顧 問 委 員 會Comissão de AssessoresAdvisory Committee編 輯 委 員Membros da Secção EditorialMembers of Editorial Office編 輯 部Secção EditorialEditorial Office主 任Coordenador EditorialEditorial Coordinator劉百球 Edmundo Patrício LOPES LAO技 術 顧 問 Assessores TécnicosTechnical Consultants丘�� IAO Lei Lei 李 � LEE Yan 李紅冰 LI Hung Ping 洪 宇 HONG Yu 洪順家 HONG Shun Jia � � HU Feng�嘉儀 FAN Ka I 徐義祥 CHOI I Cheong 張曉戰 ZHANG Xiao Zhan� 棋 LEUNG Ki ��倫 LEONG Iat Lon 許 � HUI Ping許主平 HOI Chu Peng 陳丹梅 CHAN Tan Mui 陳�輝 CHAN Chan Fai 陳惟� CHAN Wai Sin 陳�野 CHEN Xin Ye 彭洪泉 PENG Hong Quan⿈嘉東 WONG Ka Tong ��鋒 CHIO Chan Fong 劉 紅 LIU Hong 劉水明 LIU Shui Ming 劉咏儀 LAO Weng I 譚 � TAN Lei José COSTA MAIA 林�波 LAM U Po 曹亞兵 CAO Yabing 戴�浩 TAI Wa Hou方�瑩 FONG Wai Ieng 王 � WONG In 丘熹彬 QIU Xi Bin白琪文 PAI Ki Man 伍家� NG Ka Kei 江瑞� KONG Soi Chau何�發 HO Son Fat 何澄幫 HE Cheng Bang 余漢濠 YU Hon Ho吳 浩 NG Hou 吳少� NG Sio Fan 吳曉林 NG Hiu Lam呂健文 LUI Kin Man �大� SHUM Tai Chun 李 杰 LI Jie李 � LI Jun 李 � LEI Cheng 李佩儀 LEE Pui I李展潤 LEI Chin Ion 李�成 LEI Wai Seng 李�濱 LI Da Bin李鵬斌 LI Peng Bin 官建泳 KOON Kin Veng 林 � LAM Chong林 果 LAM Kuo 林志良 LAM Chi Leong 林�� LAM Chon Wa林�� LAM Sio Chong David ��堅 HOU Wei Jian 徐�波 CHOI Chong Po高景輝 Fernando C. GOMES 高�� Ricardo COELHO � 曦 AO Hei張 � ZHANG Kang 張�� CHEUNG Chun Wing 張德洪 CHEONG Tak Hong曹亞兵 CAO Ya Bing 曹�� CHOU Mei Fong 曹�勤 CHO Lai Kan� 珍 LEONG Chan � 暉 LEONG Fai �亦� LEONG Iek Hou��倫 LEONG Iat Lon ��晶 LEONG Nga Cheng � 丹 FU Dan許主平 HOI Chu Peng 郭�德 KWOK Wai Tak Victor 陳建� CHAN Kin Iong陳泰� CHAN Tai Ip 陳嘉明 CHAN Ka Ming ��� LOK Mei Kun彭 � PENG Li 彭�光 PANG Fong Kuong 曾潭飛 CHANG Tam Fei� � CHENG Kun ⿈子秉 WONG Chi Peng ⿈小彥 WONG Sio In⿈鳳欣 WONG Fong Ian ⿈穗濤 WONG Soi Tou �永賢 LIO Weng In劉中良 LAO Chong Leong 劉百球 Edmundo Patrício LOPES LAO 劉懷烈 LAU Wai Lit潘詠紅 PUN Weng Hong � � CHOI Nim 黎卓先 LAI Cheuck Seen Edward黎�盛 LAI Kai Seng �一凡 LAI Iat Fan �福明 LAI Fook Ming Lawrence錢 � CHIN Wai 錢曉暉 CHIN Hiu Fai 戴�浩 TAI Wa Hou� 昕 CHE Ian �師輝 TSE See Fai �學斌 XIE Xue Bin譚�亨 TAM Kwong Hang Pedro RESENDE
秘 書SecretárioSecretary出 版 與 發 行Publicação e distribuiçãoPublishing and distribution設 計 與 印 刷Desenho e impressãoDesign and printing林�� LAM Chon Kit Manuel�門人出版���司Os Macaenses Publicações LDA.The Macanese PubIishing LTD.�門�學專科學�Academia Médica de MacauMacao Academy of Medicine電 子 郵 箱E-mailE-mailmmj@ssm.gov.mo官 方 網 址Site OficialOfficial Websitehttps://www.am.gov.mo二 維 碼Código QRQR code《 澳 門 醫 學 雜 誌 》 電 子 版Versão electrónica da "Revista Médica de Macau"E-version of "Macao Medical Journal "澳門東望洋新街339 號衛生局行政樓五樓5/F, Administration Building of the Health Bureau, Rua Nova à Guia n.º 339, MacaoRua Nova à Guia, n.º 339, Edifício da Administração dos Serviços de Saúde, 5.º andar, MacauDOI : 10.30224/MMJ.202406_11(2).0012非 賣 品Não está à vendaNot for Sale排名按中文姓氏筆劃順序a ordem é feita de acordo com o número dos traços dos apelidos em caracteres chinesesIn the order of the number of strokes of Chinese surnames 由�門檔��提供檔��� MO/AM/ICON/1/080,fl.9仁伯��合���貌Fotografia antiga do Centro Hospitalar Conde de São JanuárioAn old photo of Conde de São Januário General Hospital
第 11 卷第 2 期 Volume 11 Número 2 Volume 11 Number 2 117目錄ÍndiceContentsComparison of clinical outcome and alignment in conventional versus computer navigation total knee arthroplastyInappropriate use of metformin in advanced chronic kidney disease’s patients with diabetes mellitus in the Macau Health Center in 2021Epidemiological report of the active surveillance program for surgical site infection in a Macao hospitalThe correlation between ventilation modes, sedativesand opioids, fluid balance, and ventilator-associated events: a matched case-control studyLeadless transcatheter pacemaker implantation in the elderly patients: single-center data from MacauOpportunistic salpingectomy should be done whenever possible to prevent ovarian cancerChronic eosinophilic pneumoniaLarge language models assist in translating and explaining pathology reports in a multilingual societyHong Mou CHAN Chu Mang HO Kit Ieng LEONG Man Chon POU Chan Wang LEIWing Yi KWONG Tak Wai AULai Si UN Fong Kuong PANGWai Man WONG Yan WANG Fong Kuong PANGKuok Wun LAM Weng Chio TAM Man Fong CHU Tou CHANG Mario Evora U Po LAM Shun jia HONG Wai Ieng FONGNin Ngan SINChan Fong CHIO Lai Fong KOK Sio In WONG Thazin HLAING119126135146167182189177156Low dose radiotherapy for cancerGuang Li XIAO
澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal118Photodynamic therapy for the eyeIn Sim NG Chan LEONG193Chi Ieng TOU Lin Feng MA199Dengue fever indicated by 18F-FDG PET/CT : a case report and literature review
Hong Mou CHAN et al.第 11 卷第 2 期 119 Volume 11 Número 2 Volume 11 Number 2Comparison of clinical outcome and alignment in conventional versus computer navigation total knee arthroplastyAbstractBackground: Total knee arthroplasty (TKA) is a good outcome surgery for knee osteoarthritis. With the development of total knee arthroplasty, compare with conventional total knee arthroplasty to computer-navigation total knee arthroplasty, to obtain better clinical results. Methods: From 2003 to 2022, 109 cases of total knee arthroplasty (Cemented) were randomly collected (Computer navigation total knee arthroplasty since 2018). Application of the American Knee Association Radiographic Evaluation System to measure the alignments and angles of components, and The Hospital for Special Surgery (HSS) Knee Replacement Expectation Scale was used to evaluate clinical outcomes before and after TKA. Results: 109 cases (30 cases received conventional total knee arthroplasty, and the other 79 cases underwent computer-navigation total knee arthroplasty) were included, more than 90% of cases achieved excellent results in post total knee arthroplasty (P < 0.001) but no significant statistical difference between both groups (P >0.05). The group of computer navigation TKA compared to the group of conventional TKAs, postoperative mechanical axis (within 4°deviations) were 96% vs 90% (178.5 ± 1.4°vs 177.2 ± 2.4°, P = 0.01). Lateral distal femoral angle (83° to 85°) and femoral flexion angle (0° to 5°) were 87% vs 62 % (83.8 ± 1.3° vs 84.5 ± 1.9°, P = 0.06) and 93% vs 100% (2.2 ± 1.3° vs 3.3 ± 3.2°, P < 0.001). The posterior slope achieved in accurate position was 92% vs 83% (2.1 ± 2°vs 2.4 ± 3.5°, P > 0.05). The varus angle of the tibial baseplate, 28% vs 40% achieved an accurate position (90 ± 1.8°vs 88.9 ± 1.7°, P < 0.05). 1.8 % total loosening rate (0.9% aseptic loosening rate) in the study. The follow-up was between 6 months to 19 years (The longest in conventional was 19 years, and navigation was 14 years). The mean duration of follow-up of conventional TKAs was 11.5 years and computer-navigation TKAs was 5.8 years.Conclusions: We concluded that computer navigation total knee arthroplasty is associated with better mechanical axial accuracy and similar complications events, but no different clinical outcome in short to mid-term follow-up. Improve the accuracy for beginner to perform this surgery.Keywords: Total knee arthroplasty; Navigation; ConventionalOrthopedic Department, Conde de São Januário General Hospital, Health Bureau, Macao, China*Corresponding to: Hou Mou CHAN, Consultant, Orthopedic Department, Conde de São Januário General Hospital, Health Bureau, Macao, China. E-mail: chanhongmou@gmail.comDOI : 10.30224/MMJ.202406_11(2).0001Hong Mou CHAN*, Chu Mang HO, Kit Ieng LEONG, Man Chon POU, Chan Wang LEI
Comparison of clinical outcome and alignment in conventional versus computer navigation total knee arthroplasty澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal1201. BackgroundTotal knee ar throplas ty (TKA) is a good outcome surgery for knee osteoarthritis. With the development of total knee arthroplasty, from conventional total knee arthroplasty to computer-navigation total knee arthroplasty, to obtain better clinical results. The literature [1-2] compared conventional versus computer navigation total knee arthroplasty, proven computer naviga t ion achieved be t te r advantages in the component alignment and even better pain relief and function in short-term follow-up. [3] However, controversy exists over whether the accuracy alignment has no obvious advantages in clinical functional results [4-5].Therefore, we investigated the mechanical and component alignment comparing the function before and post-operation between computer-navigation and conventional total knee arthroplasty in our hospital. In order to provide a safer and faster total knee replacement method that can reduce complications.2. Patients and MethodsFrom 2003 to 2022, 109 cases of total knee arthroplasty (Cemented) were randomly collected (from 94 patients, excluding revision replacement; all total knee arthroplasties were performed by the same team and used the medial parapatellar standard approach). They were divided into two groups for comparison: 30 cases received conventional total knee arthroplasty, and the other 79 cases underwent computer-navigation total knee arthroplasty (applied since 2008).The preoperative diagnosis was degenerative o s t e o a r t h r i t i s a n d s e c o n d a r y o s t e o a r t h r i t i s (Rheumatoid arthritis, bony necrosis and pigmented villonodular synovitis post-surgery and radiation).Use the weight-bearing lower limb length and short films (10 cm above and below the knee joint) as the standard film for measuring the alignments of the lower limbs. Through the application of the American Knee Association Radiographic Evaluation System [6], Mechanical axial (MA), Lateral distal femoral angle (LDFA), tibial baseplate varus angle, posterior slope, femoral flexion angle, joint line and other angle measurement. The Hospital for Special Surgery (HSS) Knee Replacement Expectation Scale [7] was used to evaluate and compare the pain, function and total scores of patients before and after TKA, and operation time were compared. The statistical methods of Independent or paired t-tests were used to analyze the differences between two groups of clinical and radiographic data. A P-value < 0.05 was considered significant.3. ResultNinety-four patients (109 TKAs) were available in the study, of which 24 were male and 70 were female. Conventional TKA involved twenty-eight patients (30 TKAs), of which 8 were male and 20 were female; the average age was 71 ± 10.18 (37-92) years old. Computer-navigation TKA involved sixty-six patients (79 TKAs), of which 16 were male and 50 were female, the average age was 72 ± 6.53 (58-86) years old. The follow-up was between 6 months to 19 years, the mean duration of follow-up of conventional TKAs was 11.5 years and computer-navigation TKAs was 5.8 years.Table 1. Demographic characteristics of the study populationConventional Computer-navigationN (patients) 28 (30 TKAs) 66 (79 TKAs)Age 69 ± 8.89 (37-92) 72 ± 6.53 (58-86)M/F ratio 8 : 20 16 : 50* Presented as mean ± SD (minimum-maximum)
Comparison of clinical outcome and alignment in conventional versus computer navigation total knee arthroplasty121 Volume 11 Número 2 Volume 11 Number 2第 11 卷第 2 期Table 2. Pain scoreConventional Computer-navigationPre-operationNo pain 0 % 0 %Mild pain 0 % 10 %Moderate pain 73% 67 %Severe pain 27% 23 %Average score 9.3 ± 3.6 (5 - 15) 11.8 ± 4.7 (5 - 20)Post-operationNo pain 74 % 76 %Mild pain 26 % 23 %Moderate pain 0 % 1 %Severe pain 0 % 0 %Average score 28.8 ± 2.2 (25 - 30) 28.6 ± 2.7 (20 - 30)* Presented as mean ± SD (minimum-maximum)Table 3. Knee scoreConventional Computer-navigationPre-operationPoor 70 % 47 %Fair 20 % 30 %Good 7 % 22 %Excellence 3 % 1 %Average score 53 ± 8.8 (41 - 71) 61 ± 11.4 (41 - 96)Post-operationPoor 0 % 0 %Fair 0 % 0 %Good 7 % 9 %Excellence 93 % 91 %Average score 89.3 ± 4.6 (82 - 98) 91.6 ± 5.3 (77 - 100)* Presented as mean ± SD (minimum-maximum)No s ign i f i can t d i f f e rence was obse rved between the two groups regarding demographic characteristics (P > 0.05). In clinical assessment with HSS score, the improvement (pain and knee score) was observed in postoperative assessment (P < 0.001), and even in conventional and computer navigation TKA, no statistically significant difference existed between the groups (P > 0.05). According to previous studies for the definition of varus or valgus deformities, mild (< 10 degrees), moderate (10-20 degrees) and severe (>20 degrees) [8-9]. 41 cases (37.6%) were mild, 53 cases (48.6%) were moderate, and 13 cases (13.8%) were severe deformities. In the group of conventional TKA, the most severe cases were 38 degrees varus and 20 degrees valgus, and 30 degrees varus and 13 degrees valgus were observed in the group computer navigation TKA. Five cases were used in the revision system in primary TKA.
