosin University College of and Pain Department of Anesthesiology Busan, Korea Anesth Pain Med 2020;15:241-246 2020;15:241-246 Med Pain Anesth https://doi.org/10.17085/apm.2020.15.2.241 pISSN 1975-5171 INTRODUCTION July 24, 2019 24, July October 23, 2019 October September 25, 2019 September ]. Therefore, appropriate pain control is important. important. is control pain appropriate Therefore, ]. 2 Postoperative pain causes patients discomfort and vaso patients causes pain Postoperative , 1 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 permits which (http://creativecommons.org/licenses/by-nc/4.0) License Non-Commercial Attribution Commons Creative the of terms the under Access article is an Open This distributed cited. is properly work original the provided in any medium, reproduction and distribution, use, non-commercial unrestricted 2020 Anesthesiologists, Society of Korean © the Copyright decelerate wound healing and increase the infection rate the infection rate and increase wound healing decelerate [ and morbidity reduces control pain postoperative Proper constriction through sympathetic hyperactivity, which may may which hyperactivity, sympathetic constriction through Fax: 82-51-254-2504 Fax: [email protected] E-mail: College of Medicine, 262 Gamcheon- Medicine, of College Korea 49267, Busan Seo-gu, ro, 82-51-990-6281 Tel: Donghee Kang, M.D. Kang, Donghee and Anesthesiology of Department University Kosin Medicine, Pain Corresponding author author Corresponding Received Received Revised Accepted Anesth Pain Med Vol. 15 No. 2 tionnaire-9 (PHQ-9) [7], Center for Epidemiological Studies used. The PHQ-2 questionnaire consisted of two items: Depression Scale [8], Beck Depression Inventory [9], and “Little interest or pleasure in doing things” and “ Feeling Geriatric Depression Scale [10], have been developed. down, depressed, or hopeless.” The available answers were: However, 30–50% of depressed patients are misdiagnosed “Not at all,” “Several days,” “More than half the days,” and due to difficulties in diagnosis [11,12]. “Nearly every day.” Each question was scored on a scale of Postoperative pain is associated with depression, there- 0–3, and the scores from both questions were added. The fore screening for preoperative depression might help with patient’s medical records (age, height, weight, and history better management of postoperative pain [4,5]. However, of psychological disorder) were also obtained. screening for depression in pre-anesthetic assessments is Pre-anesthetic medication was not administered. Propo- difficult, as it is time-consuming. Moreover, depression fol (1 mg/kg) and remifentanil (1 μg/kg) were used to in- screening is difficult for anesthesiologists, as it generally duce anesthesia. Anesthesia was maintained using sevoflu- requires professional knowledge. To screen for depression rane and remifentanil, and remifentanil was discontinued in pre-anesthetic assessments, the screening test should be during extubation. In the recovery room, fentanyl 50 μg short, with high reliability and validity. Therefore, PHQ-2 was administered in the loading dose and IV-PCA was con- could be an appropriate option, since it evaluates patients nected. The patient was then told to press the button of the using only two of the nine questions of PHQ-9, which is the IV-PCA directly if there was pain. An IV-PCA device was conventional depression screening test [13]. used with Hospira Gemstar Blue (GemStarTM, Hospira Inc., In this study, we evaluated the usefulness of the PHQ-2 USA). We mixed 1,000 μg of fentanyl (fentanyl citrate, Hana test for preoperative depression evaluation. If there was a Pharm, Korea), 50 mg of nefopam (nefopam HCl, Ilsung correlation between preoperative PHQ-2 and postopera- Pharm, Korea), and 4 mg of ondansetron to obtain a total tive pain, we considered that PHQ-2 could be used to pre- volume of 150 ml. When the bolus button was pressed, 1.5 dict postoperative pain without a definite diagnosis of de- ml (10 μg of fentanyl) of the drug mixture was injected. The pression. lock time was 5 min. The degree of postoperative pain on a numerical rating MATERIALS AND METHODS scale (NRS) and the usage amount of IV-PCA were assessed. The NRS scores were assessed at PACU, 24, and 48 This study was approved by our committee for Clinical postoperative hours. Usage amount of IV-PCA was collect- Research Ethics (no. KUGH 2017-08-033-006). A total of 55 ed at 24, 48, and 72 postoperative hours. At 72 h, the IV- patients participated in this study. The correlation coeffi- PCA device was removed. When a patient complained of cient of the study was determined to be 0.4, which can be nausea or vomited while using IV-PCA, 4 mg of ondanse- interpreted as a fair result between 0.4 and 0.6, referring to tron was additionally administered. When the complaint the previous study [14]. The minimum number of samples sustained, IV-PCA was discontinued. was 47 when α = 0.05, β = 0.20, and correlation coefficient A statistical analysis was performed using the SPSS (ver- is 0.4, and the study was conducted in 55 patients consid- sion 24.0, IBM, USA) statistical program. To analyze the ering the losers. Patients identified as American Society of correlations among the PHQ-2 score, NRS score, and fen- Anesthesiologist physical status class I–II were scheduled tanyl use, point-biserial correlation or Pearson correlation for laparoscopic cholecystectomy under general anesthe- analyses were used. Quantitative variables were expressed sia. Patients with a history of depression, current medica- as mean ± SD, and P < 0.05 was the significance level of tion, or complaint of post-anesthetic nausea and vomiting the test. in previous surgeries were excluded from this study. An anesthesiologist, who did not have prior information RESULTS regarding the patient, visited the ward to examine the PHQ-2 scores of the patients who were hospitalized a day A total of 55 patients who underwent laparoscopic chole- before the operation. Subsequently, he explained the use cystectomy under general anesthesia were enrolled in this of intravenous patient-controlled analgesia (IV-PCA). study, of which 8 complained of postoperative nausea and There were two types of PHQ-2: Short-answer PHQ-2 and received 4 mg of ondansetron intravenously. Out of the 8 score-type PHQ-2. In this study, score-type PHQ-2 was patients, 5 complained of nausea and discontinued IV-PCA

242 www.anesth-pain-med.org General - - 4 243 show show 4

, and 10.8 13.6 57.1 71.5 88.6 13.7 3 Value ± ± ± ± ± ± Total amount of of amount Total 28/22 , 88.6), and total 88.6), and total † 5 (10) 6 (12) 5 (10) 0 (0) 0 (0) ± 1938-12-01 24 (48) 24 10 (20) 10 50.9 66.3 63.3 371.6 371.6 450.9 300.3 Figs. 2

). PHQ-2 Table 2 Table 71.5 vs. 300.3 71.5 vs. ± † 1 2 3 Total amount of fentanyl in IV-PCA. fentanyl of amount Total † Variable Characteristics of Patients of Characteristics Relationship between preoperative Patient Health Health Patient preoperative between Relationship 0 0

10 80 70 60 50 40 30 20

PHQ-2 score score PHQ-2 ≥ 3 score PHQ-2 < 3 g) µ ( consumption Analgesic Sex (M/F) Sex (yr) Age (kg) Weight I/II status physical ASA score PHQ-2 Preoperative 0 1 2 3 4 5 6 (µg)* dose total Remifentanil (µg) dose total Fentanyl (min) anesthesia of Duration and 48 postoperative hours were significantly associated associated significantly were hours and 48 postoperative coefficients: 0.68 [P (correlation with score the PHQ-2 < 0.001] and 0.45 [P = 0.010], con analgesic and betweenscore PHQ-2 relationship the surgery. after day Age second, and third on first, sumption sex not was but usage with associated was fentanyl total coefficients: –0.34 [P (correlation = 0.016] and –0.69 [P = Questionnaire-2, IV-PCA: intravenous patient-controlled analgesia. analgesia. patient-controlled intravenous IV-PCA: Questionnaire-2, surgery. during remifentanil of amount *Total in IV-PCA. fentanyl 2. Fig. the on consumption analgesic and score (PHQ-2) Questionnaire-2 r = 0.68 [P < 0.001]). coefficient (correlation surgery after first day scoring < (371.6 3 points (correla with score the PHQ-2 correlated usage fentanyl coefficients: tion [P 0.33 = 24 at usage Fentanyl 0.018]). Table 1. Table ± SD. ASA: mean (%) or as number presented are Values Health Patient PHQ-2: Anesthesiologists, of Society American

- 0.24 Table 1 Table POD3

–0.69 –0.34* ). P < 0.001. † study 4 mg of the Fig. 1 Fig. ( IV-PCA due to IV-PCA ondansetron was POD2 0.45* Excluded from the injected intravenously uncontrolled symptom 5 patients discontinued † Fentanyl consumption Fentanyl 0.68 POD1 Correlation between patient health questionnaire-2 and postoperative pain postoperative and questionnaire-2 health patient between Correlation postoperative nausea 8 patients complained ). When three points on PHQ-2 was was on PHQ-2 points ). When three 3 patients had 0.13 Table 2 Table in PACU –0.25 –0.12

improved symptoms NRS score NRS inclusion criteria 55 patients meeting 55 patients Coefficient of Point-biserial Correlation or Pearson Pearson or Correlation Point-biserial of Coefficient A study flow chart. IV-PCA: intravenous patient-controlled patient-controlled chart. intravenous IV-PCA: flow study A complications Analyzed (n = 50) 47 patients had no Variable Postoperative NRS in recovery room and total fentanyl fentanyl and total room NRS in recovery Postoperative Age (yr) Age score PHQ-2 Sex (M/F) Sex www.anesth-pain-med.org 0.24 [P = 0.098], use significantly was the fentanyl score, used as the cut-off who scored in patients higher ≥ in those than 3 points usage were not significantly associated with the patient’s associated with the patient’s not significantly were usage coefficients:[P 0.13 (correlation score PHQ-2 =0.367] and conducted for about two minutes, and no patient refused refused and no patient twoconducted minutes, for about the survey. study. Finally, we analyzed 50 patients 50 patients we analyzed Finally, study. effects other Side characteristics. the demographic shows was the PHQ-2 this study, In did not occur. nausea than due to uncontrolled symptoms after a single administra a single after symptoms uncontrolled due to the from excluded were and ondansetron of mg 4 of tion scale, POD: post-operative day, PACU: post-anesthesia care unit. unit. care post-anesthesia PACU: day, POD: post-operative scale, *P < 0.05, consumption. fentanyl total POD3 means PHQ-2: Patient Health Questionnaire-2, NRS: numerical rating rating numerical NRS: Questionnaire-2, Health Patient PHQ-2: Table 2. Table NRS and Score Data/PHQ-2 Demographic between Correlations Consumption Score/Fentanyl Fig. 1. Fig. analgesia. Anesth Pain Med Vol. 15 No. 2

80 80 70 70 60 60 50 50 40 40 30 30 20 20 10 10 Analgesic consumption ( µ g) consumption Analgesic ( µ g) consumption Analgesic 0 0 0 1 2 3 4 1 2 3 4 PHQ-2 PHQ-2

Fig. 3. Relationship between preoperative Patient Health Fig. 4. Relationship between preoperative Patient Health Questionnaire-2 (PHQ-2) score and analgesic consumption on Questionnaire-2 (PHQ-2) score and analgesic consumption on the the second day after surgery (correlation coefficient r = 0.45 [P = third day after surgery (correlation coefficient r = 0.24 [P = 0.098]). 0.010]).

0.640], Table 2). cases of ear, nose, and neck surgery. These differences are probably because of differences in the type of surgery and DISCUSSION type of postoperative analgesics used. Patients who were included in this study underwent lap- The purpose of this study was to evaluate the correlation aroscopic cholecystectomy. The surgery was less painful between preoperative PHQ-2 score and postoperative pain. compared to open cholecystectomy, and IV-PCA with fen- PHQ-2 is a simple screening test using two of the nine ques- tanyl controlled postoperative pain appropriately [19]. Im- tions of PHQ-9, a previously developed depression screening mediately after the surgery, patients with higher PHQ-2 test [13]. The two questions addressed depressed mood and score had higher analgesic requirements. However, as the anorexia. There is a significant correlation with other screen- postoperative pain was controlled with a strong opioid, the ing tests, and PHQ-2 is known to increase the total score de- appropriate pain control effect might have been achieved pending on the severity of depression in the patient group regardless of the PHQ-2 score, and it is believed that there [15]. was no difference in usage. In this study, the preoperative PHQ-2 scores did not sig- PHQ-2 scores did not significantly correlate with total nificantly correlate with the postoperative NRS scores mea- fentanyl usage. However, after selecting the appropriate sured in the PACU or the total fentanyl usage (correlation cut-off score for PHQ-2, the PHQ-2 scores were associated coefficients: 0.13 [P = 0.367] and 0.24 [P = 0.098]). Howev- with total analgesic requirement. The sensitivity and speci- er, fentanyl usage during 24 postoperative hours highly ficity of depression were 91.9% and 100%, respectively, correlated with the preoperative PHQ-2 scores (0.68 [P < when the cut-off score on PHQ-2 was 3 [15]. In this study, 0.001]). Various studies on the association between post- when 3 points were used as cut-off score, fentanyl use was operative pain and preoperative depression have been significantly higher in patients who scored 3 or more conducted. De Cosmo et al. [14] reported that depression points. Therefore, 3 points as a cut-off score on PHQ-2 may was associated with tramadol use in patients after laparo- be appropriate for preoperative depression screening. scopic cholecystectomy. Schade et al. [16] reported that In this study, sex did not affect analgesic use (correlation preoperative depression affects postoperative pain and re- coefficient: –0.69 [P = 0.640]). In another study on ana- habilitation in patients with lumbar disc herniation. Oz- lyzed factors affecting postoperative pain, sex did not affect tekin et al. [17] reported that anterior cruciate ligament the postoperative pain or analgesic use [4]. However, age surgery was not associated with postoperative pain despite was a major predictor of postoperative pain and analgesic high preoperative depression scores in the patients. Kavak- use [4]. In this study, the use of analgesics was higher in ci et al. [18] found that preoperative anxiety has a greater younger patients (correlation coefficient: –0.34 [P = impact on postoperative pain compared to depression in 0.016]).