Comparison of clinical outcome and alignment in conventional versus computer navigation total knee arthroplasty澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal122We measured the postoperative mechanical axis, the varus or valgus within 4° deviations in the group of computer navigation TKA, compared to the group of conventional TKAs (96% vs 90%, P = 0.01). One case was observed as valgus 5° and 2 cases were varus 5° in the group of computer navigation TKA. Two cases of severe varus deviation (9 degrees and 11 degrees) were observed in the group of conventional TKA, but no severe valgus cases were observed. Measurement of the femoral component position, including LDFA (83° to 85° ) and Femoral flexion angle (0° to 5° ) between the group of conventional TKA and computer navigation TKA, the results of accuracy of component position were 87% vs 62 % (P = 0.06) and 93% vs 100% (P < 0.001). 6 cases existed over flexion angle or extension angle (3 cases were 8 to 10° and 1 case was 12° flexion angle, 2 cases were 1 to 2° extension angle) in conventional TKA.The operation time compared with conventional to computer navigation was 170.1 ± 30.6 (110 - 207 min) vs 153 ± 32.3 (82 - 220 min) (P = 0.02). The tourniquet time was noted in 4 cases from the conventional group (12 to 21 min) and 2 cases from For the measurement of t ibial component pos i t ion , inc luded the t ib ia l basepla te varus angle and poster ior s lope between the group of conventional TKA and computer navigation TKA. Posterior slope was achieved in 83% of conventional cases and 92% of computer navigation cases, while anterior slope occurred in 17% (1 to 4 degrees) of conventional cases and 8% (1-2 degrees) of computer navigation cases (P > 0.05).In the measurement of the varus angle of the tibial baseplate, 40% of the conventional and 28% of the computed navigation achieved an accurate position. For 1 to 4 degrees of varus in TKA cases, 40% were conventional and 35% were computed navigation, and for 1 to 3 degrees of valgus cases, 7% were conventional and 37% were computed navigation. Among them, there was one case of varus up to 8 degrees in the conventional group (P < 0.05).the computed navigation group (16 and 18 min) because only used tourniquet in inserted cemented implant during operation, the results were 12 to 185 min in the conventional group and 16 to 180 min in computed navigation group.Table 4. Radiologic measurementConventional Computer-navigation P valueMechanical axial (within 4° deviation) 177.2 ± 2.4 (169° - 180° ) 178.5 ± 1.4 (174° - 181° ) P = 0.01LDFA 83.8 ± 1.3 (81° - 87° ) 84.5 ± 1.9 (81° - 89° ) P = 0.06Femoral flexion angle 3.3 ± 3.2 (-2° - 12° ) 2.2 ± 1.3 (0° - 4° ) P = 0.01Tibial baseplate varus angle 88.9 ± 1.7 (86° - 92° ) 90 ± 1.8 (85° - 94° ) P < 0.001Posterior slope 2.4 ± 3.5 (-4° - 10° ) 2.1 ± 2 (-4° - 5° ) P = 0.37Joint line 0.1 ± 0.3 (0 - 1cm) 0.26 ± 0.5 (0 - 2cm) P = 0.02* Presented as mean ± SD (minimum-maximum)
Comparison of clinical outcome and alignment in conventional versus computer navigation total knee arthroplasty123 Volume 11 Número 2 Volume 11 Number 2第 11 卷第 2 期Only one case demonstrated aseptic loosening in conventional group; one case of septic loosening was in the navigation group. The total loosening rate (septic & aseptic) for conventional and navigation 4. DiscussionI n o u r s t u d y, c o m p u t e r n a v i g a t i o n a n d c o n v e n t i o n a l t o t a l k n e e a r t h r o p l a s t y, t h e postoperative knee score of more than 90% of cases achieved excellent results, pain and function were significantly improved, and the two groups of techniques had no significant statistical effect on the postoperative score assessment. This is consistent with the conclusions in the literatures, although it is a short-term or medium-term follow-up study. The score included in this study is relatively simple, and total knee arthroplasty in short to medium term follow-up (6 months to 19 years) was 1.8% (Aseptic loosening 0.9%).more functional scores can be added in the future to obtain more data to support the research [10-12]. However, the accuracy rate of the mechanical axial of lower limbs in the optimal alignment after computer-navigated total knee arthroplasty is better, more than 96% within 4° deviations, no severe varus or varus occurs, and the overall average is better than conventional and statistically significant. The measurement of lateral distal femoral angle found that the overall average angle was similar and had no statistical significance, while the femoral Table 5. Operation and tourniquet timeConventional Computer-navigation P valueOperation time 170.1 ± 30.6 (110 - 207 min)153 ± 32.3 (82 - 220 min) P = 0.02* Presented as mean ± SD (minimum-maximum)Table 6. ComplicationsConventional Computer-navigation1.A case of varus 11° (varus 8° of tibial baseplate) combined with osteoporosis, leading to early aseptic loosening;1.Two cases of genu varus 4-5° post operation, causing by larger valgus angle of femoral component;2.A case of lateral subluxation of the patella before operation, and patella dislocation due to avulsion fracture of the patellar tendon 8 months after operation;2.A case of valgus 3° of the tibial baseplate and decreased 2° valgus angle of femoral 3.A case of tibial baseplate component anterior slope 4° , but the knee function score was 98 points, no loosening;3.A case of varus 30° before operation, postoperative weight-bearing x-ray was varus 5° , non-weight-bearing was within the normal range (there exists soft tissue imbalance);4.A case of temporary drop foot after spinal anesthesia, recovered finally;4.A case of infection 1 year after operation, leading to revision surgery.5.Delayed infection occurred in two cases (> 1 year post operation), no loosening after treatment.
Comparison of clinical outcome and alignment in conventional versus computer navigation total knee arthroplasty澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal124flexion angle and tibial baseplate varus angle had better results in the computer navigation group with statistical significance. The accuracy of coronal and sagittal alignment of femoral and tibial components was s l ight ly bet ter in the group of computer navigation, which matches the conclusion of the mechanical axial. In addition, there is no difference in the posterior slope of the tibial component between conventional and computer navigation. Considering that the tibial component is a rotation platform (a posterior slope of 0 degrees is required), these cases were not excluded from the study, which may lead to the possibility of selective bias.The study showed that the computer navigation g r o u p w a s s h o r t e r o p e r a t i o n t i m e t h a n t h e conventional surgery group. The longer operation time in conventional and computed navigation total knee arthroplasty that exists in orthopedic residents’ education during operation was not excluded in the study. However, it was considered that the cooperation and skills of the surgical team are more skilled in computer navigation cases caused by more cases, and the distribution of various complex cases (especially in severe deformities with bone defects or the use of revision system in primary TKA) had not been analyzed to show that bias existed. In terms of complications, there are situations related to alignment and infection in both groups.The computer navigation system prompts the operator to make corrections during the operation to obtain the optimal alignment or mechanical axial. Combined with the soft tissue balance using the gap balancer, better surgical results can be obtained. However, when using computer navigation, there are still large deviations in some cases that cannot be overly relied on by the computed navigation system. The points that need to be paid attention to during the operation include: the register of pointer must be consistent over the bone surface; verify the bone cut must not break away from the bone surface; the calculator needs to be regularly corrected by the software after long-term use to avoid deviations; and in case of unexplained deviations, switch to conventional surgery.Therefore, according to the results of the study, those who are familiar with computer navigation total knee arthroplasty can obtain accurate alignment and the same clinical function. Because of the advantages of computer navigation, which can indeed improve the accuracy of total knee arthroplasty for the orthopedics beginner.5. ConclusionWe concluded that computer-navigated total knee arthroplasty is associated with a more accurate mechanical axis, similar complication events, and no difference in clinical outcome at short- to medium-term follow-up. Indeed, improve the accuracy of joint replacement for orthopedics who are just beginning to learn to perform this type of surgery.Reference[1] Parratte S, Pagnano MW, Trousdale RT, et al. Effect of postoperative mechanical axis alignment on the fifteen-year survival of modern, cemented total knee replacements. J Bone Joint SurgAm2010;92:2143–9. DOI: 10.2106/JBJS.I.01398[2] Jenny JY, Boer i C. Computer-ass is ted implantation of total knee prostheses: a case-control comparative study with classical i n s t rumen ta t i on . Compu t A ided Su rg 2001;6:217–20. DOI: 10.1002/igs.10006[3] Gunnar Petursson, Anne Marie Fenstad, et al. Computer-Assisted Compared with Conventional Total Knee Replacement: A Multicenter Parallel-Group Randomized Controlled Trial. J Bone Joint Surg Am. 2018 Aug 1;100(15):1265-1274. DOI: 10.2106/JBJS.17.01338[4] Bauwens K, Matthes G, Wich M, et al. Navigated total knee replacement. A meta-analysis. J Bone Joint Surg Am 2007; 89(2): 261–269. DOI: 10.2106/JBJS.F.00601. DOI: 10.1007/s11999-012-2528-8
Comparison of clinical outcome and alignment in conventional versus computer navigation total knee arthroplasty125 Volume 11 Número 2 Volume 11 Number 2第 11 卷第 2 期[5] Burnett RSJ and Barrack RL. Computer-assisted total knee arthroplasty is currently of no proven clinical benefit: a systematic review. Clin Orthop Relat R 2013; 471(1): 264–276. DOI: 10.1007/s11999-012-2528-8[6] Ewald FC. The Knee Society total knee arthroplasty roentgenographic evaluation and scoring system. Clin Orthop Relat Res 1989(248):9. DOI:10.1007/978-1-4471-5451-8_47[7] Insall JN, Dorr LD, Scott RD, Scott WN. Rationale of the Knee Society cl inical rating system. Clin Orthop Relat Res. 1989 Nov;248:13-4. DOI:10.1007/978-1-4471-5451-8_48[8] Ranawat, A.S., et al., Total knee arthroplasty for severe valgus deformity. J Bone Joint Surg Am, 2005. 87 Suppl 1(Pt 2): p. 271-84. DOI: 10.2106/JBJS.E.00308[9] William Colyn, A. Cleymans, et al. The lateral joint line opening: a radiographic indicative parameter for high grade varus knees. Journal of Experimental Orthopaedics volume 9, Article number: 51 (2022). DOI: 10.1186/s40634-022-00489-5[10] Robert wen wei Hsu, et al. Comparison o f c o m p u t e r a s s i s t e d n a v i g a t i o n a n d conventional instrumentation for bilateral to ta l knee ar throplas ty. The outcomes a t mid- term fol low-up. DOI: 10.1016/j.arth.2008.03.006[11] J. M. Spencer, S K Chauhan, K Sloan, A Taylor, R J Beaver, et al. Computer navigation versus conventional total knee replacement: No difference functional results at two years. J Bone Joint Surg Br. 2007 Apr;89(4):477-80. DOI: 10.1302/0301-620X.89B4.18094[12] Matthias Meyer, Tobias Renkawitz, Florian Völlner, et al. Pros and cons of navigated versus conventional total knee arthroplasty-a r e t r o s p e c t i v e a n a l y s i s o f o v e r 2 4 0 0 patients. Arch Orthop Trauma Surg. 2021 Nov;141(11):1983-1991. DOI: 10.1007/s00402-021-03834-y
Wing Yi KWONG et al.澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal126Inappropriate use of metformin in advanced chronic kidney disease’s patients with diabetes mellitus in the Macau Health Center in 2021AbstractObjectives: This study was designed to review the inappropriate use of metformin in type 2 diabetes mellitus patients with chronic kidney disease throught systemic screening of Macau health centers, study the prevalence of metformin using rate and overuse rate, and adjust the inappropriate use to prevent adverse reactions.Methods: This retrospective study searched all patients with a diagnosis of diabetes mellitus who followed in Macau health centers via the health information system from Jun 01, 2021 to May 31, 2022. Data including gender, age, the hypoglycemic medications, and renal function, and eGFR (MDRD formula) were extracted from the medical system. Determine the prevalence of metformin usage rate and incidence of metformin overuse according to American Diabetes Association guidelines.Results: This study included 28100 patients who were diagnosed with diabetes and followed up at all Macau health centers during study period. The age from 16 to 100-years-old. 10523 patients were CKD stage 1, 13609 were CKD stage 2, 2452 were CKD stage 3a, 955 were CKD stage 3b, and 422 were CKD stages 4&5.24721 (88%) patients were prescribed the hypoglycemic regimen. 22470 patients (90.9%) were prescribed metformin alone or combined. Metformin use rate in CKD 1 to 3a is 82.6%. 76.9% of patients who were safe to use metformin (reduced dosage) in stage 3b, 85 patients (23.1%) did not reduce the metformin dose to 1000 mg. 32 patients (7.5%) had a record of prescription of metformin in CKD stages 4&5. 111 patients (0.48%) were prescribed metformin but did not base on the value of eGFR during the period of study. Overall, 22242 (98.99%) patients used metformin treatment properly in health center. 117 (0.52%) patients need to reduce dosage of metformin or discontinuation of metformin and 111 patients (0.49%) should have their blood test for eGFR value or indicator.Conclusions: In our retrospective study, metformin was the most common treatment in the diabetic patient (90.9%) in Macau health centers. 98.99% of patients who properly use metformin treatment. The overall inappropriate use rate is only 0.52%, but concentrated in patients with poor renal function, as high as 23.1% in CKD stage 3b and 7.5% in CKD stages 4&5. 0.49% of patients required tracking of changes in their renal function. Although the possibility of acidosis is low, according to Food and Drug Administration guidelines, we need to find out and make corrections as soon as possible to prevent adverse reactions and use drugs safely.Abbreviation: DM: Diabetes Mellitus; CKD: Chronic kidney disease; OPD: Outpatient department; MDRD: Modification of Diet in Renal Disease; eGFR: estimating the glomerular filtration rate; OHA: Oral hypoglycemic agent; FDA: Food and Drug Administration; CMENDD: Specialty of diabetes mellitus out-patient department; T2DM: Diabetes Mellitus type 2; T1DM: Diabetes Mellitus type 1;Keywords: Metformin; Diabetes Mellitus; SafetyFai Chi Kei Health Center *Correspondence to: Wing Yi KWONG , iko_881125@hotmail.comDOI : 10.30224/MMJ.202406_11(2).0002Wing Yi KWONG*, Tak Wai AU
Inappropriate use of metformin in advanced chronic kidney disease’s patients with diabetes mellitus in the Macau Health Center in 2021127 Volume 11 Número 2 Volume 11 Number 2第 11 卷第 2 期1. IntroductionThe global prevalence of diabetes has risen from 4.7% to 8.5% in the adult population since 1980 (from 108 million in 1980 to 422 million in 2014). In 2019, diabetes was the direct cause of 1.5 million deaths and 460000 kidney disease deaths. [1,2] Therefore, the treatment of diabetes has been valued highly. According to guidelines from the American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD) 2018, recommend metformin is the first-line drug for monotherapy and combination therapy for patients with T2DM. It is a recommendation as the best initial pharmacological option by professional organizat ions because of metformin’s glucose-lowering effects, safety and tolerability, extensive clinical experience, inexpensive, potential cardiovascular benefits, and general ly mild s ide effects including no hypoglycemia. [3-5]Metformin use has broadly increased as the number of people with diabetes has increased, with the most common side effect being gastrointestinal symptoms, but there is also a risk of lactic acidosis, a medical emergency that can lead to death. The cause of metformin-associated lactic acidosis is that metformin is metabolized and eliminated through the kidneys, and when renal function is damaged, it will promote the accumulation of lactic acid, which limits the clinical use of patients with renal insufficiency. Studies show that the overall incidence of metformin-related lactic acidosis is about 3 to 10 cases per 100,000 people per year. Although the incidence of lactic acidosis is rare, and Salpeter SR reported in the literature that there is no evidence that the use of metformin compared with other glucose-lowering treatments increases the risk of lactic acidosis. However, data are limited and there are no randomized controlled trials comparing the safety of metformin in patients with severe renal impairment. [6,7]However, available evidence support metformin usage in patients with mild to moderate chronic kidney disease. Current guidel ines including Diabetes Australia Guideline, American Diabetes Association (ADA), and European Association for the Study of Diabetes (EASA) have already been published as a recommendation to use metformin when the estimated glomerular filtration rate (eGFR) down to 30 mL/min/1.73 m². However, caution should be used when eGFR is less than 60 mL/min/1.73 m². When GFR is 45-59 mL/min/1.73 m², monitoring every 3-6 months is recommended, and dose reduction should also be considered if the patient has comorbidities that increase the risk of lactic acidosis leading to hypoperfusion and hypoxia blood. For GFR 30-44 mL/min/1.73 m², further dose reduction (1000 mg) should be considered, and eGFR less than 30 mL/min/1.73 m² is contraindicated. [3, 8-9]The main purpose of this study is to statistic the metformin usage rate of diabetic patients who are followed up by the Macau Health Center, and to evaluate the prevalence of inappropriate metformin usage in different stages of renal function, in order to screen out the diabetic patients with metformin overdose. Remind the doctor to adjust the dose of metformin or discontinue metformin based on renal function. It also provides basic data for developing strategies to improve the safe use of metformin in patients with diabetes and CKD.1.1 Methods This retrospective review study searched the data from all health centers (9 health centers and 2 health stations serve an estimated 683200 persons in 2021) in Macau between Jun 01, 2021 to May 31, 2022.[10] (This research has been approved by the hospital medical ethical committee in Macau)1.2 Patient SelectionIncluded studies that fulfilled the following criteria: (1) Aged 13 years and above; (2) Diagnosed with diabetes mellitus (ICPC2 codes T89-Diabetes insulin dependent, T90-Diabetes non-insulin dependent) in adult care clinics via health information system;