244 www.anesth-pain-med.org General

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Primary Care naire JAMA primary the PHQ of PRIME-MD: study. version care 1999; 282: 1737-44 1977; 1: Meas Psychol Appl population. in the general research 385-401. with the Beck Depression inpatients in medical disorders sion 1997; 35: 785-91. Ther Res Behav for PrimaryInventory Care. screen of a geriatric depression and validation Development 1982; 17: 37-49 Res J Psychiatr report. a preliminary scale: ing in primary a internists by care: R. Recognition of depression as psychiatric standard” and “gold comparison of internist 1989; 4: 7-13 Med J Gen Intern sessments. Med Fam Arch diagnose. to difficult recognize, to easy practice: ser R. Psychological influences on surgical recovery. Perspec recovery. on surgical influences ser R. Psychological 1998; 53: Am Psychol psychoneuroimmunology. from tives 1209-18. and surgery.aesthesia 1984; 56: 725-39 Br J Anaesth 2001; 87: 62-72 Br J Anaesth outcome. a qualitative consumption: and analgesic pain postoperative Anesthesiology 2009; 111: 657-77. review. systematic Kiecolt-Glaser JK, Page GG, Marucha PT Marucha GG, JK, Page Kiecolt-Glaser Beck A Beck Ip HYV, Abrishami A, Peng PW, Wong J, Chung F. Predictors of Predictors F. Chung J, A, Abrishami PW, Wong Peng HYV, Ip Kehlet H, Holte K. Effect of postoperative analgesia on surgical on surgical K. analgesia H, Holte of postoperative Effect Kehlet Spitzer RL, Kroenke K, Williams JBW; Patient Health Question Health RL, Patient K,Spitzer JBW; Kroenke Williams Susman JL,Susman Cr Gerber PD, Barrett J, Barrett J, Manheimer E, R, Whiting Smith Manheimer J, Barrett J, Barrett Gerber PD, Tuck AN, Scribani MB, Grainger SD, Johns CA, Knight RQ. The CA, The Johns RQ. Scribani SD, Knight MB, AN, Grainger Tuck Yesavage JA, Brink TL, Rose TL, Lum O, Huang V, Adey M, et al. et M, Adey V, JA, Brink TL, Huang TL, Rose O, Lum Yesavage De Cosmo G, Congedo E, Lai C, Primieri P, Dottarelli A, Aceto P. A, P. Dottarelli Aceto E,C, Lai Congedo Primieri P, G, DeCosmo . . . . . 6 7 8. 9. 1. 2 3 4. 5. 13. 14. 10. 11 12. Dong-jin Shim, https://orcid.org/0000-0002-8704-529X https://orcid.org/0000-0002-8704-529X Dong-jin Shim, https://orcid.org/0000-0002-7740-9424 Lee, Hochul https://orcid.org/0000-0002-9236-5183 Kim, Joo-Duck https://orcid.org/0000-0001-6614-9244 Donghee Kang, ------] reported that that ] reported 20 [ ] reported that in the the in that ] reported 21 [ Correlation between patient health questionnaire-2 and postoperative pain postoperative and questionnaire-2 health patient between Correlation ]. Brander et al. ]. Brander ORCID 18 [ CONFLICTS OF INTEREST CONFLICTS AUTHOR CONTRIBUTIONS Conceptualization: Yusom Shin. Data acquisition: Tae Tae acquisition: Data Shin. Yusom Conceptualization: No potential conflict of interest relevant to this article this article to relevant conflict of interest potential No In conclusion, the PHQ-2 test is composed test the PHQ-2 of two conclusion, simple In This study has a few limitations. First, anxiety in not was First, a few limitations. has study This www.anesth-pain-med.org Yusom Shin, https://orcid.org/0000-0002-4829-0866 Shin, Yusom https://orcid.org/0000-0003-4032-4424 Park, Woo Tae https://orcid.org/0000-0003-2330-1458 Kim, Huiyoung inal draft: Yusom Shin, Tae Woo Park. Writing—review & & Writing—review Park. Woo Tae draft: Shin, inal Yusom Donghee Lee, Kang. Hochul editing: Woo Park, Dong-jin Shim. Formal analysis: Huiyoung Kim. Kim. analysis: Huiyoung Formal Dong-jin Shim. Park, Woo Writing—orig Donghee Kang. Kim, Supervision:Joo-Duck was reported. reported. was score, the PHQ-2 score was associated with the dosage of with associated of was the dosage score PHQ-2 the score, be expected could to demand and the analgesic analgesics, with scores. bePHQ-2 high higher pression. Despite the simple questions, it highly correlated correlated it highly questions, Despite the simple pression. peri postoperative in the early consumption with fentanyl used cut-off as the were when 3 points od. Particularly, questions and can be performed and can questions in two minutes; therefore, de preoperative for test be useful screening a as could it more aggressively by increasing the amount of pain medi of pain the amount increasing by aggressively more with scores. PHQ-2 high in patients IV-PCA cation to have higher analgesic requirements and more negative negative and more requirements analgesic higher have to control pain evaluate could studies effects Future of pain. pain postoperative when controlling satisfaction or patient group with depression, the pain threshold was lower than than lower was threshold pain the withdepression, group who patients Depressed without depression. in the group believed were pain for postoperative thresholds lower had tend to assess the efficacy of PHQ-2 as a predictor of post assess the efficacy to tend as a predictor of PHQ-2 et al. Marazziti pain. operative Second, the diagnosis of depression was not an inclusion not an inclusion was Second, of depression diagnosis the who on patients study in a controlled criterion. Therefore, we in disorders, for depressive diagnosed or treated were depression had a greater effect on postoperative chronic chronic effect on postoperative a greater had depression surgery anxiety before should anxiety. than Patients’ pain been examined confirm to with its association pain. have vestigated. Anxiety plays a major role in acute pain, includ pain, in acute role a major Anxiety plays vestigated. pain postoperative ing Anesth Pain Med Vol. 15 No. 2

tient-controlled analgesia. Clin J Pain 2008; 24: 399-405. operative anxiety and depression on the postoperative pain in 15. Shin JH, Kim HC, Jung CH, Kim JB, Jung SW, Cho HJ, et al. The ear, nose and throat surgery. Indian J Otol 2012; 18: 82-7. Standardization of the Korean Version of the Patient Health 19. Kang DH, Kim DS, Kim JD, Kim JW. A comparison of fentanyl Questionnaire-2. J Korean Neuropsychiatr Assoc 2013; 52: 115- and morphine for patient controlled analgesia after laparo- 21. scopic cholecystectomy. Anesth Pain Med 2013; 8: 21-5. 16. Schade V, Semmer N, Main CJ, Hora J, Boos N. The impact of 20. Brander VA, Stulberg SD, Adams AD, Harden RN, Bruehl S, Sta- clinical, morphological, psychosocial and work-related factors nos SP, et al. Predicting total knee replacement pain: a pro- on the outcome of lumbar discectomy. Pain 1999; 80: 239-49. spective, observational study. Clin Orthop Relat Res 2003; 17. Oztekin HH, Boya H, Ozcan O, Zeren B, Pinar P. Pain and affec- (416): 27-36. tive distress before and after ACL surgery: a comparison of am- 21. Marazziti D, Castrogiovanni P, Rossi A, Rosa C, Ghione S, Di ateur and professional male soccer players in the early postop- Muro A, et al. Pain threshold is reduced in depression. Int J erative period. Knee 2008; 15: 368-72. Neuropsychopharmacol 1998; 1: 45-8. 18. Kavakci Ö, Altuntas EE, Müderris S, Kugu N. Effects of the pre-

246 www.anesth-pain-med.org General ------

]. However, these modifica ]. However, Case Report Case Report 7 , 6 [ We performed submental intubation by using a laparo using by performedintubation submental We was then used as a passage for inserting the endotracheal then used for insertingwas as a passage endotracheal the and trauma reduced trocar use The of a laparoscopic tube. time. intubation There are several modifications of this technique, includ of this technique, modifications several are There tra the Seldinger technique and useing of percutaneous kit dilatation cheostomy as oc such problems, with associated potential tions are and blood soft tissues by tube of endotracheal clusion effective a more identify to we attempted Therefore, clots. con trocar A laparoscopic intubation. of submental way a of creation After needle. trocar and sleeve trocar of sists nee position, the trocar in the desired withpassage trocar is inserted and the instrument subsequently dle is removed sleeve. the trocar through trocar The passage. a submental in making scopic trocar 247 - - - - - eISSN 2383-7977 • Submental intubation with laparoscopic trocar is a one-step method and is is and method is a one-step trocar with laparoscopic intubation Submental Submental intubation is commonly used during general anesthesia for maxil for anesthesia general during used is commonly intubation Submental Airway management; Intubation, intratracheal; Maxillofacial injuries; Trocar. Trocar. injuries; Maxillofacial intratracheal; Intubation, management; Airway ]. Furthermore, ]. Furthermore, : A 52-year-old male with maxillofacial injury was scheduled to undergo an open reduc an open undergo to scheduled was injury with maxillofacial male : A 52-year-old 5 – 1 Keywords: Keywords: lofacial surgeries as it provides a safe unrestricted surgical access compared to tracheosto to access surgical compared unrestricted a safe as it provides surgeries lofacial en in the lodged can become clots tissues blood soft and intubation, submental my. During trocar. used a laparoscopic we this problem, overcome To tube. dotracheal Case trocar, laparoscopic using intubation submental performed We fixation. internal and tion convention Unlike tube. endotracheal the insertion of the for space sufficient created which less significantly caused dissection and blunt any require not did method our methods, al less time. significantly required and tissuesoft damage Conclusions: with less complications. technique easy-to-perform and quick Novel alternative for submental intubation intubation for submental alternative Novel - - A case report Choi, Ju, Sijin Ji Youn Byung Hoon Yoo, Inyoung Jung, Lee Yong and Woo Lim, Yun-Hee Kye-Min Kim, Jun Heum Yon, Hospital, Inje University Medicine, Sanggye Paik and Pain Department of Anesthesiology Seoul, Korea College of Medicine, Background: Anesth Pain Med 2020;15:247-250 2020;15:247-250 Med Pain Anesth https://doi.org/10.17085/apm.2020.15.2.247 pISSN 1975-5171 ]. Therefore, submen ]. Therefore, 8 – 6 [ ]. Moreover, it can be reversed after after be reversed it can ]. Moreover, 5 , 4 July 24, 2019 24, July September 25, 2019 September September 24, 2019 24, September Submental intubation is commonly performed is commonly intubation during Submental 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 which (http://creativecommons.org/licenses/by-nc/4.0) License Non-Commercial Attribution Commons Creative the of terms the under Access article is an Open This distributed cited. is properly work original the provided in any medium, reproduction and distribution, use, non-commercial unrestricted 2020 Anesthesiologists, Society of Korean © the Copyright cations of surgical tracheostomy tracheostomy of surgical cations surgeries. widely is used maxillofacial in intubation tal surgery, allowing easy extubation of the patient. In addi In of the patient. surgery, extubation easy allowing serious compli potentially the avoids technique this tion, interferes with the surgical approach during maxillofacial during maxillofacial approach with the surgical interferes and undisturbed provides intubation submental surgeries, [ access surgical safe complex fractures in maxillofacial injuries may lead to the to lead injuries in maxillofacial may fractures complex turbi nasal by tube of the nasotracheal occlusion luminal intubation nasotracheal While blood clots. mucous, nates, complications, including epistaxis, accidental cranial or in cranial accidental epistaxis, including complications, [ and meningitis intubation, tracranial midface or nasoethmoidal of comminuted the presence general anesthesia for maxillofacial surgeries, especially in surgeries, for maxillofacial anesthesia general potential cause can intubation nasotracheal where cases Tel: 82-2-950-1170 Tel: 82-2-950-1323 Fax: [email protected] E-mail: Inje University College of Medicine, Medicine, of College University Inje Seoul Nowon-gu, Dongil-ro, 1342 Korea 01757, Byung Hoon Yoo, M.D., Ph.D. M.D., Ph.D. Yoo, Hoon Byung and Anesthesiology of Department Hospital, Paik Sanggye Medicine, Pain Corresponding author author Corresponding Revised Revised Accepted Received Received Anesth Pain Med Vol. 15 No. 2