Inappropriate use of metformin in advanced chronic kidney disease’s patients with diabetes mellitus in the Macau Health Center in 2021澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal128(3) Excluded type 1 or special diabetic patients who followed up in CMENDD consultation;(4) The latest consultation was recorded if more than one consultation. (5) The result of creatinine and eGFR is the most recent blood test before the date of the patient's last visit.1.3 Extracted Data We extracted the following data in EXCEL form through the health information system according to the inclusion criteria, including the last consulted health center and responsible doctor, the date of the latest consultation and next consultation, patient name and medical number, age and gender, the latest serum creatinine before the last consultation and eGFR (MDRD formula), using hypoglycemic agents and metformin dosage, respectively. 1.4 Estimation of the GFRIn this study, we searched the latest serum creatinine and automatic calculation of eGFR according to the MDRD formula, usually classified into 6 stages (Normal or CKD stage 1: eGFR ≥ 90 ml/min/1.73m², CKD stage 2: eGFR = 60-89 ml/min/1.73m², CKD stage 3a: eGFR = 45-59 ml/min/1.73m², CKD stage 3b: eGFR = 30-44 ml/min/1.73m², CKD stage 4: eGFR = 15-29 ml/min/1.73m², CKD stage 5: eGFR < 15 ml/min/1.73m²). However, the study aims is to determine the prevalence of inappropriate metformin usage in chronic kidney disease according to the American Diabetes Association guideline (2018), which recommended contraindication to use metformin when eGFR < 30ml/min/1.73m²; reduced dosage when eGFR ≥30-44 mL/minu te /1 .73 m² and reduction to 1000mg/ day was suggested. [3, 8] We designed to divide into three groups: (1) Metformin Normal Dose Group (MNDG, eGFR ≥45 ml /min/1.73m²); (2) Metformin Reduced Dose Group (MRDG, eGFR ≥30 to <45 mL/minute/1.73 m²); and (3) Metformin Contraindication Group (MCG, eGFR < 30ml/min/1.73m²). 1.5 Hypoglycemic AgentsAll hypoglycemic agents in Macau health center were recorded in the studies, including Metformin, Insulin, Sulfonylurea, Thiazolidinedione, DPP-4 inhibitor, Glinide, SGLT2 inhibitor, Alpha glucosidase inhibitor, respectively. 2. ResultsThe study included 28100 patients (14530 males and 13570 females, M:F ratio = 1: 1.07) who were diagnosed with diabetes and followed up at health centers in Macau between Jun 01, 2021 to May 31, 2022. The age from 16-years-old to 100-years-old. The average age was 60, 66, 73, 76 and 73 years, corresponding to CKD stages 1, 2, 3a, 3b and stage 4&5, respectively. (Figure 1).The results of the number of patients who used hypoglycemic medica t ions in research , 3379 (n=28100, 12%) patients did not use any hypoglycemic agents or from other hospitals, another 24721 (n=28100, 88%) patients were prescribed single hypoglycemic agent or combination regimen. (Figure 2).Among the patients who used hypoglycemic drugs, 22470 patients (n=24721, 90.9%) were prescribed Metformin, 8687 patients (n=24721, 35.1%) were prescribed Sulfonylurea, 4675 patients (n=24721, 18.9%) were prescribed DPP-4 inhibitor, 3243 patients (n=24721, 13.1%) were prescribed Insulin, 2833 patients (n=24721, 11.5%) were prescribed SGLT2 inhibitor, 2050 patients (n=24721, 8.3%) were prescribed Alpha-glucosidase inhibitor, 2050 patients (n=24721, 8.3%) were prescribed Thiazolidinedione, and 110 patients (n=24721, 0.49%) were prescribed Glinide, respectively. Those data might be single use alone or concomitant use with other agents. (Figure 3).We reached 27961 patients (n= 28100, 99.5%) who had serum creatinine and eGFR results before consultation, and a total of 26584 patients had eGFR ≥ 45 ml/min/1.73m². The following data is using metformin in health center (Excluded those who did not use hypoglycemic drugs or used out-of-health centers or non-metformin), in which 8991 patients (n=10523,
Inappropriate use of metformin in advanced chronic kidney disease’s patients with diabetes mellitus in the Macau Health Center in 2021129 Volume 11 Número 2 Volume 11 Number 2第 11 卷第 2 期85.4%) were CKD stage 1, 11233 patients (n=13609, 82.5%) were CKD stage 2, 1735 patients (n=2452, 70.8%) were CKD stage 3a, all of them (n=21959) were used metformin and included into metformin normal dose group, and overall metformin using rate is 82.6%% (n=26584). (Figure 4).368 patients (n=955 (CKD stage 3b), 38.5%) were included in the metformin reduced dose group (CKD stage 3b). Of these 368 patients, 85 patients (n=368, 23.1%) did not reduce the metformin dose to 1000 mg were found. (Figure 5).422 patients were included in the metformin contraindication group (296 patients were eGFR between 29-15 ml/min/1.73m², 126 patients were eGFR less than 15 ml/min/1.73m²). However, 32 patients (n=422, 7.5%%) had a record of prescription of metformin (Figure 6).From the results of the research, we found 111 patients who have prescribed metformin but did not base on the value of eGFR during the period of study.Overall, 22242 (n=22470, 98.99%) patients who safe to use metformin treatment in Macau health center. 117 (n=22470, 0.52%) patients used with caution in metformin, of which 85 patients required a dose reduction of metformin, 32 patients should be discontinued metformin, and 111 patients (n=22470, 0.49%) should have their blood test of eGFR result possible.Figure 1. The average age of diabetic patients at different stages of chronic renal disease in health centers
Inappropriate use of metformin in advanced chronic kidney disease’s patients with diabetes mellitus in the Macau Health Center in 2021澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal130Figure 2. The proportion of diabetes patients using hypoglycemic agents (recorded) in the health centersFigure 3. Number of hypoglycemic agents in diabetes patients in health centers
Inappropriate use of metformin in advanced chronic kidney disease’s patients with diabetes mellitus in the Macau Health Center in 2021131 Volume 11 Número 2 Volume 11 Number 2第 11 卷第 2 期Figure 4. The proportion of diabetic patients using metformin in different stages of CKD in health centersFigure 5. Proportion of reduced dosage and inappropriate dosage of using metformin in diabetic patients with CKD stage 3b in health centers
Inappropriate use of metformin in advanced chronic kidney disease’s patients with diabetes mellitus in the Macau Health Center in 2021澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal132Figure 6. The proportion of inappropriate use of metformin in diabetic patients with CKD stages 4&5 in health centers3. DiscussionIn our retrospective study, 24721 patients were diagnosed with diabetes and prescribed hypoglycemic agents in health centers of Macau. 90.9% of these patients were taking metformin as a hypoglycemic agent, either as monotherapy or in combination. This was a satisfactory result in our study, metformin was the initial first treatment to the diabetic patient except for contraindications, that achieved with the clinical guidelines of the International and Macau health center for the treatment of diabetes mellitus. [3,12,13]Metformin was proven its beneficial effects on HbA1c, weight, reduced cardiovascular outcomes, progression of renal function, as well as mortality in CKD with the diabetic patients, especially those with CKD stage 3b. [4,14] However, our study shown the metformin usage rate in diabetic patients with chronic kidney disease, was 85.4%, 82.5%, 70.8%, and 38.5% from CKD stage 1 to CKD stage 3b, respectively. We can be seen that when the renal function of diabetic patients gradually declines, the clinical use of metformin-based therapy regimens gradually decreases. This may be due to clinicians' concerns about the increased risk of side effects, including lactic acidosis, when prescribing metformin to patients with chronic kidney disease (usually elderly patients or with comorbidities). In addition, the FDA updated and modified the use of metformin after April 2016, expanding the use of metformin to some patients with moderate CKD. [15, 16] This may have resulted in some long-term diabetic patients with mild to moderate renal insufficiency who could not use metformin before 2016, did not resume metformin after 2016.Indeed, recent literature highlights the rarity of metformin-associated lactic acidosis (MALA) and supports the cautious expansion of metformin use. Some reports indicate its adverse effects as well that are negligible when its benefits are brought into account. [15] Further than more, clinicians can update the latest medication knowledge through regular medical education. Moreover, clinicians should regularly review their renal function and prescriptions, in order to improve the efficacy and safety of metformin.
Inappropriate use of metformin in advanced chronic kidney disease’s patients with diabetes mellitus in the Macau Health Center in 2021133 Volume 11 Número 2 Volume 11 Number 2第 11 卷第 2 期FDA changed labeling for metformin, allowing use up to a GFR of 30 ml/min/1.73m², which was intended to provide a safety margin to minimize the risk of metformin-associated lactic acidosis (MALA). [16]According to this principle, we screened 85 patients (23.1%) in the metformin reduced dose group (CKD stage 3b) who were over 1000mg/d and 32 patients (7.5%) in metformin contraindication group (CKD stages 4&5) had a prescription of metformin in our study. It may be due to doctors underestimating the impact of drugs on renal insufficiency; insufficient awareness of drugs that require dose adjustment for renal insufficiency; insufficient consultation time; multi-prescribing drugs; temporary job replacement; insufficient eGFR warnings in the system, etc. However, it should adjust their medications by their responsible physicians to make drug adjustments as soon as possible, to increase to drug safety clinically. Additionally, 111 patients were found to be using metformin without an eGFR blood test. It may be because the patient forgot to draw blood before the appointment; the doctor did not prescribe a blood test; or the test was recently performed at a medical facility in a private practice.98.99% of pat ients who were safe to use metformin treatment in Macau health center. Overall inappropriate use rate is only 0.52%, but in their CKD stages, the rate will increase to 23.1% and 7.5%. It should be concern by our attention.Through our research, except for patients with severe renal insufficiency, the clinical application of metformin is very safe and effective. The doctors in Macau Health Center can make appropriate treatment for diabetic patients according to the guidelines, the overall result is satisfactory. There are still a small number of patients who use metformin inappropriately, which increases the risk of clinical adverse reactions. Due to the clinical complexity, we can better improve the use and safety of metformin through systematic testing and doctor's education.4. ConclusionIn our retrospective study, metformin was the most common treatment in the diabetic patient (90.9%) in health centers in Macau. 98.99% of patients who were safe to use metformin treatment. The overall inappropriate use rate is only 0.52%, but concentrated in patients with poor renal function, as high as 23.1% in CKD stage 3b and 7.5% in CKD stages 4&5. Further 0.49% of patients required tracking of changes in their renal function. Although the possibility of acidosis is low, according to FDA guidelines, we need to find out and make corrections as soon as possible to prevent adverse reactions and use drugs safely.5. Limitations of the studyThere are some limitations exist in the study, including incorrect ICPC2 codes in our system; metformin was prescribed by doctors out of the health centers system; the doctor changed the dose of metformin by oral orders; acute exacerbation of renal function in the period of study, are resulting in the possibility of bias of study.6. AcknowledgmentsI would like to appreciate Dr. Au Tak Wai (Doctor in Fai Chi Kei Health Center, Macau) and the staff in I.T. department (C.H.C.S.J.) for helping with this research report.Potential Conflict of Interest:The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.Reference[1] Global report on diabetes (WHO). www.who.int/diabetes/global-report[2] Global Burden of Disease Collaborative Network. Global Burden of Disease Study 2019. Results. Institute for Health Metrics and Evaluation. 2020[3] Melanie J. Davies, David A. D’Alessio, et
Inappropriate use of metformin in advanced chronic kidney disease’s patients with diabetes mellitus in the Macau Health Center in 2021澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal134al. Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018 Dec;41(12):2669-2701 DOI: 10.2337/dci18-0033[4] Maruthur NM, Tseng E, Hutfless S, et al. Diabetes medications as monotherapy or metformin-based combinat ion therapy for type 2 diabetes: a systematic review a n d m e t a - a n a l y s i s . A n n I n t e r n M e d 2016;164:740-751 DOI: 10.7326/M15-2650[5] Griffin SJ, Leaver JK, Irving GJ. Impact of metformin on cardiovascular disease: a meta-analysis of randomised trials among people with type 2 diabetes. Diabetologia. 2017 Sep;60(9):1620-1629 DOI: 10.1007/s00125-017-4337-9[6] Silvio E. Inzucchi, Kasia J. Lipska et al. Metformin in Patients With Type 2 Diabetes and Kidney Disease: A Systematic Review. JAMA. 2014 Dec 24-31; 312(24): 2668–2675 DOI: 10.1001/jama.2014.15298[7] S a l p e t e r S R , G r e y b e r E , e t a l . R i s k o f f a t a l a n d n o n f a t a l l a c t i c a c i d o s i s with metformin use in type 2 diabetes melli tus. Cochrane Database Syst Rev. 2010 Apr 14;2010(4) :CD002967 DOI: 10.1002/14651858.CD002967.pub4[8] Ian H. de Boer, et al. Diabetes Management in Chronic Kidney Disease: A Consensus Report by the American Diabetes Association (ADA) and Kidney Disease: Improving G loba l O u tcomes (K DIGO ) D iabe t e s Care. 2022 Dec; 45(12): 3075–3090. DOI: 10.2337/dci22-0027[9] Colagiuri S, Dickinson S, Girgis S. et al. National Evidence Based Guideline for Blood Glucose Control in Type 2 Diabetes Canber ra : Diabe tes Aus t ra l i a and the NHMRC, 2009. (18 December 2015, date last accessed)[10] Health Statistics in Macau (2021). www.ssm.gov.mo/statistic/2021/pdf/pdf.html[11] Lipska KJ, Bailey CJ, Inzucchi SE, et al. Use of metformin in the setting of mild-to-moderate renal insufficiency. Diabetes Care. 2011;34(6):1431-1437 DOI: 10.2337/dc10-2361[12] Type 2 diabetes in adults: management. NICE guideline.[13] Guidel ines on Management of Type 2 Diabetes Mellitus in MCHC. [14] Soie Kwon, Yong Chul Kim, et al. The Long-term Effects of Metformin on Patients With Type 2 Diabetic Kidney Disease. Diabetes Care . 2020 May;43(5) :948-955 . DOI: 10.2337/dc19-0936[15] Crowley MJ, et al. Metformin Use in Patients with Contraindications or Precautions. VA ESP Project #09-010; 2016.[16] The U.S. Food and Drug Administration (FDA). Drug Safety Communicat ions: FDA revises warnings regarding use of the diabetes medicine metformin in certain pat ients with reduced kidney funct ion [Internet], 2016. Available from https://www.fda.gov/downloads/Drugs/DrugSafety/UCM494140.pdf. Accessed 7 March 2017
Lai Si UN et al.135 Volume 11 Número 2 Volume 11 Number 2第 11 卷第 2 期Epidemiological report of the active surveillance program for surgical site infection in a Macao hospitalAbstractObjective: To describe the evolution of local trends and risk factors of active surgical site infection (SSI) surveillance in a Macao Hospital over the 2013-2022 period.Methods: We implemented an active SSI surveillance program in 2013 at the 623-bed Hospital of Macao. Our hospital’s health information system collected data with following the United States Center for Disease Control SSI criteria. The SSI rate was the ratio of the number of SSI to the number of included procedures. The procedures documented by the surgeon and reviewed by the infection control nurse for the presence/absence of SSI were deemed validated.Results: In 2013-2022, 48 SSIs from a total of 9094 surgical procedures for ten types of surgical procedures were reported. Length of stay (post-operative) was significantly higher in patients who developed SSI (5.00 vs. 26.00, day). In multivariable analysis, SSI was found to be positively associated with the 75th percentile of the duration of operation above 48 minutes (OR 4.58; 95% CI 1.02-20.50) for cesarean section operations, and diabetes mellitus (OR 6.50; 95% CI 1.18-35.91) for hip prosthesis operations. Conclusions: SSI is an important indicator of healthcare quality. Prompt recognition and control of potentially modifiable risk factors may improve the burden and outcomes in this high-risk population. We successfully built up an SSI epidemiological database through active surveillance. The study data will be important reference data when analyzing and exploring future local surveys, or when possibly looking into new methods for surveillance of SSI. Keywords: Surgical site infection; SSI; Surveillance; Length of stay; Macao Hospital Hygiene Committee, Conde de São Januário General Hospital, Health Bureau, Macao, China*Correspondence to: Lai Si UN, mercyun@ssm.gov.moDOI : 10.30224/MMJ.202406_11(2).0003Lai Si UN*, Fong Kuong PANG1. IntroductionSurgical site infection (SSI) is a common healthcare-associated infection (HAI) [1]that occurs following surgical procedures. It is estimated to affect up to one-third of patients undergoing surgery[2], resulting in increased financial burden, prolonged hospital stays, and even mortality. Therefore, it is an important indicator of healthcare quality [1-6]. However, only sparse data are available on the recent epidemiology of SSI in Macao.Most surgical site infections can be prevented if appropriate strategies are implemented[8]. One effective approach involves the implementation of an active HAI surveillance program[9], which includes the collection and analysis of data on SSI rates and feedback of this information to surgeons. This feedback enables surgeons to identify areas for improvement and implement targeted interventions
Epidemiological report of the active surveillance program for surgical site infection in a Macao hospital澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal1362. Method2.1 SettingWe implemented an active SSI surveillance program since 2013 at the 623-bed Hospital of Macao, which inc ludes medica l , emergency, intensive care, and surgical units. Initially, only reduction of fracture or fixation (FX) participated in the surveillance program. By 2019, the SSI active surveillance program includes ten types of surgical procedures (Table 1): breast surgery (BRST), colectomy (COLO), cesarean section (CSEC), hernia(HER), hip prosthesis (HPRO), nephrectomy (NEPH), prostatectomy (PRST), reduction of fracture or fixation (FX), thyroid/ parathyroid surgery (THYR) and ventriculo-peritoneal shunt (VSHN).2.2 Surveillance methodOur surveillance relied on our hospital’s HAI System. Data are collected by the Health Information System (HIS) of our hospital in accordance with agreed surveillance definitions. Data are submitted to the infection control nurse (ICN) and undergo quality checks before entry into the database monthly. The source data of our monitoring included the surgeon’s clinical examination of the patient and the ICN’s analysis of the patient’s medical record. The ICN highlighted the SSI suspected procedure with appropriate microbiology results. Difficult cases were resolved by discussion between ICN then entered these data in an Excel database.2.3 FeedbackEvery 3 months, each surgical unit received a report containing the results of the SSI surveillance analysis for their index procedures. Table 1. Index procedures under surveillance year30-day follow-up Period 90-day follow-up PeriodCOLO CSEC NEPH PRST THYR BRST FX HER HPRO VSHN2013 ✓2014 ✓ ✓ ✓ ✓2015 ✓ ✓ ✓ ✓2016 ✓ ✓ ✓ ✓ ✓ ✓2017 ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓2018 ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓2019 ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓2020 ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓2021 ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓2022 ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓BRST: breast surgery, COLO: colectomy, CSEC: cesarean section, HER: hernia, HPRO : hip prosthesis, NEPH: nephrectomy, PRST: prostatectomy, FX : reduction of fracture or fixation, THYR : thyroid/ parathyroid surgery, VSHN : ventriculoperitoneal shunt.to reduce SSI rates[10].This paper aims to describe the evolution of local trends and risk factors in prospective active SSI surveillance and the implementation of SSI prevention measures in a Macao hospital throughout 2013-2022.
Epidemiological report of the active surveillance program for surgical site infection in a Macao hospital137 Volume 11 Número 2 Volume 11 Number 2第 11 卷第 2 期2.4 DefinitionsWe used the United States Center for Disease Control definitions [11], adapted from the Chinese national SSI surveillance definitions [12], to classify infections as superficial, deep, organ/space SSI. The procedures documented by the surgeon and reviewed by the ICN for the presence/absence of SSI were deemed validated.The SSI active surveillance program includes ten types of surgical procedures. SSI detected within a defined follow-up period were included in the analysis. The standardized follow-up period was 30 days (where day 1= the procedure date). For deep or organ/space infections following operations with an implant in place (BRST/FX/HER/HPRO/VSHN), the follow-up period was extended to 90 days. 2.5 AnalysisThe SSI rate was the ratio of the number of SSI to the number of included procedures. We assessed the usually described SSI risk factors: age, gender, diabetes mellitus (DM), the American Society of Anaesthesiologists (ASA) score, urgent operation, intervention duration (median duration of operation and 75th percentile of the duration of operation), and length of postoperative stay (days).2.6 Statistical analysisThe study database was created with Excel software and SPSS Version 23 ®. Continuous variables were presented as medians and qualitative variables were described as percentages and a 95% confidence interval (CI). SSI rates were compared based on risk factors using the CHI test (χ2) and Mann–Whitney U test. To control for confounding effects, a multivariable analysis of SSI was conducted using binary logistic regression. A p-value of less than 0.05 was considered statistically significant.3. Results3.1 Characteristic of patients by type of surgical procedureData was collected from 1 January 2013 to 31 December 2022 (Table 2). The most frequently recorded types of surgical procedure were CSEC, followed by FX and HER. The median age of patients varied from 31 years in CSEC operations to 81 years in HPRO and FX operations. The proportion of individuals aged above 65 was the highest in HPRO operations. The proportion of diabetes mellitus was the highest in NEPH operations. The proportion of urgent operations was the highest in CSEC operations. The ASA score≥ III was the VSHN operations. The median duration of operation was the longest in COLO operations and the median length of post-operative stay was the longest in VSHN operations. 3.2 SSI rate and the type of SSIIn 2013-2022, 48 SSIs from a total of 9094 surgical procedures for ten types of surgical procedures were reported. The SSI rate varied from 0.10% in HER operations to 4.41% in COLO operat ions (Table 3) . Of these, 43.75% were superficial, 39.58% deep, and 16.67% were organ/space SSIs. The length of post-operative stay was significantly longer in the SSI group (26.00 vs. 5.00 days), as shown in Table 4. The proportion of deep or organ/space SSI was 28.57% in CSEC operations and 36.84% in COLO operations. VSHN operations only reported organ space SSI. FX operations only reported deep SSI. The deep SSIs and organ/space SSIs for HPRO operations are 83.33% and 16.67% (Figure 1).
Epidemiological report of the active surveillance program for surgical site infection in a Macao hospital澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal1383.3 Isolated pathogensThe most common pathogens identified were methicillin-resistant Staphylococcus aureus (MRSA) (19.05%), Escherichia coli (ESBL+) (11.90%), and Pseudomonas aeruginosa (11.90%), as shown in Table 5. 3.4 SSI risk factors In the bivariate analysis and multivariable analysis (binary logistic regression), SSI was also found to be positively associated with the 75th percentile of the duration of operation above 48 minutes for CSES operations, and DM for HPRO operations, as shown in Tables 6 and 7. The result (p<0.05) of an odds ratio is interpreted as follows: The CSES opera t ions pa t ien ts who the 75 th percentile of the duration of operation above 48 minutes SSI 4.58 times more often than patients in the 75th percentile of the duration of operation below 48 minutes. The HPRO operations patients who have diabetes SSI 6.5 times more often than patients who have no diabetes.Figure 1. Type of SSI by type of surgical procedureBRST: breast surgery, COLO: colectomy, CSEC: cesarean section, FX: reduction of fracture or fixation, HER: hernia, HPRO: hip prosthesis, NEPH: nephrectomy, PRST: prostatectomy, SSI: surgical site infection, THYR: thyroid/ parathyroid surgery, VSHN : ventriculoperitoneal shunt.
Epidemiological report of the active surveillance program for surgical site infection in a Macao hospital139 Volume 11 Número 2 Volume 11 Number 2第 11 卷第 2 期Table 2. Characteristics of patients by type of surgical procedure, patient-based dataTotal(n=9094)BRST(n=559)COLO(n=431)CSEC(n=4272)FX(n=1173)HER(n=969)HPRO(n=517)NEPH(n=166)PRST(n=254)THYR(n=639)VSHN(n=114)Sex: Male (%) 25.41 1.07 57.08 0 35.98 92.16 30.37 59.04 100.00 26.76 56.14Female (%) 74.59 98.93 42.92 100.00 64.02 7.84 69.63 40.96 0 73.24 43.86Median age (years) 41.00 57.00 68.00 31.00 81.00 68.00 81.00 67.00 68.00 56.00 56.50Age≥ 65 (%) 29.99 27.01 57.77 0 73.15 59.75 88.01 55.42 67.32 22.38 25.44Urgent operations (%) 66.77 2.15 24.36 99.65 87.13 11.97 85.11 12.65 0 1.88 76.32DM (%) 10.37 11.81 20.19 3.02 19.86 12.69 24.18 27.71 16.54 11.74 14.91ASA score= I (%) 18.28 6.08 2.55 32.05 4.60 8.98 0.97 3.61 1.18 14.24 1.75ASA score= II (%) 51.09 68.34 47.10 54.03 31.88 59.96 28.43 34.94 68.50 64.95 3.51ASA score≥ III & unknown (%) 30.63 25.58 50.35 13.92 63.52 31.06 70.60 61.45 30.32 20.81 94.74Median duration of operation (minutes)53.00 117.00 153.00 40.00 70.00 64.00 73.00 175.00 180.50 106.00 84.5075th percentile of the duration of operation (minutes)95.00 152.00 195.00 48.00 106.00 86.00 93.00 233.75 227.00 143.00 146.00Median length of postoperative stay (days)5.00 3.00 7.00 5.00 27.00 2.00 29.00 9.50 14.00 2.00 36.00ASA : the American Society of Anaesthesiologists, BRST: breast surgery, COLO: colectomy, CSEC: cesarean section, DM: diabetes mellitus, FX: reduction of fracture or fixation, HER: hernia, HPRO: hip prosthesis, NEPH: nephrectomy, PRST: prostatectomy, THYR: thyroid/ parathyroid surgery, VSHN: ventriculoperitoneal shunt.