CASE REPORT ed to the breathing circuit (Fig. 2). The position of the tracheal tube was checked using capnography and chest aus- Informed consent was obtained from the patient for the cultation, and the distance marking on the endotracheal publication of this report. tube at the exit site on the skin was carefully noted. The A 52-year-old male with fractures of the zygomaticomax- tube was then secured to the skin of the submental region illary, zygomatic arch, and right inferior orbital floor (Lefort with a heavy (2⁄0) black silk suture. The surgery was suc- II fracture) was scheduled to undergo open reduction and cessful and without any adverse effects. After completion internal fixation. For this patient, instead of conventional of the surgery, the abovementioned procedures were re- nasotracheal intubation, we planned a submental intuba- versed. The skin sutures were cut, and the tracheal tube tion because nasotracheal intubation in patients with Lefort II was briefly disconnected from the breathing circuit. There- or III fracture can lead to potential complications, such as intra- after, the connector was removed and the tube was pulled cranial intubation, meningitis, and the luminal occlusion of en- back through the passage in the floor of the mouth. The dotracheal tube by nasal turbinates, mucous, and blood clots. connection was then reestablished and the tube was se- However, even submental intubation has several complications cured. The submental incision was closed using three associated with its use. To overcome these problems, we used a monofilament skin sutures, which were removed 5–7 days 12-mm laparoscopic trocar (Laport, Korea) for pulling out the postoperatively. No attempt was made to close the oral defect. endotracheal tube from the oral cavity to the submental area The use of a laparoscopic trocar for submental intuba- during submental intubation. Before the procedure, we con- tion significantly reduced the inflow of soft tissues and firmed that the armored endotracheal tube (internal diameter, blood into the endotracheal tube. This method was much 7.5 mm) could pass through the trocar. After removal of the easier than the passing the tube from the oral cavity to the connector of the armored tube, the endotracheal tube was submental incision site. passed through the trocar's 12-mm diameter internal lumen (Fig. 1). DISCUSSION After standard orotracheal intubation, the tongue was retracted to expose the floor of the mouth. After making a Submental intubation is an effective alternative for air- 1.5-cm incision, the 12-mm laparoscopic trocar was passed way management in select patients undergoing surgery for in the skin-to-oral direction. After ventilating the patient maxillofacial injuries. It avoids complications associated with 100% oxygen for several minutes, the tracheal tube with tracheostomy, such as hemorrhage, emphysema, tube was briefly disconnected from the breathing circuit. The blockage, tracheal stenosis, and scarring [6,8,9]. In addi- connector of the armored tube was removed and the proxi- tion, it provides unrestricted access to the surgical site. mal part of the tube was pulled through the passage in the Generally, submental intubation is performed after stan- lumen of the trocar. Thereafter, the trocar was removed. dard orotracheal intubation. After submental incision and The connector was reattached and the tube was reconnect- dissection towards the mouth floor, the proximal part of

A B A B

Fig. 1. (A) Removal of the armored tube connector. (B) The Fig. 2. (A) The 12-mm laparoscopic trocar is inserted in the skin- armored endotracheal tube (internal diameter, 7.5 mm) passes to-oral direction. (B) The tube is pulled through the passage of the through the 12-mm diameter lumen of the laparoscopic trocar. trocar’s lumen.

248 www.anesth-pain-med.org General ------.

249

ORCID REFERENCES , Chira T. Perimortem intracranial orogastric tube tube orogastric Perimortem intracranial T. , Chira AUTHOR CONTRIBUTIONS CONTRIBUTIONS AUTHOR

T, Orser BA. External compression of a nasotracheal tube tube Orser BA. of a nasotracheal compression External T,

e AS, Borle RM, Madan RS, Bhola ND, Jadhav AA, Bhoyar Jadhav ND, Bhola RS, Borle RM, Madan e AS, Sprung J, Bourke DL, Harrison C, Barnas GM. Endotracheal DL, Bourke GM. Endotracheal C, Harrison Barnas J, Sprung Junsanto T Junsanto Walker DG. Complications of tracheostomy: their prevention their prevention of tracheostomy: Complications DG. Walker Bähr W, Stoll P, Schilli W, Scheramet R. [Nasal intubation for for intubation R. Schilli [Nasal W, Scheramet P, W, Stoll Bähr Kita R, Kikuta T, Takahashi M, Ootani T, Takaoka M, Matsuda M, Matsuda Takaoka M, Ootani T, Takahashi T, R, Kikuta Kita Schade K,Schade of malposition Borzotta A, A. Michaels Intracranial tubation compared with tracheostomy in maxillofacial trauma trauma in maxillofacial with tracheostomy compared tubation Sci 2016; 58: 23-8. J Oral patients. a prospective intubation: endotracheal submental tions from 2013; 29: 197-202 Traumatol Dent review. and literature study in intubation endotracheal Transmylohoid/submental AG. frontobasal fractures?]. Dtsch Zahnarztl Z 1992 47: 43-5. Ger fractures?]. frontobasal man. frac with skull a basilar patient insertion in a pediatric trauma 1997; 42: 746-7. J Trauma ture. 49: 967-8. 2000; nasopharyngeal airway. J Trauma frac LeFort of multiple fragments the displaceddue to bony Anesthesiology 2000; 92: 1830-2. tures. of hypoventi obstruction as causes and tracheobronchial tube 1994; 105: 550-2. Chest with inspiratory pressures. high lation 2017; 43: Surg Emerg J Trauma Eur technique. dilational novel 359-62. 1973; 31: 480-2 Surg J Oral and treatment. in tracheal of submental M, et al. Efficacy and complications Joo D Ujam A, Perry M. Minimally traumatic submental intubation: a intubation: submental A,Ujam traumatic Perry M. Minimally Tidk de Toledo GL, SC, Bueno RA, Mesquita MB. Complica de Toledo Amaral . . Conceptualization: Byung Hoon Yoo, Inyoung Jung. Data Data Jung. Inyoung Yoo, Hoon Byung Conceptualization: 9 1. 2. 3. 4. 5. 6. 7 8. 10. acquisition: Ji Young Ju, Sijin Choi. Writing—original draft: Writing—original Choi. Sijin Ju, Young Ji acquisition: Yoo, Hoon Byung & editing: Writing—review Jung. Inyoung Lee. Yong Woo Lim, Yun-Hee Kim, Kye-Min Yon, Heum Jun https://orcid.org/0000-0002-6221-9177 Jung, Inyoung https://orcid.org/0000-0002-1958-8380 Yoo, Hoon Byung https://orcid.org/0000-0001-9069-4189 Ju, Youn Ji https://orcid.org/0000-0003-1860-3320 Choi, Sijin https://orcid.org/0000-0002-2997-2191 Yon, Heum Jun https://orcid.org/0000-0003-1298-7642 Kim, Kye-Min https://orcid.org/0000-0003-2399-4768 Lim, Yun-Hee https://orcid.org/0000-0002-1632-1314 Lee, Yong Woo ------Submental intubation with a trocar intubation Submental ]. Moreover, we did not perform dissec blunt ]. Moreover, CONFLICTS OF INTEREST CONFLICTS 0 1 [ ]. However, our technique required significantly less less significantly technique required our ]. However, 12 , No potential conflict of interest relevant to this article this article to relevant conflict of interest potential No We therefore recommend performing in the submental recommend therefore We 11 www.anesth-pain-med.org was reported. reported. was tubation technique using a laparoscopic trocar. trocar. a laparoscopic technique using tubation a rapid one-step method, which is easy and quick to per to and quick method, is easy which one-step a rapid form complications. withminimal mal hemorrhage. Moreover, the laparoscopic trocar is a de trocar the laparoscopic Moreover, hemorrhage. mal Thus, room. in the operating accessible is easily vice which is intubation for submental trocar the use of a laparoscopic [ time (< did not tube the endotracheal 5 min). Additionally, and mini damage soft tissue of reduced occlude because tube through the submental area; however, the percutane area; the submental however, through tube min 10 than less took kit dilatation tracheostomy ous ously, it took 15–20 min to perform the Kelly's blunt dissec blunt performit tookto 15–20 min ously, the Kelly's time needed cre to of the prolonged because tion, mostly of the endotracheal for the passage space sufficient ate be similar with that occurring during the conventional occurring withbe similar during the conventional that method Previ damage. soft tissue minimal caused tion, and thus, during conventional blunt dissection. Therefore, the de dissection. Therefore, blunt during conventional to is considered intubation with submental damage of gree submental intubation due to misplacement of the trocar. In In of the trocar. misplacement due to intubation submental into inserting the trocar set by was the direction case, our applied that to similar the passage at incision the initial Injury to Wharton’s duct, sublingual salivary gland, and salivary and gland, sublingual duct, InjuryWharton’s to nerve as the lingual such in the floor other vital structures, arise can during that complications potential are of mouth, mately 1–2 mm larger than the outer diameter of the endo diameter the outer than 1–2 mm larger mately offered trocar a laparoscopic case, our In tube. tracheal tube. of the endotracheal the passage for space sufficient the 12-mm laparoscopic trocar. In our experience, it is ad experience, our In trocar. the 12-mm laparoscopic with of approxi an inner diameter use to a trocar visable lot line, a trocar with an inner diameter slightly larger than than larger withslightly diameter inner an trocar a line, lot we verified trocar, the using Before required. was mm 10.3 through pass could E-tube inner diameter 7.5-mm the that endotracheal tube. The outer diameter of the armored en armored of the diameter outer The tube. endotracheal However, 10.3 mm. used tube was case our in dotracheal of the connection betweenbecause and the pi the E-tube the endotracheal tube is pulled out through the submental the submental through out is pulled tube the endotracheal soft because is difficult tis this process However, incision. occlusion the of luminal cause and bloodsues can clots Anesth Pain Med Vol. 15 No. 2

pan-facial trauma: a paradigm shift in airway management craniomaxillofacial fractures: a case series. Indian J Anaesth with prospective study of 35 cases. Indian J Otolaryngol Head 2014; 58: 48-50. Neck Surg 2013; 65: 255-9. 12. Biswas BK, Joshi S, Bhattacharyya P, Gupta PK, Baniwal S. Per- 11. Saheb SM, Nath VN, Kumar KP, Padmaja PP. A novel method cutaneous dilational tracheostomy kit: an aid to submental using Seldinger's technique for submental intubation in major intubation. Anesth Analg 2006; 103: 1055.

250 www.anesth-pain-med.org General ------

Case Report Case Report CASE REPORT A 23-year-old, 168 cm tall female patient, weighing 42 kg, 42 kg, weighing patient, 168 cm tall female A 23-year-old, The present case report was published with the prior published with was the prior report case present The visited the emergency room with a chief complaint of ab of visited with the emergency complaint a chief room nau by accompanied pain, abdominal The pain. dominal hours. eight for gradually increasing kept seaand vomiting, developed ACS due to excessive eating, and in whom isch eating, developed ACS excessive due to injury,emia-reperfusion intravascular and disseminated decompression, (DIC) surgical after occurred coagulation death. to leading guardians. of the patient’s consent

251 - - - eISSN 2383-7977 • Under suspected ACS conditions, we should be aware of various symptoms symptoms various of be aware should we conditions, ACS suspected Under Abdominal compartment syndrome (ACS) occurs due to increased abdominal abdominal increased occurs to due (ACS) syndrome compartment Abdominal Bulimia; Intra-abdominal hypertension; Reperfusion injury; Shock, hemorrhagic. Shock, injury; Reperfusion hypertension; Intra-abdominal Bulimia; A patient presented with rapid stomach swelling due to excessive food intake and and intake food excessive to due swelling stomach with rapid presented A patient : ulation, which occurred after surgical decompression. decompression. surgical after occurred which ulation, Conclusions: be pre it is important to and helpful, are decompression for attempts Early can occur. that attempts. decompression surgical to prior injury reperfusion for pared Keywords: cavity pressure, causes multiple organ damage, and leads to fatal consequences. Increased Increased consequences. fatal to leads and damage, organ multiple causes pressure, cavity dam in serious result does not generally reasons different to due pressure intraperitoneal the exceeds pressure the when However, wall. abdominal the of compliance the to due age, organs. the to damage fatal causing thereby develops, limit, ACS Case ab changes, Mental in ACS. resulted now had which nervosa, bulimia have to known was seen. were acidosis and injury, kidney legs, acute in the change color distension, dominal coag intravascular disseminated and injury ischemia-reperfusion to due expired patient The Background: Abdominal compartment syndrome caused by caused syndrome compartment Abdominal and fatal in bulimia nervosa gastric distension surgical decompression injury following - - A case report Tae, Hyun Kyoung Lim, Nayoung Byeong Hun Eom, and Helen Ki Shinn Hospital, Inha Medicine, Inha University and Pain Department of Anesthesiology Medicine, Incheon, Korea University School of Anesth Pain Med 2020;15:251-258 2020;15:251-258 Med Pain Anesth https://doi.org/10.17085/apm.2020.15.2.251 pISSN 1975-5171