Epidemiological report of the active surveillance program for surgical site infection in a Macao hospital澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal140Table 3. SSI rate (95%CI) by type of surgical procedureType SSI case Total procedures SSI rate (95%CI)BRST 1 559 0.18 (0.01 to 0.88)COLO 19 431 4.41 (2.73 to 6.76)CSEC 7 4272 0.16 (0.07 to 0.32)FX 8 1173 0.68 (0.32 to 1.30)HER 1 969 0.10 (0.01 to 0.51)HPRO 6 517 1.16 (0.47 to 2.41)NEPH 1 166 0.60 (0.03 to 2.97)PRST 2 254 0.79 (0.13 to 2.60)THYR 1 639 0.16 (0.01 to 0.77)VSHN 2 114 1.75 (0.29 to 5.80)Total 48 9094 0.53 (0.39 to 0.69)BRST: breast surgery, COLO: colectomy, CSEC: cesarean section, FX: reduction of fracture or fixation, HER: hernia, HPRO: hip prosthesis, NEPH: nephrectomy, PRST: prostatectomy, THYR: thyroid/ parathyroid surgery, SSI: surgical site infection, VSHN: ventriculoperitoneal shunt. Table 4. Effect of SSI on length of post-operative stayVariable Total procedures SSI No SSI PLength of postoperative stay (days)# 5.00(4.00-9.00) 26.00(9.00-68.00) 5.00(4.00-8.00) <0.001*#Median (IQR), SSI: surgical site infection,* p<0.054. DiscussionSSI surveillance is crucial for preventing healthcare-associated infections and monitoring the effectiveness of prevention and control measures [2,3,5-8,13]. In this study, the overall SSI rate was 0.53%, which is lower than the European SSI rate (2018-2020) of 1.57%[4]. Escherichia species were the most common pathogen identified in COLO operations, accounting for 5 (27.78%), which is similar to a 2021 hospital-wide survey report in Alabama [14]. Data on microorganisms were reported for 42 microorganisms resulting in 48 SSI. MRSA(19.05%) was the most common in orthopedic operations (FX/HPRO), accounting for 10.42% (5 cases). This is in contrast with a United States study reporting higher rates of MRSA SSI (10.2%)[15]. Decolonization is one method used to reduce surgical site infections b y t r e a t i n g p a t i e n t s [ 1 6 ] w i t h a n i n t r a n a s a l antimicrobial, skin agent, or both to eliminate or temporarily reduce S. aureus colonization prior to surgery. This measure is strongly recommended for high-risk surgical procedures such as prosthetic joint replacement [2,3,8,12].
Epidemiological report of the active surveillance program for surgical site infection in a Macao hospital141 Volume 11 Número 2 Volume 11 Number 2第 11 卷第 2 期Table 5. Organisms reported as causing SSI by procedure groupCOLO CSEC FX HER HPRO NEPH PRST THYR VSHNTotal Gram-positives (n=18, 42.85%)Staphylococcus aureus (methicil-lin-resistant)1 1 2 3 1Staphylococcus epidermis 2Enterococcus faecalis 2Staphylococcus capitis 1 1Staphylococcus aureus(methicillin-sensitive)1Coagulase Negative Staphylococci 1Staphylococcus epidemidis + Strep-tococcus anginosus1Enterococcus faecium 1Total Gram-negatives (n=18, 42.85%)Morganella morganii 1Pseudomonas aeruginosa+ Acine-tobacter junii1Salmonella enterica ssp enterica 1Enterobacter cloacae complex+ Acinetobacter baumannii1Escherichia coli 1 1 1 1Pseudomonas aeruginosa 2 1 1 1Escherichia coli (ESBL+) 4 1Total Fungus, Candida (n=1, 2.38%)1Total Mixed Gram- negatives and positives (n=5, 11.90%)4 1BRST: breast surgery, COLO: colectomy, CSEC: cesarean section, ESBL: Extended Spectrum Beta-Lactamase, FX: reduction of fracture or fixation, HER: hernia, HPRO: hip prosthesis, NEPH: nephrectomy, PRST: prostatectomy, SSI: surgical site infection, THYR: thyroid/ parathyroid surgery, VSHN: ventriculoperitoneal shunt.
Epidemiological report of the active surveillance program for surgical site infection in a Macao hospital澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal142Table 6. Analysis of SSI Risk Factors by procedure groupProcedure No. of ProceduresNo. of SSI Risk factors SSI No SSI χ2 OR (95% CI) PCSEC 4272 7 Age: Age> 31 4(0.09%) 2039(47.73%) 0.244 1.46 (0.33-6.51) 0.621Urgent operation: Yes 7(0.16%) 4250(99.49%) 0.025 1.00 (1.00-1.00) 0.875DM: Yes 1(0.02%) 128(3.00%) 3.039 5.39 (0.64-45.07) 0.081ASA: ASA> I 6(0.15%) 2685(66.13%) 1.185 3.06 (0.37-25.42) 0.27675th percentile of the duration of operation (minutes)Duration >48 4(0.09%) 975(22.82%) 4.650 4.50 (1.01-20.14) 0.031*HPRO 517 6 Gender: Male 2(0.39%) 155(29.98%) 0.025 1.15 (0.21-6.34) 0.874Age: Age>81 3(0.58%) 253(48.94%) 0.001 1.02 (0.20-5.10) 0.981Urgent operation: Yes 6(1.16%) 434(83.95%) 1.062 1.01 (1.00-1.03) 0.303DM: Yes 4(0.77%) 121(23.40%) 5.978 6.45 (1.17-35.63) 0.014*ASA: ASA> II 5(0.99%) 346(68.79%) 0.529 2.18 (0.25-18.84) 0.46775th percentile of the duration of operation (minutes):Duration>93 1(0.19%) 126(24.37%) 0.204 0.61 (0.07-5.28) 0.651ASA: the American Society of Anaesthesiologists score, CSEC: cesarean section, DM: diabetes mellitus, HPRO: hip prosthesis, SSI: surgical site infection, * p<0.05Table 7. Results of multivariable analysis (binary logistic regression)Procedure Variable Wald OR (95% CI) PCSEC 75th percentile of the duration of operation (> 48 minutes) 3.959 4.58 (1.02-20.50) 0.047*HPRO DM 4.600 6.50 (1.18-35.91) 0.032*The top three SSI rates identified were COLO operations (4.41%), VSHN operations (1.75%), and HPRO operations (1.16%) which is similar to data reported from a French teaching hospital from 2003 to 2016[9]. In our study, we observed a significant association between diabetes (OR 6.50, 95% CI 1.18-35.91) and the risk of SSI in HPRO operations. Hyperglycemia impairs the innate immune system and promotes glycosylation of proteins, which compromises wound healing[17]. Diabetes can lead to higher perioperative glucose levels and hyperglycemia which is more difficult to treat. Perioperative hyperglycemia in patients with or without diabetes is associated with SSI, and randomized clinical trials support perioperative glucose control as an evidence-based practice to decrease the risk of SSI [2,3,8,12].Compared to the ECDC’s published survey data, CSEC: cesarean section, DM: diabetes mellitus, HPRO: hip prosthesis, * p<0.05
Epidemiological report of the active surveillance program for surgical site infection in a Macao hospital143 Volume 11 Número 2 Volume 11 Number 2第 11 卷第 2 期the 75th percentile intervention duration for COLO operations, CSEC operations, and HPRO operations is 190 minutes, 47 minutes, and 86 minutes. These results are 1-7 minutes shorter than those of our study. However, the SSI rates for these procedures were found to be 8.1%, 1.30%, and 1.2%[4], which is higher than our survey results by 0.04-3.68%. In our study, we only found that the 75th percentile of the duration of operation (> 48 minutes) is a significant SSI risk for CSES operations (OR 4.58, 95% CI 1.02-20.50). In bivariate analysis regarding SSI risk, the 75th percentile intervention duration for COLO operations and HPRO operations were found to be 195 minutes and 93 minutes and did not show statistical significance. To reduce the risk of SSI in patients undergoing these procedures, intervention duration should be controlled as much as possible. Longer operative time is associated with higher damage to wound cells, wound contamination[18], and exposure to the outside environment[8]. Moreover, ECDC’s survey is country-specific, has high heterogeneity among patients, and includes data on patient history, wound class, ASA score, and other unreported factors that may affect the occurrence of SSI. Therefore, different results can be referenced but not directly compared.The outcome of our study was assessed in terms of the length of post-operative stay (days). The length of post-operative stay was significantly increased by SSI. We observed a longer median duration of postoperative stay of 26.00 (9.00-68.00) days in participants with SSI when compared with 5.00 (4.00-8.00) days in those without SSI. Multiple previous studies reported similar findings with significantly longer hospital stays in patients with SSI. For instance, a United States study reported an increase of 14 days in the median length of hospital stay if the patient developed SSI[19]. A French study reported an increase in median length of hospital stay from 7 days the SSI-free patients to 22 days in patients who developed SSI[20]. The findings from this study will provide valuable insights into the local trends and risk factors associated with SSI, as well as the impact of prevention strategies. This information can be used to guide future efforts in reducing SSI rates and improving patient outcomes. Ultimately, the goal is to enhance patient safety and promote better surgical outcomes through the implementation of evidence-based practices and targeted interventions to prevent surgical site infection.5. LimitationsOur surveillance study has several limitations. Although we were able to describe SSI rates from 2013-2022, we did not establish the impact of specific preventative measures such as preoperative smoking cessation, prophylactic antibiotics (preoperative and duration), blood transfusion, and maintaining normothermia during the surgical procedure. These data may more effectively reflect the clinical team’s control of SSI rates. Additionally, we found that collaboration between the ICN and surgical team and regular quarterly feedback to the surgical unit reinforced their motivation and played a key role in good SSI risk control. However, our method was time-consuming, and the evolution toward automated methods based on algorithms to index procedures and SSI evaluation. This would provide the ICN with more dedicated time for analysis. To improve information dissemination, a more secure and automated hospital-acquired infection surveillance software is being deployed in our hospital’s IT system. Currently, our study is limited to analyzing electronic records. 6. ConclusionsOver the years, we built up an important SSI surveillance program and database representing the surgery variety of a Macao hospital. The success of this monitoring relied on the surgery units and ICN involvement in the regular review of procedures and resulted in a good teamwork collaboration.In the study period from 2013 to 2022, a total of 48 SSIs were reported out of 9094 surgical procedures across ten types of surgeries. The most frequently reported microorganisms associated with SSIs were MRSA (19.05%). Patients who developed an SSI had a significantly longer post-operative length of stay compared to those without an infection (5.00 vs. 26.00, day). In the multivariable analysis, SSI was found to