November 19, 2019 19, November August 20, 2019 August

November 15, 2019 15, November Along with a literature review, the authors seek to report seek report to the authors review, withAlong a literature Abdominal compartment syndrome (ACS) is a disease (ACS) is a disease syndrome compartment Abdominal 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 which (http://creativecommons.org/licenses/by-nc/4.0) License Non-Commercial Attribution Commons Creative the of terms the under Access article is an Open This distributed cited. is properly work original the provided in any medium, reproduction and distribution, use, non-commercial unrestricted 2020 Anesthesiologists, Society of Korean © the Copyright not commonly reported. not commonly their experience who had with nervosa a bulimia patient, inal wall compliance. Therefore, cases of ACS cases gas due to Therefore, compliance. wall inal are food intake excessive by caused distension trointestinal ACS may occur due to various causes that increase the in increase that causes occur various due to ACS may in IAP within a (IAP), an increase pressure tra-abdominal abdom due to damage organ does not cause certain range edema or increased pressure in the abdominal tissue, due due tissue, the abdominal in pressure or increased edema fluid excessive trauma, abdominal as sepsis, such factors to While or ascites. tumor, abdominal hematoma, supply, that causes multiple organ damage as a consequence of as a consequence of damage organ multiple causes that Fax: 82-32-881-2476 Fax: [email protected] E-mail: Medicine, 27 Inhang-ro, Jung-gu, Jung-gu, Inhang-ro, 27 Medicine, 22332, Korea Incheon 82-32-890-3968 Tel: Department of Anesthesiology and and Anesthesiology of Department University Inha Medicine, Pain of School University Inha Hospital, Corresponding author author Corresponding M.D., Ph.D. Shinn, Ki Helen Revised Revised Accepted Received Received Anesth Pain Med Vol. 15 No. 2

The patient was diagnosed with major depression and bu- pressure, 160 beats/min heart rate, 22 times/minute aspi- limia nervosa nine years ago. The patient also had a history ration rate, and 36.4°C temperature. Other findings includ- - of frequent vomiting after episodes of binge eating, along ed pH 7.076, PaCO2 22.3 mmHg, PaO2 122 mmHg, HCO3 with numerous suicide attempts. Ten hours before report- 6.3 mM/L, base excess (BE) 23.7 mM/L, and lactic acid 11.1 ing to the hospital, the patient ate a very large quantity mM/L, which were measured in the arterial blood gas anal- food, equivalent to approximately ten portions; however, the ysis and, thus, metabolic acidosis was confirmed. The electro- quantity of the vomit was much less, relative to the amount of lyte levels Na+ 157 mM/L, K+ 6.2 mM/L, and Cl- 130 mM/L, food taken. The physical examination revealed abdominal indicated that the electrolyte imbalance was severe (Table 1). pain and distension in the entire region, along with tender- In addition, the patient was in a severe hypoglycemic state ness, but no rebound tenderness. Subsequent abdominal with a blood sugar level of 15 mg/dl; because of an elevated computed tomography (CT) revealed clear gastric disten- creatinine level of 2.84 mg/dl, acute renal failure was suspect- sion. The results of various blood tests were normal. In the ed. First, to treat the metabolic acidosis, sodium bicarbonate joint general surgery consultation that followed, it was de- was set at 80 mEq/h. In the abdominal X-ray, the gastrointes- cided that an immediate surgical treatment was not neces- tinal tract (GIT) was seen to be filled with a large amount of sary; hence, the need for continuous observation of the food but without any bowel gas (Fig. 1). Abdominal CT re- condition was explained, and a gastroenterological or psychiatric hospitalization was advised, but both the patient and her guardians declined hospitalization. Afterward, they were warned of the possible complications, such as electrolyte imbalance, aspiration pneumonia, gastrointestinal perforation, ischemic changes, due to the pressure applied by gastrointestinal distension, and the possibility of death, in case the condition worsened. The self-discharge form was signed, and they returned home. Seven hours after returning home, the patient re-visited the emergency room due to persistent abdominal pain, and mental confusion. At the time of the visit, the patient was unconscious. On physical examination, a more severe abdominal distension, and signs of abdominal rigidity were observed. Both legs of the patient had turned pale in color. No auscultation sounds were heard over the abdomen, and the dorsalis pedis pulse was not felt on either Fig. 1. The plain abdominal X-ray image shows markedly dilated foot. Shock was suspected due to a 60/40 mmHg blood state in stomach with abundant food materials.

Table 1. Changes in Arterial Blood Gas Analysis

- + + Time pH pCO2 (mmHg) HCO3 (mM/L) Hb (g/dl) Na (mM/L) K (mM/L) Re-visit ER 21:23 7.07 22.3 6.3 14.9 157 6.2 Prior to OP 01:03 7.43 21.5 14.1 164 4 OP starts 03:20 1st 03:25 7.45 20.8 14.4 6.8 161 3.8 2nd 03:57 6.75 46 6.5 146 7.5 3rd 04:09 7.01 33.9 8.4 4.3 157 6.7 4th 04:28 6.98 22.1 5.2 5.9 154 6.7 5th 04:42 6.94 18.1 3.8 6.7 138 6 OP ends 05:05 ICU arrival 05:20 7.29 48.8 23.3 3.5 148 6.7 Expired* 08:10 6.91 34.4 7 1.8 Hb: hemoglobin, ER: emergency room, OP: operation, ICU: intensive care unit. *5 min before the patient expired.

252 www.anesth-pain-med.org General ------253 ). It was also suspected that insertion not possi also was suspected was that ). It Axial (A) and coronal (B) images of the abdomen-pelvis abdomen-pelvis the of (B) images coronal (A) and Axial B A After reaching the operation room, the patient’s blood blood the patient’s room, the operation reaching After There was no decompression through the nasogastric the nasogastric through no decompression was There Fig. 3 Fig. Fig. 3. Fig. tip in distal L-tube of coiling (CT). CT shows tomography computed esophagus. pressure was 70/46 mmHg and the heart rate was 128 128 was and the heart rate mmHg 70/46 was pressure crystal signs, the vital improve to in order First, beats/min. speed the via the highest at administered loid fluid was the central and via catheter venous peripheral arm’s right in The vein. jugular internal of the right catheter venous the esophagus, which made further insertion impossible. further made insertionwhich impossible. the esophagus, CT performedAn abdominal observation for follow-up re filled still with was the abdomen food, and the that vealed twisted the end of the esophagus was tube nasogastric at ( or esopha deviation junction gastroesophageal ble due to seen. was sign no such geal stenosis; however, of the patient state and as time passed, the mental tube, vital signs patient’s The of confusion. a state into changed and the symptoms Since unstable. became increasingly of per instead exacerbated, blood results test follow-up decided at it was to drainage, forming percutaneous a the patient subsequently, decompression; a surgical tempt the after hours six room the operation to transferred was of 3,170 ml of crys a total the emergency In room, re-visit. a 5% glucosetalloid fluid, in which solution included, was not measured. was volume Urine administered. was - - - ). Fig. 2 Fig. Abdominal compartment syndrome and complications due to bulimia nervosa bulimia to due complications and syndrome compartment Abdominal The abdomen-pelvis computed tomography axial (A) and (A) and axial tomography computed abdomen-pelvis The was measured to be 88%, endotracheal intubation intubation be to endotracheal 88%, measured was 2 B A www.anesth-pain-med.org Fig. 2. Fig. dilated stomach, distended markedly revealing images (B) coronal duodenum. proximal and distal esophagus insert a nasogastric tube to relieve gastrointestinal pres gastrointestinal insert relieve to tube a nasogastric near a blockage due to not drained the food was but sure, ter was inserted into the right jugular vein. For continuous continuous For vein. inserted jugular was the right ter into was a conduit vital signs, in the monitoring of changes artery. to made radial was placed in the right An attempt urine was drained; an emergency hemodialysis was pre emergency an was hemodialysis urinedrained; was cathe venous a central fluid supply, and for enough pared, impossible and spontaneous respiration decreased; as as decreased; respiration spontaneous and impossible SpO inserted, then was no but performed. catheter was A Foley aorta, and the right kidney was pressed upwards ( upwards pressed kidney was and the right aorta, the patient's One re-visit, the emergency after hour room became became lethargic—communication state mental vealed a very large dilation of the stomach, esophagus, and and esophagus, a veryvealed of the stomach, dilation large the second part of the duodenum; suspected it was that the descending the against pressing were organs distended Anesth Pain Med Vol. 15 No. 2 stillation of norepinephrine was initiated with sustained due to ischemia-reperfusion injury after surgical decom- dosing at an additional rate of 0.2 μg/kg/min, and continu- pression, and DIC. Since the patient’s vital signs steadily ous infusion of vasopressin at 4–8 unit/h was also initiated. worsened, it was decided that the abdomen be closed ur- Subsequently, general anesthesia was induced using sevo- gently, and the patient moved to the intensive care unit flurane 1–2 vol% and rocuronium 50 mg. In the arterial (ICU). blood gas analysis conducted after entering the operating One hour after the start of the operation, suturing after + room, pH 7.45, PaCO2 20.8 mmHg, PaO2 335 mmHg, Na gastrectomy was completed. When the closing of the abdo- 161 mM/L, K+ 3.8 mM/L, glucose 205 mg/dl, lactate 13 men started, non-invasive blood pressure was not mea- - mM/L, hemoglobin 6.8 g/dl, and HCO3 14.4 mM/L were sured, and flat waveforms were observed in the catheter of measured (Table 1). Four units of erythrocytes were pre- the right radial artery. There was no pulse detected via pal- scribed to correct the reduced hemoglobin, and 20 mg of pation, and after confirming pulseless electrical activity furosemide was injected due to a continuous lack of urina- through the observation of electrocardiogram, an addition- tion. Furthermore, for rapid transfusion, the rapid infusion al 1 mg of epinephrine was injected, and cardiopulmonary system (RIS) was connected to the central venous catheter resuscitation (CPR) was initiated. of the right internal jugular vein, and the transfusion of A total of 3 mg of epinephrine was injected, with cardiac four erythrocyte units was initiated. rhythm monitoring at 2 min intervals; afterward, 2 units of The operating surgeon planned and performed a gastrot- vasopressin were injected at 2 min intervals, totaling an in- omy, after making a skin incision of approximately 10 cm jection of 4 units of vasopressin. After completing the ab- and within 20 min of beginning the surgery. The food and dominal closure while performing CPR, the patient was 5,000 ml of body fluid present in the stomach were drained transferred to the intensive care unit, and no urine output via suction. Thirty minutes after the operation, blood pres- was seen until the patient left the operation room. sure was maintained low at 60/40 mmHg and almost all The operation was conducted for 1 h 20 min, and the an- food was drained; as a large amount of continuous gastric esthesia time was 1 h 50 min. During the operation, a total bleeding occurred after decompression, a total of 6,000 ml of 800 ml, four erythrocyte units, were transfused, and was drained into the suction bottle. In the follow-up arteri- 6,200 ml of crystalloid fluid were administered. A total of al blood gas analysis, results showed: pH 6.75, PaCO2 46 6,000 ml was drained into the suction bottle—5,000 ml of mmHg, and lactate 20 mM/L. Acidosis had worsened, the food and body fluid through the suction unit via gastrecto- blood sugar level had significantly increased to 469 mg/dl, my, and 1000 ml due to bleeding that had occurred after electrolyte imbalance had exacerbated with K+ 7.5 mM/L, decompression from the start of the operation until finish; and hemoglobin had fallen to 4.3 g/dl, suggesting a large however, as mentioned earlier, the incision area was small, amount of bleeding. To correct this, 60 mEq of sodium bi- and bleeding occurring from other abdominal organs carbonate, and two units of insulin were administered. could not be confirmed, making it difficult to estimate the Further, 1.2 g of calcium chloride was administered to treat exact estimated blood loss. Additionally, prescribed eryth- hyperkalemia. Moreover, additional 20 μg of epinephrine rocytes and fresh frozen plasma were transfused through was injected to correct persistent hypotension. the RIS as the patient left the operation room. Bleeding in the stomach continued, and despite initiat- After entering the ICU, CPR was stopped due to a return ing erythrocyte transfusion via RIS, hemoglobin level de- of spontaneous circulation, but the existing usage of epi- creased. As a result, a large amount of internal bleeding nephrine, norepinephrine, and vasopressin was preserved, was suspected, and additional eight units of erythrocytes, and transfusion continued. However, blood pressure was and eight units of fresh frozen plasma were prescribed. The still not measured, an additional 1,000 ml of bleeding was operating surgeon tried to determine the cause and area of confirmed through the nasogastric tube, and bleeding from bleeding, but as the surgical incision was only 10 cm, ab- the closed abdominal area continued. Subsequently, as 3.5 dominal organs other than the stomach could not be iden- g/dl hemoglobin was measured in the follow-up test, trans- tified with the naked eye. To reduce bleeding, the operating fusion continued, and a 113.1-second prothrombin time, surgeon considered performing a total gastrectomy or ex- 180-s activated partial thromboplastin time, and platelet tending the abdominal incision to confirm the bleeding ar- count of 22,000/μl were found, confirming that the patient eas from, other organs but concluded that the bleeding was was in a state of DIC. Despite continuous drug administra-

254 www.anesth-pain-med.org General ------], a ], a 4 255 ], in ] also 6 7 [ O immediately after an after O immediately O after surgical decom surgical O after 2 2 ]. 3 [ ]. The reported risk reported in factors ]. The 3 [ ] reported that from an IAP of 15–20 IAP of 15–20 an from that ] reported 8 [ O PEEP), we conjectured that the IAP in IAP the that we PEEP), O conjectured 2 ], IAP grades can be divided into Grade I Grade be divided into can ], IAP grades = ]. In their study, Flores-Alvarez et al. Flores-Alvarez their study, ]. In 3 3 [ [ ]. 5 [ In the IAP measuring method recommended by WSACS, WSACS, by method the IAP measuring recommended In As mentioned above, IAP is important because through through because is important IAP above, As mentioned mmHg IAP, anuria occurs; taking into consideration that that occurs; anuria consideration into taking IAP, mmHg a anuria, of state a in was case present the in patient the IV beena grade in having patient the of possibility high as The be inferred. can 30 mmHg with an IAP above state such for causing responsible be considered could pect that IAP in an increased in kidney function is that a decrease compressed and portal are vein cava the inferior vena state, reported reported and con bladder solutionsaline the empty is injected into transducer the pressure to nects catheter the inserted Foley and monitor ACS obtain an early indirectly IAP to measured indirectly were IAH III–IV grade and anuria notedand that diagnosis the mortality. In impacting factors important the most due not be measured the IAP could however, case, present ade of lack a and measurement IAP for time of lack a to et al. [ Torquato to According equipment. quate reference With the airway pressure. IAP increases creased between positive the correlation regarding this finding to the air that given and IAP, (PEEP) end expiratory pressure 28 cmH to increased pressure way 10 cmH to and dropped esthesia control (volume setting ventilator under the same pression 12 times/min respi volume, 400 ml tidal mode, ventilation cmH 6 rate, ration Furthermore, state. elevated in a significantly was this case and Shapiro Bailey 30 above and decrease, starts to urine volume mmHg, recommends measuring IAP in patients who possess risk who possess risk IAP in patients measuring recommends with patients’ is correlated IAH since ACS, for IAH or factors pre and treating morbidity mortality and and, therefore, important are it venting position, prone surgery, trauma, abdominal clude major these infection. circumstances Among and intra-abdominal swell gastrointestinal included as risk factors, were which suggest case, in our present were sepsis, and acidosis, ing, of ACS possibility a high ing be predict can and prognosis state present the patient´s it, Kirk to with mortality.ed,it is correlated and According et al. patrick II Grade 15 mmHg, IAP 12 to = Grade 20 mmHg, IAP 16 to III = IV and Grade 25 mmHg, IAP 21 to = IAP > 25 mmHg. et al. [ performed the study to Prasad by According with a higher correlated significantly IAP grade higher been mortality 71–85% has IV case, Grade a mortality.In ------]. 3 ], while gastrointestinal gastrointestinal while ], ] reported similar cases. cases. similar ] reported 1 2 [ [ Abdominal compartment syndrome and complications due to bulimia nervosa bulimia to due complications and syndrome compartment Abdominal DISCUSSION ] and Youm et al. ] and Youm 1 [ IAH, which can be considered as the stage before ACS, ACS, before as the stage be considered can IAH, which To understand ACS, it is important to first differentiate differentiate first to important is it ACS, understand To Kim et al. Kim Dozens of cases have been reported that required surgi required been that reported have of cases Dozens ], changes in the vital signs and mental state also oc state and mental the vital signs in ], changes 2 www.anesth-pain-med.org can also cause various severe complications. The World So World The complications. severe various also cause can (WSACS) Syndrome Compartment ciety of the Abdominal stricted, and the increased pressure causes fluids to pene fluids to causes stricted, pressure and the increased further of the abdomen, in organs the various into trate [ failure organ causing thereby the pressure, creasing nal pressure (AP) exceeds the abdominal wall compliance, compliance, wall (AP) exceeds the abdominal pressure nal becomes re the organs to of bloodthe supply and oxygen only means a state of increased IAP but also a state in in also IAP but a state of increased a state means only a new or by accompanied 20 mmHg, IAP is above which in abdomi When the increase dysfunction. organ ongoing the normal level. IAP is defined as the pressure in the ab IAP is defined level. as the pressure the normal normal. While IAH is is considered domen, and 5–7 mmHg ACS not 12 mmHg, IAP is above in which defined as a state between ACS and intra-abdominal hypertension (IAH). (IAH). hypertension between ACS and intra-abdominal above IAP increases of the two is that common feature The fore decompression, including mental state changes and and changes state mental including decompression, fore failure. respiratory curred two hours after admission. However, in this case, case, in this However, two admission. after curred hours hos the since present were and acidosis failure renal acute seen be even were ACS symptoms and severe pital visit, no signs of other organ failures were seen, thus showing no showing seen, thus were failures of other organ no signs al. et Youm by report case the In of ACS. symptoms clear [ overeating were shown before surgical decompression, vi decompression, surgical before shown were overeating and normal, closeto were results blood test and signs tal In the case report by Kim et al. al. et Kim by report the case In due to leg and pain, color changes abdominal distension, prior decompression, causing hypovolemic shock due to due to shock hypovolemic causing prior decompression, inju ischemia-reperfusion by caused hemorrhage massive ry death. to leading and DIC, ultimately which ACS occurred due to rapid abdominal distension distension abdominal ACSwhich rapid due to occurred and eating, binge to due necrosis, or perforation without performed was without decompression effective surgical addressed the problems associated with the occurrence of with associated the occurrence the problems addressed in reported, is not commonly a case such However, ACS. cal treatment due to bulimia nervosa, the prob bulimia mentioned to due treatment cal or or perforation, necrosis gastrointestinal by lems caused tion and transfusion, the hemoglobin level decreased to 1.8 to hemoglobin the decreased level tion and transfusion, disap the heartbeat in the ICU, hours three after g/dl, and dead. declared was the patient and peared, Anesth Pain Med Vol. 15 No. 2 due to pressure; venous return decreases and the intra-tho- mortality [5]. Therefore, in order to prepare for the phe- racic pressure increases, thereby reducing the flow of the nomenon of ischemia- reperfusion, systemic vascular re- superior and inferior vena cava and, thus, reducing the sistance, and a rapid decrease of IAP after decompression, cardiac output. According to the report by Bailey and Sha- the administration of sufficient fluid is needed before de- piro [8], even after the restoration of cardiac output in a compression [9]. state of renal failure due to ACS, the impairment of kidney Since the problems caused by increased IAP are import- function did not recover. Through this observation, they ant, the treatment and prevention of IAH and isch- reported that rather than the cause of renal failure being emia-perfusion injury are also important. According to the influenced by decreased cardiac output, if the parenchyma ACS guideline published by the WSACS in 2013, it was rec- of the kidney was compressed, renal vascular resistance ommended that anxiety and pain be reduced in patients could increase from 500% to 1,500%, and this phenomenon through sedation and anesthesia to prevent and treat IAH; could increase the secretion of renin, antidiuretic hor- it also reported that temporary use of neuromuscular mones, and aldosterone, further increasing the renal vas- blockers can reduce IAP by reducing the abdominal muscular resistance and exacerbating renal dysfunction [8]. cle tension, and increasing abdominal compliance [3]. Ma- Therefore, it is necessary to anticipate that high grade IAH calino et al. [13] reported that neuromuscular blockers im- and high mortality rates may be present in cases of exacer- proved IAP, blood pressure, airway pressure, and urine bation and to prepare for active treatment. output volume before surgery. Moreover, in case intraperi- Saggi et al. [9] reported that intestinal perfusion damage toneal fluid is clearly present in the abdominal cavity, per- occurs at mucosal and submucosal levels in IAPs above 20 cutaneous drainage was deemed to be helpful, and it was mmHg, which reduces tissue oxygen tension and increases recommended to attempt a decompression via a nasogas- acidosis and free radical production. This ischemic dam- tric or rectal catheter if the GIT was enlarged. Diuretics, al- age, increased free radicals, and endotoxins lead to multi- bumin, and dialysis, on the other hand, were not helpful ple organ failure [10]. Recent studies have revealed a cor- and therefore, not recommended. While the aforemen- relation between increased IAPs above 10 mmHg with sep- tioned methods can improve the patients’ state, ultimately sis, mortality, and multiple organ failure [9]. a surgical method should be employed, and decompres- An important factor contributing to the death of patients sion laparotomy should be performed in order to reduce with long-term failure due to ACS is ischemia-reperfusion IAP and improve the organ function. Muresan et al. [14] in- injury. This means that the tissue damage occurs when tis- vestigated how decompression laparotomy could reduce sues are reperfused after a period of ischemia, during mortality in patients with ACS. Treatment in this study which blood is not supplied or oxygenated for any reason. used a four-step therapy protocol. The first step was to in- During the ischemic period, many changes occur in the sert a nasogastric catheter into the patient, give an ade- cells; if ischemia persists, the cells die, or if reperfusion oc- quate sedation effect, and not to supply excessive fluids. curs in already changed cells, the cells generate free radi- Step two was to manage the edema of the tissue using di- cals. The resulting oxidative stress causes inflammatory uretics and hypertonic or colloid solutions in a Trelenden- and oxidative reactions that damage tissues. When this burg position. Step three was to stop nutrition and insert a damage occurs in microvessels, the permeability of the rectosigmoid aspiration catheter or puncture for discharge cells increases, and fluids, including blood, easily escape using ultrasound or CT to decompress the colon before the tissues [11,12]. Such tissue damage is likely to worsen mechanical ventilation after endotracheal intubation. In organ failure and simultaneously cause massive hemor- step four, despite the medical treatment, surgical decom- rhage and induce DIC. pression was attempted if the IAP remained above 20 Reperfusion syndrome can frequently occur during de- mmHg after 24 h after IAP elevation. After decompression, compression surgery and be a cause of death. Rapid dila- the Vivano® Med Abdominal Kit (Paul Hartmann AG, Ger- tion of the abdominal and pelvic vein after decompression, many) was used to continuously lower IAP and reduce the and tissue damage and increased blood vessel permeabili- tissue edema. The Vivano® Med Abdominal Kit used foams ty due to ischemia-reperfusion injury cause massive hem- and layers to keep the abdominal wound open without su- orrhage, leading to a state of low blood pressure, cardiac turing and to control the intraperitoneal pressure using a atrophy and ventricular arrhythmias, and resulting in high suction catheter connected to the foam. Several days later,

256 www.anesth-pain-med.org General ------

257 World So World

uez JL, Reynoso-Talamantes D. D. JL,uez Reynoso-Talamantes

ean Surg Soc 1: S1-5. 2011; 81 Suppl Surg ean ORCID . REFERENCES CONFLICTS OF INTEREST OF INTEREST CONFLICTS AUTHOR CONTRIBUTIONS Torquato JA, Lucato JJ, Antunes T, Barbas CV. Interaction be Interaction CV. Barbas T, Antunes JJ, JA, Lucato Torquato Kirkpatrick AW, Roberts DJ, De Waele J, Jaeschke R, Malbrain R, Malbrain Jaeschke J, De Waele Roberts DJ, AW, Kirkpatrick Bailey J, Shapiro MJ. Abdominal compartment syndrome. Crit syndrome. compartment Abdominal MJ. Shapiro J, Bailey vera-Barragán V, López-Rodríg V, vera-Barragán with abdominal associated risk and factors diagnosis [Early Cir Cir 2005 73: 179-83. Spanish. syndrome]. compartment expiratory and positive-end pressure tween intra-abdominal 105-12 2009; 64: Paulo) Clinics (Sao pressure. compartment syndrome caused by a bulimic attack in a buli attack a bulimic by caused syndrome compartment J Kor nervosamia patient. disorder: with eating female report. a case in a young outcome 2015; 68: 188-92. J Anesthesiol Korean and hypertension Intra-abdominal al. B,et ML,De Keulenaer consensus updated syndrome: compartment abdominal the the from guidelines practice definitions and clinical Intensive Syndrome. Compartment ciety of the Abdominal 2013; 39: 1190-206. Med Care preventing in pressure intra-abdominal of measurement tine Assoc Pediatr J Indian syndrome. compartment abdominal 2017; 22: 134-8 Surg stenosis. pyloric of complication as syndrome compartment 2007; 5 [cited [serial on the Internet]. J Gastroenterol Internet http://ispub.com/IJGE/5/2/6299/. from 13]. Available 2019 Jul Prasad GR, Subba Rao JV, Aziz A, of rou role TM. The Rashmi JV, Rao GR, Subba Prasad Youm SM, Kim JY, Lee JR. Acute gastric dilatation causing fatal fatal causing Lee dilatation gastric JR. Acute JY, Kim SM, Youm . . No potential conflict of interest relevant to this article this article to relevant conflict of interest potential No acquisition: Data Lim. Kyoung Hyun Conceptualization: Kim BS, Kwon JW, Kim MJ, Ahn SE, Park HC, Lee Abdominal BH. Ahn SE, Park MJ, JW, Kim Kwon BS, Kim 7 8. 2. 3. 4 and abdominal dilatation gastric Acute CK, G. Sakman 5. Parsak JC, Ri GE, Torre-González de la E, Avila-Cuevas 6. Flores-Alvarez 1. was reported. reported. was Writing—origi Shinn. Supervision: Ki Helen Tae. Nayoung draft: Eom. nal Hun Byeong https://orcid.org/0000-0001-8776-5855 Eom, Hun Byeong https://orcid.org/0000-0003-2694-1258 Lim, Kyoung Hyun https://orcid.org/0000-0001-7211-9527 Tae, Nayoung https://orcid.org/0000-0003-1703-5501 Shinn, Ki Helen