Epidemiological report of the active surveillance program for surgical site infection in a Macao hospital澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal144be positively associated with the 75th percentile of the duration of operation (> 48 minutes) for CSES operations (OR 4.58; 95% CI 1.02-20.50) and DM (OR 6.50; 95% CI 1.18-35.91) for HPRO operations.The study data will be important reference data when analyzing and exploring future local surveys, or when possibly looking into new methods for surveillance of SSI. It allowed analysis of local SSI risk factors, which helped clinical teams focus on controlling and following up with surgical patients. Nevertheless, our study has shown that long-term active SSI surveillance, although resource-intensive, can effectively control SSI.7. AcknowledgmentsThe authors express their gratitude to the dedicated colleagues from the surgical ward and IT department for their active involvement in the surveillance of SSI.Reference[1] Chinese Society of Surgical Infection and Intensive Care, Chinese Society of Surgery, Chinese Medical Association; Chinese College of Gastrointestinal Fistula Surgeons, Chinese College of Surgeons, Chinese Medical Doctor Association. Chinese guidelines for the prevention of surgical site infection. Zhonghua Wei Chang Wai Ke Za Zhi. 2019;22(4):301-314. doi:10.3760/cma.j.issn.1671-0274.2019.04.001.[2] World Health Organization. Global guidelines for the prevention of surgical site infection (2nd ed.). Geneva: WHO, 2018. https://apps.who.int/iris/handle/10665/277399.[3] Liston J, Bayles A. Surgical site infections. Surgery (Oxford). 2023; 41(2): 65-70. doi: 10.1016/j.mpsur.2022.11.009.[4] European Centre for Disease Prevention and Control. Healthcare-associated infections: surgical site infections. Stockholm: ECDC, 2023.[5] United Kingdom Health Security Agency. Surveillance of surgical site infections in NHS hospitals in England, April 2020 to March 2021. London: UKHSA, 2022.[6] South Australia Health. SA Healthcare-associated Infection Surveillance Program Surgical Site Infection 2020 Annual Report. Adelaide: SA Health, 2021.[7] Curcio D, Cane A, Fernández F, Correa J. Surgical site infection in elective clean and clean-contaminated surgeries in developing countries. Int J Infect Dis. 2019; 80:34-45. doi: 10.1016/j.ijid.2018.12.013. [8] Seidelman JL, Mantyh CR, Anderson DJ. Surgical Site Infection Prevention: A Review. JAMA. 2023;329(3):244-252. doi: 10.1001/jama.2022.24075.[9] Bataille C, Venier AG, Caire F, Salle H, Le Guyader A, Pesteil F, Chauvet R, Marcheix PS, Valleix D, Fourcade L, Aubry K, Brie J, Robert PY, Pefau M, Ploy MC, D’Hollander-Pestourie N, Couve-Deacon E. Benefits of a 14-year surgical site infections active surveillance programme in a French teaching hospital. J Hosp Infect. 2021;117:65-73. doi: 10.1016/j.jhin.2021.08.001.[10] Li, Q., Soe, M., Nkwata, A., Russo, V., Dudeck, M., & Edwards, J. Surgical Site Infection Trend Analysis Following Colon Surgeries, National Healthcare Safety Network, 2009–2018. Infect Control Hosp Epidemiol. 2020; 41(S1), S397-S397. doi:10.1017/ice.2020.1040[11] Zhang, Y., Liu, S., Li, L., et al. Multicenter study on targeted monitoring of surgical site infection and risk factors. Chinese J. of Infect Cont. 2015; (4): 544-547.[12] Berríos-Torres SI, Umscheid CA, Bratzler DW, Leas B, Stone EC, Kelz RR, Reinke CE, Morgan S, Solomkin JS, Mazuski JE, Dellinger EP, Itani KMF, Berbari EF, Segreti J, Parvizi J, Blanchard J, Allen G, Kluytmans JAJW, Donlan R, Schecter WP; Healthcare Infection Control Practices Advisory Committee. Centers for Disease Control and Prevention Guideline for the Prevention of Surgical Site Infection,
Epidemiological report of the active surveillance program for surgical site infection in a Macao hospital145 Volume 11 Número 2 Volume 11 Number 2第 11 卷第 2 期2017. JAMA Surg. 2017;152(8):784-791. doi: 10.1001/jamasurg.2017.0904.[13] Zingg W, Holmes A, Dettenkofer M, Goetting T, Secci F, Clack L, Allegranzi B, Magiorakos AP, Pittet D; systematic review and evidence-based guidance on organization of hospital infection control programs (SIGHT) study group. Hospital organization, management, and structure for prevention of health-care-associated infection: a systematic review and expert consensus. Lancet Infect Dis. 2015;15(2):212-24. doi: 10.1016/S1473-3099(14)70854-0. [14] Alabama Public Health. Healthcare-Associated Infections in Alabama Annual Report 2021. Alabama: APH, 2022.[15] Seidelman JL, Baker AW, Lewis SS, Advani SD, Smith B, Anderson DJ. 903. SSI Trends in Community Hospitals from 2013 to 2018. Open Forum Infect Dis. 2020; 7(Suppl 1): S485–6. doi: 10.1093/ofid/ofaa439.1091. [16] Popovich KJ, Aureden K, Ham DC, Harris AD, Hessels AJ, Huang SS, Maragakis LL, Milstone AM, Moody J, Yokoe D, Calfee DP. SHEA/IDSA/APIC Practice Recommendation: S t r a t e g i e s t o p r e v e n t m e t h i c i l l i n -resistant Staphylococcus aureus transmission and infection in acute-care hospitals: 2022 Update. Infect Control Hosp Epidemiol. 2023; 44(7):1-29. doi: 10.1017/ice.2023.102.[17] Martin ET, Kaye KS, Knott C, Nguyen H, Santarossa M, Evans R, Bertran E, Jaber L. Diabetes and Risk of Surgical Site Infection: A Systematic Review and Meta-analysis. Infect Control Hosp Epidemiol. 2016; 37(1):88-99. doi: 10.1017/ice.2015.249.[18] Li L, Cui H. The risk factors and care measures of surgical site infection after cesarean section in China: a retrospective analysis. BMC Surg. 2021 May 19;21(1):248. doi: 10.1186/s12893-021-01154-x. [19] Ebogo Titus NT, Nzinga JR, Nchufor NR, Njuma TE, Ntih LM, Sena GR, Pisoh CT. Epidemiology of Surgical Site Infection Following Abdominal Surgeries at a Reference Hospital in North-West Cameroon. J West Afr Coll Surg. 2021 Apr-Jun;11(2):1-6. doi: 10.4103/jwas.jwas_51_22.[20] L a m a r s a l l e L , H u n t B , S c h a u f M , Szwarcensztein K, Valentine WJ. Evaluating the clinical and economic burden of healthcare-associated infections during hospitalization for surgery in France. Epidemiol Infect. 2013 Dec;141(12):2473-82. doi: 10.1017/S0950268813000253.
Wai Man WONG et al.澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal146The correlation between ventilation modes, sedatives and opioids, fluid balance, and ventilator-associated events: a matched case-control studyAbstractObjective: The United States Centers for Disease Control and Prevention (CDC) introduced new surveillance definitions for Ventilator-Associated Event (VAE). VAEs are associated with adverse patient outcomes. However, research demonstrating the preventability of VAEs remains scarce. This study aims to investigate the incidence rate of VAE, and identify the correlation between ventilation modes, the use of sedatives and opioids, fluid balance, and the occurrence of VAEs.Methods: This study was a matched case-control study that adopted the definition of VAE adjusted by the CDC in 2020. Adult patients who were mechanically ventilated for ≥4 calendar days between August 2018 and July 2020 at the Centro Hospitalar Conde de São Januário in Macau were included. For each VAE case, five matched controls were selected on the basis of sex, age group, and duration of mechanical ventilation.Results: There were 1,334 adult patients who were on mechanical ventilation, of which 608 were for ≥4 calendar days. A total of 43 VAEs were identified, with an incidence rate of 2.92 cases per 1,000 ventilator-days. Each case was matched with five controls, resulting in a total inclusion of 258 patients. Conditional logistic regression revealed a significant difference between the case group and the control group in terms of days in mandatory ventilation modes as a percentage of days on mechanical ventilation [100(IQR:88.9-100) vs 90.9(IQR:66.7-100), OR=1.05, 95%CI(1.02,1.08), P=0.002]. Additionally, the case group was observed to have a higher dosage of sedatives and opioids as well as a larger fluid load without statistical significance.Conclusions: Mandatory ventilation mode is a risk factor for VAEs in adult. Strategies for reducing the duration of mandatory ventilation modes could be considered for inclusion in VAE prevention protocols.Keywords: Ventilator-Associated Event; Ventilation mode; Sedative; Opioid; Fluid balance1Conde de São Januário General Hospital, Macau 999078, China 2Macao Polytechnic University, Macau SAR, China*Corresponding to: Yan WANG, Email: ywang@mpu.edu.moDOI : 10.30224/MMJ.202406_11(2).0004Wai Man WONG1,2, Yan WANG2*, Fong Kuong PANG1
147 Volume 11 Número 2 Volume 11 Number 2第 11 卷第 2 期The correlation between ventilation modes, sedatives and opioids, fluid balance, and ventilator-associated events: a matched case-control study1. IntroductionVentilator-Associated Event (VAE) is a surveillance definition released by the United States Centers for Disease Control and Prevention (CDC) in 2013, replacing Ventilator-Associated Pneumonia (VAP) as the surveillance method for adult patients receiving invasive mechanical ventilation (IMV). Evidence suggests that chest radiograph findings do not accurately identify VAP. The subjectivity and variability inherent in chest radiograph technique, interpretation, and reporting make chest imaging ill-suited for inclusion in a definition algorithm to be used for the potential purposes of inter-facility comparisons and public reporting.[1] With using objective and readily available data elements, the VAE definition algorithm can broaden the focus of surveillance to include both infectious and non-infectious pulmonary complications that may lead to oxygenation deterioration. Clinical conditions that trigger VAE mainly include pneumonia (25%-40% of cases), fluid overload including pulmonary edema (20%-40%), atelectasis (10%-15%), and acute respiratory distress syndrome (10%-20%). [2] Multiple studies have shown a significant correlation between VAEs and adverse patient outcomes, including prolonged mechanical ventilation, increased length of stay in the intensive care unit, and increased mortality rate. [3-4] The findings highlight the clinical value of VAE surveillance and prevention.Few studies have defined the influencing factors for VAEs. The risk factors with stronger evidence include mandatory modes of mechanical ventilation, sedatives (especially benzodiazepines and propofol), opioids, positive fluid balance, etc. Other factors, such as oral care with chlorhexidine, stress ulcer prophylaxis, gastric retention, and re-intubation, are only supported by weak evidence. The literature demonstrating the preventability of VAEs is also scarce. The best-studied interventions to date that have been associated with lower VAE rates in interventional trials include spontaneous awakening trials, spontaneous breathing trials, and conservative fluid management. [5]The Centro Hospitalar Conde de São Januário (C.H.C.S.J.) is the first hospital in Macau to implement VAE surveillance. This study analyzed the surveillance data of the first two years of the hospital and investigated the correlation between ventilation modes, sedatives and opioids, fluid balance, and VAE occurrence. It provided a reference basis for formulating preventive strategies against VAEs.2. Definitions2.1 Ventilator-Associated EventThe CDC defined a VAE as a sustained increase in ventilator support following a period of stable or decreasing ventilator support. The VAE definition is operationalized using the following elements: changes in ventilator settings, white blood cell count, body temperature, use of antimicrobial agents, and laboratory evidence of respiratory infection. Depending on the number of elements met, there are three tiers within the VAE algorithm: Ventilator-Associated Condition (VAC), Infection-related Ventilator-Associated Complication (IVAC), and Possible Ventilator-Associated Pneumonia (PVAP). VAEs and VACs are synonymous and are defined as an increase in the daily minimum positive end expiratory pressure (PEEP) of ≥3 cmH2O sustained for ≥2 calendar days after ≥2 days of stable or decreasing daily minimum PEEP, or an increase in the fraction of inspired oxygen (FiO2) of ≥20 points sustained for ≥2 days after ≥2 days of stable or decreasing daily minimum FiO2 levels. [1]2.2 Mandatory modes of mechanical ventilationMandatory modes of mechanical ventilation refer to the ventilator providing ventilation assistance for each breath according to preset inspiratory time, tidal volume, or ventilation pressure, regardless of spontaneous breathing. The ventilator can also intermittently perform mandatory ventilation, allowing spontaneous breathing between two mechanical ventilations, at which time only airflow is provided. [6] The following are mandatory modes: volume control ventilation (VCV), pressure control ventilation (PCV), volume assist ventilation (VAV), pressure assist ventilation (PAV), volume assist-control ventilation (V-A/C), pressure assist-control ventilation (P-A/C), intermittent mandatory ventilation (IMV), and synchronized intermittent mandatory