------] reported that that ] reported 14 [ Abdominal compartment syndrome and complications due to bulimia nervosa bulimia to due complications and syndrome compartment Abdominal SUPPLEMENTARY MATERIALS SUPPLEMENTARY ], 1 g of 0.45% normal saline was mixed with mixed man g was 50 saline normal 0.45% of g 1 ], Supplementary data containing Korean version of this this of version Korean containing Supplementary data In conclusion, we report a case in which bulimia nervosa bulimia which in case a we conclusion, report In The unfortunate aspect in this case was that the wound the wound that aspect was in this case unfortunate The As previously mentioned, ischemia-reperfusion injury ischemia-reperfusion mentioned, As previously 15 www.anesth-pain-med.org article is available at https://doi.org/10.17085/apm.2020. at articleavailable is 15.2.251. IAP with open wound are expected to reduce mortality. expected reduce IAP with to open wound are patient’s state. Prophylactic treatment with mannitol and and with mannitol treatment Prophylactic state. patient’s minimize to prior decompression to sodium bicarbonate injuryischemia-reperfusion adjusting after and suturing lieved via surgical decompression as soon as possible, and as soon as possible, decompression lieved surgical via insertion tube nasogastric and the use of neuromuscular the prior be helpful in alleviating surgery to blockers may and progression of ACS, may be useful detec for the early may of ACS, and progression of the occurrence of IAP and, thus, tion and prediction be re critical, condition is AP should If the patient’s ACS. cally difficult; thus, evaluating the clinical symptoms that difficult; that cally symptoms the clinical evaluating thus, IAP of the increase on depending occur the patient, in may povolemic shock and ultimately death. If it is possible to to possible is it If death. ultimately and shock povolemic bepre can prognosis and state patient’s the IAP, measure realisti is IAP measuring emergencyin dicted,but rooms, increased IAP and progressed to ACS; after surgical de ACS; to surgical after IAP and progressed increased isch to due occurred hemorrhage massive a compression, injuryemia-reperfusion and DIC, of hy a state to leading the survival rate. the survival rate. and IAP was not controlled. Muresan et al. Muresan not controlled. and IAP was the IAP with suturing in mind that keep to it is important condition and improve patient improve open can wounds sion injury.sion laparotomy, decompression after closedwas immediately age due to the reperfusion washout effect of the anaerobic effect of the anaerobic washout the reperfusion due to age prior volume sur to sufficient providing and byproducts, gery, of ischemic reperfu helped which in the reduction [ dam minimize to sodium and 50 mEq nitol bicarbonate and shock due to DIC are more likely to occur after de occur to after likely more DIC are to due and shock Morris et al. by the report In laparotomy. compression ported that the shorterported time between that onset the of ACS and prognosis; the the better prog laparotomy, decompression poor exceeded the time was in case nosis 24 h. suturing was performed after the IAP, and the wound was and the wound was performedwas suturing the IAP, after de surgical that showed study of the result The stabilized. re was It 8.7%. by mortalitythe rate reduced compression Anesth Pain Med Vol. 15 No. 2

Care 2000; 4: 23-9. Med Cell Longev 2018; 2018: 3804979. 9. Saggi BH, Ivatury R, Sugerman HJ. Part XVI. Surgical critical 13. Macalino JU, Goldman RK, Mayberry JC. Medical management care issues. In: Surgical treatment: evidence-based and prob- of abdominal compartment syndrome: case report and a cau- lem-oriented. Edited by Holzheimer RG, Mannick JA: Munich, tion. Asian J Surg 2002; 25: 244-6. Zuckschwerdt. 2001. Available from https://www.ncbi.nlm. 14. Muresan M, Muresan S, Brinzaniuc K, Voidazan S, Sala D, Jim- nih.gov/books/NBK6908/. borean O, et al. How much does decompressive laparotomy 10. Yoshikawa T, Kondo M. Free radicals in multiple organ failure. reduce the mortality rate in primary abdominal compartment Jpn J Med 1990; 29: 683-5. syndrome?: a single-center prospective study on 66 patients. 11. Carden DL, Granger DN. Pathophysiology of ischaemia-reper- Medicine (Baltimore) 2017; 96: e6006. fusion injury. J Pathol 2000; 190: 255-66. 15. Morris JA Jr, Eddy VA, Blinman TA, Rutherford EJ, Sharp KW. 12. Sun MS, Jin H, Sun X, Huang S, Zhang FL, Guo ZN, et al. Free The staged celiotomy for trauma. Issues in unpacking and re- radical damage in ischemia-reperfusion injury: an obstacle in construction. Ann Surg 1993; 217: 576-84. acute ischemic stroke after revascularization therapy. Oxid

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Enacted: May 15, 2006 Recently revised (12th): April 30, 2020

Anesthesia and Pain Medicine (APM) is the official scientific 2. Language journal of Korean Society of Neuroscience in Anesthesiology and Critical Care (KSNACC), The Korean Society for Anesthetic APM publishes articles in English. Manuscript submitted in Pharmacology (KSAP), The Korean Society of Obstetric Anes- Korean will be translated into English by the society after accep- thesiologists (KSOA), The Korean Society of Pediatric Anesthe- tance, Korean version will be published only on the website siologists (KSPA), Korean Neuromuscular Research Society (www.anesth-pain-med.org). (KNRS), Korean Society of Cardiothoracic and Vascular Anes- Spellings should abide by American spellings. Medical termi- thesiologists (KSCVA), Korean Society of Transplantation Anes- nology should be written based on the most recent edition of thesiologists (KSTA), and The Korean Spinal Pain Society (KSPS) Dorland’s Illustrated Medical Dictionary. Accepted manuscripts and Korean Society of Regional Anesthesia (KSRA). The abbre- are requested to be proofread by professional English editors. viated title is “Anesth Pain Med”. It is published four times a year on the last day of January, April, July, and October in English. 3. Submission of manuscripts

I. Editorial Policy In addition to members of the Korean Society of Anesthesiol- ogists, any researcher throughout the world can submit a man- The Editor assumes that all authors listed in a manuscript uscript if the scope of the manuscript is appropriate. Authors have agreed with the following policy of the APM on submis- are requested to submit their papers electronically by using the sion of manuscript. Except for the negotiated secondary pub- online manuscript submission system, available at: http://sub- lication, manuscript submitted to the APM must be previously mit-apm.org. Authors, reviewers, and editors send and receive unpublished and not be under consideration for publication all correspondences through this system. Final revisions by au- elsewhere. Under any circumstances, the identities of the ref- thors should be submitted within 1 week of the request. erees will not be revealed. Minimum publication charges and additional fee for reprints will due on every manuscript. All 4. Peer review process published manuscripts become the permanent property of the Korean Society of Anesthesiologists (KSA) and may not be APM uses double-blind review, which means that both the published elsewhere without written permission. APM ad- reviewer and author identities are concealed from the review- heres completely to guidelines and best practices published ers, and vice versa, throughout the review process. To facilitate by professional organizations, including Recommendations this, authors need to ensure that their manuscripts are prepared for the Conduct, Reporting, Editing, and Publication of Schol- in a way that does not give away their identity. If one or more of arly Work in Medical Journals (http://www.icmje.org/icm- edtors are involved as authors, the editor(s) should not be inje-recommendations.pdf) from ICMJE and Principles of volved in the peer reviewer selection, evaluation, or decision Transparency and Best Practice in Scholarly Publishing (joint process. Submitted manuscripts will be reviewed by 2 or more statement by COPE, DOAJ, WAME, and OASPA; http://doaj. experts in the corresponding field. The Editorial Board may re- org/bestpractice) if otherwise not described below. quest authors to revise the manuscripts according to the reviewer’s opinion. After revising the manuscript, the author II. General information should upload the revised files with a reply to each item of the reviewer’s opinion. Additions and amendments to the revised 1. Publication types manuscript should be highlighted in red. The author’s revisions should be completed within 60 days after the request. If it APM focuses on clinical research, experimental research, is not received by the due date, the Editorial Board will not case reports, reviews, and letters to the editor, online images consider it for publication. To extend the revision period to and various introductions. more than 60 days, the author should negotiate with the Edito-

www.anesth-pain-med.org rial Board. The manuscript review process should be finished www.kamje.or.kr/board/view?b_name=bo_publication&bo_ the second review. If the reviewers wish further review, the id= 7) or the “Ethical Guidelines on Good Publication” (http:// Editorial Board may consider it. The Editorial Board will make publicationethics.org/resources/guidelines) or “Ethical Consid- a final decision on the approval for publication of the submit- erations in the International Committee of Medical Journal Edi- ted manuscripts and can request any further corrections, revi- tors” (http://www.icmje.org/recommendations) are applied. sions, and deletions of the article text if necessary. Statistical editing is also performed if the data need professional statisti- 1. Conflict-of-interest statement cal review by a statistician. The review and publication processes that are not described in the Instructions for Authors The corresponding author is required to summarize all au- will be incorporated into the Editorial Policy Statements ap- thors’ conflict of interest disclosures. Disclosure form shall be proved by the Council of Science Editors Board of Directors, same with ICMJE Uniform Disclosure Form for Potential Con- available at: www.councilscienceeditors.org/. flicts of Interest (www.icmje.org/conflicts-of-interest). A conflict of interest may exist when an author (or the author’s institution 5. Article processing charge and publication fee or employer) has financial or personal relationships or affiliations that could influence (or bias) the author’s decisions, work, There is no charge for submitting and processing a paper. But, or manuscript. All authors should disclose their conflicts of in- the APM charges a publication fee for each printed page of KRW, terest, i.e., (1) financial relationships (such as employment, except for an invited manuscript. Publication fees are waived if consultancies, stock ownership, honoraria, paid expert testimo- the affiliation of corresponding author is outside Korea. ny), (2) personal relationships, (3) academic competition, and (4) intellectual passion. These conflicts of interest must be in- 6. Copyrights and secondary publication cluded as a footnote on the title page or in the Acknowledge- ments section. Copyrights of all published materials are owned by the APM. All sources of funding should be declared on the title page or in On behalf of co-author(s), corresponding author must complete the Acknowledgements section at the end of the text. If an au- and submit the journal’s copyright transfer agreement, which thor’s disclosure of potential conflicts of interest is determined to includes a section on the disclosure of potential conflicts of in- be inaccurate or incomplete after publication, a correction will be terest based on the recommendations of the International published to rectify the original published disclosure statement, Committee of Medical Journal Editors, “Uniform Requirements and additional action may be taken as necessary. for Manuscripts Submitted to Biomedical Journals”. A copy of If one or more of editors are involved as authors, the authors the form is made available to the submitting author within the should declare conflict of interests. online manuscript submission process. It is possible to repub- Ex) AAA has been an editor of the Anesthesia and Pain Medi- lish manuscripts if ONLY the manuscripts satisfy the condition cine since 2017; however, he was not involved in the peer re- of secondary publication of the Uniform Requirements for viewer selection, evaluation, or decision process of this arti- Manuscripts Submitted to Biomedical Journals, available at: cle. No other potential conflicts of interest relevant to this ar- http://www.icmje.org ticle were reported.

7. Open access 2. Statement of informed consent

APM is an Open Access journal accessible for free on the In- Copies of written informed consents and Institutional Review ternet. Accepted peer-reviewed articles are freely available on Board (IRB) approval for clinical research are recommended the journal website for any user, worldwide, immediately upon kept. The editor or reviewers may request copies of these docu- publication without additional charge. ments to make potential ethical issues clear.

III. Research and Publication Ethics 3. Protection of privacy, confidentiality, and Guidelines written informed consent

For the policies on research and publication ethics, the “Good Identifying details should not be published in written de- Publication Practice Guidelines for Medical Journals” (https:// scriptions, photographs, or pedigrees unless it is essential for

www.anesth-pain-med.org scientific purposes and the patient (or his/her parents or guard- 6. Reporting guidelines ian) provides written informed consent for publication. Addi- tionally, informed consent should be obtained in the event that The APM recommends a submitted manuscript to follow re- anonymity of the patient is not assured. For example, masking porting guidelines appropriate for various study types. Good the eye region of patients in photographs is not adequate to en- sources for reporting guidelines are the EQUATOR Network sure anonymity. If identifying characteristics are changed to (www.equatornetwork.org) and the NLM’s Research Reporting protect anonymity, authors should provide assurance that alter- Guidelines and Initiatives (www.nlm.nih.gov/services/re- ations do not distort scientific meaning. When informed con- search_report_guide.html). sent has been obtained, this should be indicated in the published article. 7. Author and authorship

4. Protection of human and animal rights An author is considered as an individual who has made substantive intellectual contributions to a published study and In the reporting of experiments that involve human subjects, whose authorship continues to have important academic, so- it should be stated that the study was performed according to cial, and financial implications. the Helsinki Declaration of 1975 (revised 2008) (Available from Authorship credit should be based on: (1) substantial con- https://www.wma.net/wpcontent/uploads/2018/07/DoH- tributions to the conception or design of the work, or to the Oct2008.pdf) and approved by the Institutional Review Board acquisition, analysis, or interpretation of data for the work; (2) (IRB) of the institution where the experiment was performed. the drafting of the article or revising it critically for important Clinical studies that do not meet the Helsinki Declaration will intellectual content; (3) final approval of the version to be not be considered for publication. Identifying details should not published; and (4) agreement on taking accountability for the be published (such as name, initial of name, ID numbers, or accuracy or integrity of the work. Authors should meet these date of birth). four criteria. These criteria distinguish the authors from other In the case of an animal study, a statement should be provid- contributors. ed indicating that the experimental processes, such as the When a large, multicenter group has conducted the work, breeding and the use of laboratory animals, were approved by the group should identify the individuals who accept direct re- the Research Ethics Committee (REC) of the institution where sponsibility for the manuscript. When submitting a manu- the experiment was performed or that they did not violate the script authored by a group, the corresponding author should rules of the REC of the institution or the NIH Guide for the Care clearly indicate the preferred citation and identify all individu- and Use of Laboratory Animals (Institute of Laboratory Animal al authors as well as the group name. Acquisition of funding, Resources, Commission on Life Sciences, National Research collection of data, or general supervision of the research group Council, https://www.nap.edu/catalog/5140/guide-for-the- alone does not constitute authorship. Journals generally list care-and-use-oflaboratory-animals). The authors should pre- other members of the group in the Acknowledgments section. serve raw experimental study data for at least 1 year after the publication of the paper and should present this data if required 8. Plagiarism and duplicate publication by the Editorial Board. Plagiarism is the use of previously published material without 5. Registration of the clinical research attribution. Prior to peer review, all manuscripts are screened for plagiarism by the Editor-in-Chief using iThenticate. When It is recommended that all clinical trials be registered in the plagiarism is detected at any time before publication, the APM primary registry before submission. APM accepts registration in editorial office will take appropriate action as directed by the any of the primary registries that participate in the World Health standards set forth by the Committee on Publication Ethics Organization (WHO) International Clinical Trials Portal (http:// (COPE). For additional information, please visit http://www. www.who.int/ictrp/en), NIH ClinicalTrials.gov (http://www. publicationethics.org. Text copied from previously published clinicaltrials.gov), or Korea Clinical Research Information Ser- work is interpreted using the following taxonomy: vice (CRiS, http://cris.nih.go.kr). 1) Intellectual theft Deliberate copying of large blocks of text without attribution

www.anesth-pain-med.org 2) Intellectual sloth 1. Word processors and format of manuscripts Copying of “generic” text, e.g., a description of a standard technique, without clear attribution A manuscript must be written in proper and clear English or 3) Plagiarism for scientific English Korean. Our preferred file format is DOCX or DOC. Manuscripts Copying of verbatim text, often from multiple sources should be typed double-spaced on A4-sized paper, using 12 4) Technical plagiarism point font in English, using 10 point font in Korean. Use of verbatim text without identifying it as a direct quota- tion but citing the source 2. Abbreviation of terminology 5) Self-“plagiarism” Abbreviations should be avoided as much as possible. When Manuscripts are only accepted for publication if they have they are used, full expression of the abbreviated words should not been published elsewhere. Manuscripts published in this be provided at the first use, with the abbreviation following in journal should not be submitted for publication elsewhere. Du- parentheses. plicate submissions identified during peer review will be imme- Ex) target controlled infusion (TCI) diately rejected. Duplicate submissions that are discovered after After that, “TCI” can be used instead of “target controlled in- publication will be retracted. It is mandatory for all authors to fusion.” Common abbreviations may be used, however, such resolve any copyright issues when citing a figure or table from a as DNA. Abbreviations can be used if they are listed as a different journal that is not open access. MeSH subject heading (https://www.ncbi.nlm.nih.gov/ When duplicate publication is detected, the APM editorial mesh). office will notify the counterpart journal on this violation. Ad- ditionally, it will be notified to the authors’ affiliation and pen- 3. Word spacing alties will be imposed on the authors. It is possible to repub- lish manuscripts if the manuscripts satisfy the condition of 1) Leave 1 space on each side when using arithmetic marks secondary publication of the Uniform Requirements for Man- such as +,–, × , etc. uscripts Submitted to Biomedical Journals, available at: www. Ex) 24 ± 2.5 icmje.org. If the author or authors wish to obtain a duplicate Leave no space when using hyphen between words. or secondary publication for reasons such as publication for Ex) intra-operative readers of a different language, the author(s) should obtain 2) When using parentheses, leave 1 space on each side in En- approval from the Editors-in-Chief of both the first and second glish, and leave no space in the Korean manuscript. journal. 3) When using brackets in parentheses, apply square brackets. Ex) ([ ]) IV. Manuscript Preparation 4) Manuscripts in Korean should obey the rules of Korean spelling (www.korean.go.kr). APM recommends compliance with some or all of the following guidelines (www.equatornetwork.org/library). 4. Citations CONSORT for reporting of randomized controlled trials (http://www.consort-statement.org) 1) If a citation has 2 authors, write as “Hirota and Lambert”. If STARD for reporting of diagnostic accuracy studies (http:// there are more than 3 authors, apply “et al.” at the end of www.stard-statement.org) the first author’s surname. STROBE for reporting of observational studies in epidemiolo- Ex) Kim et al. [1] gy (http://www.strobe-statement.org) 2) Citations should be applied after the last word. PRISMA for reporting of systematic reviews (http://www.pris- Ex) It is said that hypertension can be induced [1] and the ma-statement.org) way to injure the brain [2] is… MOOSE for reporting of observational studies (http://www. Ex) Choi and Kim [1] reported… emgo.nl/kc/reporting-your-study-results-in-a-scientific-article) 3) Apply citations before a comma or period. GLOBAL ADVANCES in Health and Medicine for reporting of Ex) ....is reported [1], clinical cases (http://www.gahmj.com) 4) Several or coupled superscripts can be written as [1–5] or [1,3,5].

www.anesth-pain-med.org 5. Arrangement of manuscript location of the conference may be described. Funding statement ⑤ The manuscript should be organized in the order of title, ab- Disclosure of all financial support for the work, in- stract, introduction, materials and methods, results, discussion, cluding departmental or institutional funding/sup- acknowledgments, references, tables, figures, and figure leg- port. ends. Figures should be uploaded as separate files. The title of Conflicts of interest ⑥ each new section should begin on a new page. The conclusion Any conflicts of interest for any or all authors within should be included in the discussion section. Number pages the 36 months of submission. If no competing inter- consecutively, beginning with the first page of the manuscript. ests, please add the following statement: “The au- Page numbers should be placed at the middle of the bottom of thors declare no competing interests.” If any of these the page. For survey-based clinical studies, the original survey elements are not applicable to your submission, document does not need to be included in the body of the man- write “not applicable” after thenumber and topic; for uscript but may be included as a supplement in an appendix. example, “Prior Presentations: Not applicable.” (2) Manuscript 6. Organization of manuscript Title and Running title (without author information) ① It should be the same as the Cover page. 1) Clinical or experimental research Abstract ② (1) Cover page (upload separately) All manuscripts should contain a structured abstract Title that is written only in English. Authors should pro- ① Title should be concise and precise. The first word vide an abstract of no more than 250 words. It should should be capitalized. Drug names in the title should be contain 4 subsections: Background, Methods, Re- written with generic names, not brand names. For the sults, and Conclusions. Citation of references is not title, only the first letter of the first word should be capi- permitted in the abstract. A list of key words at least 4, talized. with a maximum of 10 items, should be included at Ex) Effect of smoking on bronchial mucus transport the end of the abstract. Key words should be selected velocity under total intravenous anesthesia ·········· from MeSH (https://www.ncbi.nlm.nih.gov/mesh), [ ] and these should be written in small letters with the ○ Ex) Effect of Smoking on Bronchial Mucus Transport first letter capitalized. Separate each word with a Velocity under Total Intravenous Anesthesia ········ [× ] semicolon (;), and include a period (.) at the end of Provide drug names as generic names, not product the last word. Ex) Keywords: Carbon dioxide; Cere- names. bral vessels; Oxygen; Spinal analgesia. Ex) In CPR, Isosorbide Dinitrate is, ·········· [ ] Introduction ○ ③ Ex) In CPR, Isosorbide Dinitrate (Isoket®) is, ········ [× ] The introduction should address the purpose of the Ex) In CPR, Isoket® is, ·········· [× ] article concisely and include background informa- Running title tion that is relevant to the purpose of the paper. ② A running title of no more than 40 characters, includ- Materials and Methods ④ ing letters and spaces in Korean, or 10 words in En- The materials and methods section should include glish, should be provided. If this title is inappropriate, sufficient details regarding the design, subjects, and the Editorial Board may revise it. methods of the research in order, as well as methods Ex) Kim et al. [1] used for data analysis and control of bias in the study. Author information Sufficient details must be provided in the methodol- ③ First name, middle initial, and last name of each author, ogy section of an experimental study so that it can be with their highest academic degree(s) (M.D., Ph.D., further replicated by others. etc.), and institutional affiliations; make sure the names Institute and author names should be avoided. of and the order of authors as they appear on the Title When reporting experiments with human or animal Page and entered in the system match exactly. subjects, the authors should indicate whether they Previous presentation in conferences received approval from the Institutional Review ④ Title of the conference, date of presentation, and the Board for the study. When reporting experiments

www.anesth-pain-med.org with animal subjects, the authors should indicate should be used, insert it in parentheses after the ge- whether the handling of the animals was supervised neric name. Provide® or TM as a superscript and the by the Institutional Board for the Care and Use of manufacturer’s name and country.

Laboratory Animals. Demographic data should be ● Ions included in the materials and methods section if ap- Ex) Na+[ ], Mg2+[O], Mg++[× ], Mg+2[× ] ○ plicable. As a rule, subsection titles are not recom- Ex) Premedicated magnesium [O] mended. If several study designs were used, then Ex) Premedicated Mg2+ [O] subtitles can be used without assigning numbers. Results ⑤ Ensure correct use of the terms sex (when reporting bi- Results should be presented in a logical sequence in ological factors) and gender (identity, psychosocial or the text, tables, and figures, giving the main or most cultural factors), and, unless inappropriate, report the important findings first. Do not repeat all of the data sex and/or gender of study participants, the sex of ani- provided in the tables or figures in the text; empha- mals or cells, and describe the methods used to deter- size or summarize only the most important observa- mine sex and gender. If the study was done involving an tions. Results can be sectioned by subsection titles exclusive population, for example in only one sex, au- but should not be numbered. Citation of tables and thors should justify why, except in obvious cases (e.g., figures should be provided as Table 1 and Fig. 1. prostate cancer). Authors should define how they deter- Type or print each table on a separate page. Figures mined race or ethnicity and justify their relevance. should be uploaded as separate tif, jpg, pdf, gif, ppt

● Units Laboratory information should be reported files. using the International System of Units [SI], available Statistics ⑥ at: https://www.nist.gov/pml/special-publica- Precisely describe the methods of statistical analysis tion-811 and computer programs used. Mean and standard < Exceptions> deviation should be described as mean ± SD, and A. The unit for volume is “L”, while others should be mean and standard error should be written as mean written as “dl, ml, μl”. ± SEM. Median and interquartile should be de- Ex) 1 L, 5 ml scribed as median (1Q, 3Q). When displaying P val-

B. The units for pressure are mmHg or cmH2O. ues, use a capital P and do not put a “-” between “P” instead of Pascal. and “value”. C. Use Celsius for temperature. °C A. Describe the statistical tests employed in the study D. Units for concentration are M, mM, μM. with enough detail so that readers can reproduce Ex) μmol/L; [× ] the same results if the original data are available. E. When more than 2 items are presented, diago- The name and version of the statistical package nal slashes are acceptable for simple units. should be provided. Negative exponents should not be used. B. Authors should describe the objective of the study Ex) mg/kg/min [O], mg kg-1 min-1 [×] and hypothesis appropriately. The primary/sec- ㆍ ㆍ F. Leave 1 space between number and units, except ondary endpoints are predetermined sensibly ac- %, oC. cording to the objective of the study. Ex) 5 mmHg C. The characteristics of measured variables should Ex) 5%, 36oC determine the use of a parametric or nonpara- G. Units of time metric statistical method. When a parametric Ex) hour: 1 h = 60 min = 3,600 s, day: 1 d = 24 h method is used, the authors should describe = 86,400 s whether the basic statistical assumptions are met.

● Machines and equipment For an analysis of a continuous variable, the nor- Provide model name and manufacturer’s name, and mality of data should be examined. Describe the country. Do not put “.” between words when writing name and result of the particular method to test the names of countries. normality. Ex) U.S.A. [× ], USA [O] D. When analyzing a categorical variable, if the num- For drug names, use generic names. If a brand name ber of events and sample is small, exact test or as-

www.anesth-pain-med.org ymptotic method with appropriate adjustments should conform to the most recent edition of the should be used. The standard chi-squared test or American Medical Association Manual of Style. difference-in-proportions test may be performed Discussion ⑦ only when the sample size and number of events The discussion should be described to emphasize are sufficiently large. the new and important aspects of the study, includ- E. The APM strongly encourages authors to show ing the conclusions. Do not repeat in detail the re- confidence intervals. It is not recommended to sults or other information that is provided in the in- present the P value without showing the confi- troduction or the results section. Describe the con- dence interval. In addition, the uncertainty of esti- clusions according to the purpose of the study but mated values, such as the confidence interval, avoid unqualified statements that are not adequately should be described consistently in figures and supported by the data. Conclusions may be stated tables. briefly in the last paragraph of the discussion section. F. Except for study designs that require a one-tailed Acknowledgments ⑧ test, for example, non-inferiority trials, the P val- Persons or institutes that contributed to the manu- ues should be two-tailed. A P value should be ex- script but not sufficiently to be coauthors may be rec- pressed up to three decimal places (ex. P = 0.160 ognized. Financial support, including foundations, not as P = 0.16 or P < 0.05). If the value is less institutions, pharmaceutical and device manufactur- than 0.001, it should be described as “P < 0.001” ers, private companies, or intramural departmental but never as “P = 0.000.” For large P value greater sources, or any other support, should be described. than 0.1, the values can be rounded off to one References ⑨ decimal place, for example, P = 0.1, P = 0.9. ● References should be obviously related to docu- G. A priori sample size calculation should be de- ments and should not exceed 30. References should scribed in detail. Sample size calculation must be numbered consecutively in the order in which aim at preventing false negative results pertain- they are first mentioned in the text. Provide cita- ing to the primary, instead of secondary, end- tions in the body text. All references should be list- point. Usually, the mean difference and standard ed in English, including author, title, name of jour- deviation (SD) are typical parameters in estimat- nal, etc.

ing the effect size. The power must be equal to or ● The format for references follows the descriptions greater than 80 percent. In the case of multiple below. Otherwise, it follows the NLM Style Guide comparisons, an adjusted level of significance is for Authors, Editors, and Publishers (Patrias, K. Cit- acceptable. ing medicine: the NLM style guide for authors, edi- H. When reporting a randomized clinical study, a tors, and publishers [Internet]. 2nd ed. Wendling, CONSORT type flow diagram, as well as all the DL, technical editor. Bethesda (MD): National Li- items in the CONSORT checklist, should be in- brary of Medicine (US); 2007 [updated 2015 Oct 2; cluded. If limited in terms of the space of the cited Year Month Day]. Available at: www.ncbi.nlm. manuscript, this information should be submitted nih.gov/books/NBK7256/).

as a separate file along with the manuscript. ● If necessary, the Editorial Board may request origi- I. Results must be written in significant figures. The nal documents for the references.

measured and derived numbers should be round- ● The journal title should be listed according to the ed off to reflect the original degree of precision. List of Journals Indexed for MEDLINE, available at: Calculated or estimated numbers (such as mean https://www.nlm.nih.gov/archive/20130415/tsd/ and SD) should be expressed in no more than one serials/lji.html, or the List of KoreaMed Journals significant digit beyond the measured accuracy. (journal browser of KoreaMed Services), available Therefore, the mean (SD) of cardiac indices in pa- at: http://koreamed.org/JournalBrowserNew.php.

tients measured on a scale that is accurate to 0.1 ● Six authors can be listed. If there are more than 6 L/min/m2 should be expressed as 2.42 (0.31) L/ authors, only list 6 names with “et al.”. 2 min/m . ● Provide the start and final page numbers of the cit- J. Except when otherwise stated herein, authors ed reference.

www.anesth-pain-med.org ● Abstracts of conferences may not be included in the Ex) Sampson AL, Singer RF, Walters GD. Uric acid references. The American Society of Anesthesiolo- lowering therapies for preventing or delaying gists (ASA) refresher course lecture is not accept- the progression of chronic kidney disease. Co- able as a reference. chrane Database Syst Rev 2017; 10: CD009460.

● Description format F. Advance access article A. Regular journal Ex) Baumbach P, Gotz T, Gunther A, Weiss T, Meis- Author name. Title of article. Name of journal pub- sner W. Chronic intensive care-related pain: lished year; volume: start page-final page. Ex) Ros- Exploratory analysis on predictors and influ- enfeld BA, Faraday N, Campbell D, Dorman T, ence on health-related quality of life. Eur J Pain Clarkson K, Siedler A, et al. Perioperative platelet 2017. Advance Access published on Nov 5, activity of the effects of clonidine. Anesthesiology 2017. doi:10.1002/ejp.1129. 1992; 79: 256-61. Tables ⑩ Ex) Hirota K, Lambert DG. Ketamine: its mecha- ● Only one table is to be drawn per page in the order nism(s) of action and unusual clinical uses. Br cited in the text.

J Anaesth 1996; 77: 741-4. ● The title of the table is to be in English and written Ex) Kang JG, Lee SM, Lim SW, Chung IS, Hahm TS, at the top of the table in the form of a phrase.

Kim JK, et al. Correlation of AEP, BIS, and OAA/ ● Words in the table excluding the title should use S scores under stepwise sedation using propo- capital letters for the first word, and the following fol TCI in orthopedic patients undergoing total words are to be written in small letters.

knee replacement arthroplasty under spinal an- ● For demographic data, gender is recorded as M/F, esthesia. Korean J Anesthesiol 2004; 46: 284-92. age as yr, (if necessary, use days or months in chil- Ex) ‘2006; 7(Suppl 1): 64-96’ ‘2007; 76: H 232-8’ dren) without decimal point. The “±” sign within B. Monographs the table is to be aligned with the rows above and - Author. Book name. Edition. Place, press. Pub- below.

lished year, pp (start page)-(End page). ● Footnotes are to be written in the following order: - If reference page is only 1 page, mark ‘p’. “Values are mean ± SD (or SEM) or median (1Q, - Note if it is beyond the 2nd edition. 3Q)”, the explanations for the groups and the abbre- Ex) Nuwer MR. Evoked potential monitoring in the viations in order of appearance, and statistics. Ab- operating room. 2nd ed. New York, Raven breviations apart from internationally recognized Press. 1986, pp 136- 71. abbreviations are to be explained with their full - Translated documents cannot be used as refer- spellings at the bottom of the table. Full spellings ences. The original documents should be provided are to be presented even for repeated abbreviations as references. for each table in order of appearance.

C. Chapter ● Significance marks are to conform to the Vancouver Any separate author of a chapter should be provid- style (Uniform Requirements for Manuscripts Sub- ed. mitted to Biomedical Journals. JAMA 1997; 227: Ex) Blitt C. Monitoring the anesthetized patient. In: 927-34). In other words, these must be in the order Clinical Anesthesia. 3rd ed. Edited by Barash of *, †, ‡, §, ∥, ¶, **, ††, ‡‡ and written as superscripts. PG, Cullen BF, Stoelting RK: Philadelphia, Lip- Legends for figures and photographs ⑪ pincott -Raven Publishers. 1997, pp 563-85. ● All of the figures and photographs should be de- D. Electronic documents scribed in the text separately.

Ex) Grainge MJ, Seth R, Guo L, Neal KR, Coupland ● The description order is the same as in the foot- C, Vryenhoef P, et al. Cervical human papillo- notes in tables and should be in recognizable sen- mavirus screening among older women. tences.

Emerg Infect Dis [serial on the Internet]. 2005 ● Define all abbreviations every time they are repeat- Nov [2005 Nov 25]. Available from www.cdc.gov/ ed. ncidod/EID/vol11no11/05-0575.htm. (3) Figures and Photographs E. Online journal article APM encourages authors to use color to increase the ①

www.anesth-pain-med.org clarity of figures. Please note that color figures are process and finally confirmed by the Editorial Board used without charge. at the end of the review process. Standard colors should be used (black, red, green, Video clips are uploaded as the last file(s) at the time ② ③ blue, cyan, magenta, orange, and gray). Avoid colors of manuscript submission and should be marked as that are difficult to see on the printed page (e.g., yel- supplementary video files. low) or are visually distracting (e.g., pink). Figure The video clip(s) should have simple file names (e.g., ④ backgrounds and plot areas should be white, not Video 1, Video 2) and should include the appropriate gray. Axis lines and ticks should be black and thick extension (e.g., .mov, .mpg, .avi). enough to clearly frame the image. Axis labels should The maximum number of video clips is 20. ⑤ be large enough to be easily readable, and printed in The video clip(s) should be playable on Microsoft ⑥ black. Windows OS. The video clip(s) should be tested for Figures should be uploaded as separate tif, jpg, pdf, playback before submission, preferably on comput- ③ gif, or ppt files. Width of figure should be 84 mm (one ers not used for their creation, to check for any com- column). Contrast of photos or graphs should be at patibility issues. least 600 dpi. Contrast of line drawings should be at Individual video files should be a minimum of 480 × ⑦ least 1,200 dpi. Number figures as “Fig. (Arabic nu- 320 pixels (smaller clips will not be accepted) and a meral)” in the order of their citation (ex. Fig. 1). maximum of 2 GB. Files of < 15 MB will be rejected Photographs should be submitted individually. If Fig. outright unless special arrangements have been ④ 1 is divided into A, B, C, and D, do not combine it made with the editorial board prior to submission. into 1, but submit each of them separately. Authors Approval of files of > 2 GB will be made at the end of should submit line drawings in black and white. the review process. In horizontal and vertical legends, the letter of the Supplemental still images that correspond to the re- ⑤ ⑧ first English word should be capitalized. spective video clip(s) should be, but are not always Connections between numbers should be denoted required to be, accompanied by legends. The video ⑥ by “–”, not “~”. Do not space the numbers (ex. 2–4). clip file name(s) should refer to the corresponding An individual should not be recognizable in photo- figure number(s). ⑦ graphs or X-ray films unless written consent has been The author will be able to find additional information ⑨ obtained from the subject and is provided at the time in the Figures and photographs section. of submission. Pathological samples should be pictured with a mea- 2) Case Reports ⑧ suring stick. A case report is almost never a suitable means to describe (4) Video (movie) clip(s) the efficacy of a treatment or a drug; instead, an adequately The APM publishes supplemental video (movie) clip(s) powered and well-controlled clinical trial should be per- that will be available online. Authors should submit vid- formed to demonstrate such efficacy. The only context in eos according to our video submission guidelines. which a case report can be used to describe efficacy is in a Each video clip should clearly illustrate the primary clinical scenario, or population, that is so unusual that a ① findings within an adequate amount of viewing time clinical trial is not feasible. Case reports of humans must and should be discussed in the text. Authors should state in the text that informed consent to publication was provide appropriate labeling (e.g., arrows, abbrevia- obtained from the patient or guardian. Copies of written tions of anatomic structures, etc.) in the video clips. informed consents should be kept. If necessary, the editor However, all identifying information, including pa- or reviewers may request copies of these documents. If tient names and/or ID numbers, hospital names, and these steps are impossible, Institutional Review Board ap- dates of the procedures, should be removed. proval should be obtained prior to submission. Rarity of a Video clips should contain succinct teaching points disease condition is itself not an acceptable justification for ② that must be supported by the current literature or a case report. standard reference texts, preferably those most ac- (1) Cover page: Same as that for clinical and experimental cessible to the general reader. The adequacy of the studies. teaching points will be evaluated during the review (2) Abstract: All case reports should contain a structured

www.anesth-pain-med.org abstract that is written only in English. Provide an abstract of no more than 150 words. It should contain 3 4) Letters to the Editor subsections: Background, Case, and Conclusions. A list Letters to the Editor should include brief constructive com- of keywords, with a minimum of 3 and maximum of 10 ments that concern previously published articles and inter- items, should be included at the end of the abstract. esting cases. Letters to the Editor should be submitted no (3) Introduction: Should not be separately divided. Briefly more than 3 months after the paper has been published. describe the case and background without a title. (1) Cover pages should be formatted in the same way as (4) Case report: Describe only the clinical information that those of clinical research papers. The corresponding au- is directly related to the diagnosis and anesthetic man- thor should be the first author. A maximum of five au- agement. thors is allowable. (5) Discussion: Briefly discuss the case, and state conclu- (2) The body text should not exceed 1,000 words and sions at the end of the case. Do not structure the con- should have no more than 5 references. A figure or a ta- clusion section separately. ble may be used. (6) References: The number of references should be less (3) Letters may be edited by the Editorial Board, and if nec- than 15. However, if necessary, the number of reference essary, responses by the author of the subject paper may can be added in accordance with the decision of the be provided. editorial committee. (7) Tables and figures: Proportional to those for clinical and 5) Book reviews and announcements experimental studies. Book reviews as well as news of scientific societies and scientific meeting dates in Korea or abroad can be included. 3) Reviews Their formats will be same as those of Letters to the Editor. Review articles synthesize previously published material into an integrated presentation of our current understand- 6) Images and Videos in APM ing of a topic. Review articles should describe aspects of a This feature is intended to capture the sense of visual dis- topic in which scientific consensus exists, as well as aspects covery and variety that anesthesiologists experience. that remain controversial and are the subject of ongoing (1) The title should contain no more than 8 words. No more scientific disagreement and research. Review articles than 2 authors should be listed. should include unstructured abstracts written in English (2) The legend should contain no more than 250 words. equal to or less than 250 words. The organization should be (3) If there is more than one panel, please label them Panel in order of abstract, introduction, text following each title, A, Panel B, etc. conclusion and references. Figures and tables should be (4) The legends to the images and videos should briefly provided in English. Body text should not exceed 30 A4- present relevant clinical information, including a short sized pages, and the number of figures and tables should description of the patient’s history, relevant physical each be less than 6. However, if necessary, the number of and laboratory findings, clinical course, response to pages, number of figures and tables can be added in accor- treatment (if any), and condition at the last follow-up. dance with the decision of the editorial committee.