The correlation between ventilation modes, sedatives and opioids, fluid balance, and ventilator-associated events: a matched case-control study澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal148ventilation (SIMV).3. Methods3.1 Study populationThis study was performed in C.H.C.S.J. and involved adult patients who had undergone IMV via endotracheal tubes or tracheostomy tubes for ≥4 calendar days between August 2018 and July 2020. Patients on high-frequency ventilation, extracorporeal life support, or extracorporeal membrane oxygenation therapy were excluded.During the study period, a total of 1,334 adult patients underwent IMV, of which 608 patients underwent IMV for ≥4 calendar days and were screened by inclusion and exclusion criteria. A total of 43 VAE patients and 565 non-VAE patients were found. 3.2 Study designThis study was a 1:5 matched case-control study. Individual matching was used, with sex, age group, and duration of IMV as matching criteria. SPSS was used to select 5 controls for each VAE case. A total of 43 cases and 215 controls were included, with a sample size of 258. The appropriate sample size for this study was calculated using the Power and Sample Size Program (version 3.1.6). In this program, a dichotomous output with a matched case-control study was modeled to identify the sample size sufficient to detect the difference between two odds ratios. The following inputs were used to calculate the statistical power (probability of correctly rejecting the null hypothesis, 1-b): type I error probability for a two-sided test (α) of 0.05; case group size of 43; matching ratio of 1:5; probability of exposure in controls (p0) of 0.2; an odds ratio of exposure in cases relative to controls (y) of 3. The software showed that the statistical power was 0.867.3.3 Data extractionBy reviewing electronic medical records and preserved files, the following clinical characteristics were extracted: baseline data: including demographic information, duration of IMV, comorbidities and severity of disease; ventilator modes; sedative and opioid dosage; fluid balance; VAE occurrence.3.4 MeasurementsIn this study, we adopted the definition of VAE [1] as revised by CDC in 2020. For ease of analysis, the CDC has provided a VAE calculator on its official website.Comorbidity refers to any additional disease burden that is not related to the primary diagnosis. To assess comorbidity, we used the Charlson Comorbidity Index (CCI), which encompasses nineteen comorbid conditions. The Health Bureau assigns codes to medical diagnoses using the International Classification of Diseases-Ninth Revision-Clinical Modification (ICD-9-CM) and the International Classification of Primary Care-2 (ICPC-2). The comorbidity categories within the CCI can be defined through these coding systems.The severity of disease was assessed using the Acute Physiology and Chronic Health Evaluation II (APACHE II), with higher scores corresponding to more severe disease and a higher risk of death. The assessment includes three parts: acute physiology score, age score, and chronic health score. The sedative and opioid dosage conversion formulas developed by Devlin & Roberts [7] and Barr et al. [8] were adopted. These formulas can convert different types of sedatives and opioids into equivalent doses of fentanyl or midazolam, facilitating comparisons between patients. We considered the impact of insensible fluid loss [9], such as body fluid lost from respiratory system, skin, and water in the excreted stool. The average daily fluid balance was defined as (daily intake - daily output)/monitoring days - 500 mL.3.5 Statistical analysisStatistical analysis was performed using SPSS 28.0, with a significance level set at α=0.05. Categorical variables were presented as frequencies and percentages. Continuous variables with normal distributions were presented as mean and standard deviation (Mean±SD), and those with non-normal distributions were presented as median (Md) and interquartile range (IQR). Univariate conditional logistic regression was used to analyze the correlation between each variable and VAEs, calculating the odds ratio (OR), 95% confidence interval of the OR, and P-value.
149 Volume 11 Número 2 Volume 11 Number 2第 11 卷第 2 期The correlation between ventilation modes, sedatives and opioids, fluid balance, and ventilator-associated events: a matched case-control study3.6 Ethical ApprovalThis study was approved by the Hospital Medical Ethical Committee of C.H.C.S.J. and the Teaching and Technology Committee of the Faculty of Health Sciences and Sports of Macau Polytechnic University. Only existing medical records were collected. There was no transfer of personal information or exposure to special risk. Therefore, the need for patient consent was waived.4. Results4.1 Incidence of VAEDuring the study period, there were a total of 1,334 adult patients who underwent IMV, with a total of 14,725 days of IMV. Among them, 608 patients who underwent IMV for ≥4 calendar days were included in this study. 4.3 Comorbidity and Severity of Disease of Case and Control GroupsIn this study, 43 case-control pairs were obtained through a 1:5 match, totaling 258 patients were included in the analysis. Given that sex, age group, and duration of IMV were used as matching criteria, these variables exhibited similar distributions in both the case and control groups.CCI was used to assess comorbidities suffered within one year prior to admission. Although the CCI score of the case group was higher, the difference was not statistically significant [2(IQR:1-4) vs 2(IQR:0-4), According to the definition of VAE, we identified 43 cases of VAE, which included 43 cases of VAC, 12 cases of IVAC-plus (the sum of IVAC and PVAP), and 3 cases of PVAP. The incidence of VAE was 3.22% (43/1334×100%), and there were 2.92 cases per 1,000 ventilator-days (43/14725×1000). 4.2 Characteristics of Patients with and without VAEsAmong the 608 patients who underwent IMV ≥4 calendar days, a significantly larger proportion of VAE patients were male compared to non-VAE patients (83.7% vs 66.9%, P=0.02). There was no significant difference in age and age group distribution. However, VAE patients had a significantly longer duration of IMV [20 (IQR:12-37) vs 8 (IQR:6-13), P<0.001]. (Table 1)OR=1.11, 95%CI(0.96,1.28), P=0.15]. APACHE II was used to assess the severity of disease within the first 24 hours of IMV. Despite the total APACHE II score of the case group being higher than that of the control group (31.3±8.2 vs 28.9±8.8), and both the acute physiology score and chronic health score also being higher, these differences did not reach statistical significance.The results indicated that there was baseline comparability between the groups. (Table 2)Table 1. Demographic characteristics and duration of IMV of patients with and without VAEs (n=608)Characteristic VAE (n=43) Non-VAE (n=565) PSex-male, n (%) 36 (83.7%) 378 (66.9%) 0.02Age (y), Md(IQR) 68 (60-78) 67 (57-76.5) 0.42Age group, n (%) 0.70≤44 2 (4.7%) 55 (9.7%)45-54 3 (7.0%) 59 (10.4%)55-64 13 (30.2%) 138 (24.4%)65-74 12 (27.9%) 148 (26.2%)≥75 13 (30.2%) 165 (29.2%)Duration of IMV (days), Md(IQR) 20 (12-37) 8 (6-13) <0.001
The correlation between ventilation modes, sedatives and opioids, fluid balance, and ventilator-associated events: a matched case-control study澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal150Table 2. Comorbidity and Severity of Disease of Case and Control Groups (n=258)Items Cases(n=43)Controls(n=215)Conditional logistic regressionOR 95%CI PCCI, Md(IQR) 2 (1-4) 2 (0-4) 1.11 0.96-1.28 0.15APACHE II, Mean±SD 31.3±8.2 28.9±8.8 1.03 0.99-1.08 0.09Acute Physiology Score of APACHE II, Mean±SD 25.6±8.1 23.8±7.9 1.03 0.99-1.08 0.16Chronic Health Score of APACHE II, Md(IQR) 0 (0-5) 0 (0-0) 1.10 0.94-1.27 0.244.4 The Correlation Between Ventilation Modes, Sedatives and Opioids, Fluid Balance and VAEsDays in mandatory ventilation modes as a percentage of days on mechanical ventilation, showed a statistically significant difference between the case group and the control group [100(IQR:88.9-100) vs 90.9(IQR:66.7-100), OR=1.05, 95%CI(1.02,1.08), P=0.002]. This suggested that increased percentage of days in mandatory ventilation mode was associated with a higher probability of VAE occurrence.Sedatives commonly used were benzodiazepines, propofol, and dexmedetomidine. Benzodiazepines included alprazolam, diazepam, lorazepam, and midazolam. There was no significant difference in the proportion of sedative use during IMV between the case group and the control group [88.4% vs 93.5%, OR=0.53, 95%CI(0.18,1.56), P=0.25]. Further analysis of sedative dosages revealed that the average daily dosage of sedatives and benzodiazepines (in mg midazolam equivalents) was greater in the case group, although this difference was not statistically significant. The average daily dosage of propofol and dexmedetomidine also had no significant difference.Opioids commonly used were codeine, fentanyl, methadone, morphine, oxycodone, and pethidine. The proportion of opioid use did not show a significant difference between the case group and the control group [83.7% vs 88.8%, OR=0.66, 95%CI(0.27,1.61), P=0.36]. Further analysis of opioid dosages revealed that the average daily dosage of opioids (in 100 μg fentanyl equivalents) was greater in the case group, although this difference was not statistically significant.The case group exhibited a larger fluid load but no significant difference [0.29±0.53 vs 0.13±0.66 liters, OR=1.46, 95%CI(0.87,2.45), P=0.15]. Similarly, the case group demonstrated a higher tendency towards a positive fluid balance, but this was also not statistically significant [65.1% vs 53.5%, OR=1.65, 95%CI(0.82,3.33), P=0.16]. When comparing average daily fluid balances exceeding 50 mL, 300 mL, 500 mL or 800 mL, the case group had a higher proportion, but these differences were not significant.
151 Volume 11 Número 2 Volume 11 Number 2第 11 卷第 2 期The correlation between ventilation modes, sedatives and opioids, fluid balance, and ventilator-associated events: a matched case-control studyTable 3. The Correlation Between Ventilation Modes, Sedatives and Opioids, Fluid Balance and VAEs (n=258)ItemsCases(n=43)Controls(n=215)Conditional logistic regressionOR 95%CI PDays in mandatory ventilation modes as a percentage of days on mechanical ventilation, Md(IQR)100 (88.9-100) 90.9 (66.7-100)1.05 1.02-1.08 0.002Sedative use, n(%) 38 (88.4%) 201 (93.5%) 0.53 0.18-1.56 0.25Average daily dosage of sedatives, Md(IQR) Total sedatives (benzodiazepines+propofol), mg midazolam equivalents20.5 (5.2-34.8) 16.2 (4.9-30.8) 1.01 1.00-1.03 0.09 Benzodiazepines, mg midazolam equivalents19.9 (5.2-34.2) 15.4 (4.8-29.2) 1.01 1.00-1.03 0.08 propofol, mg midazolam equivalents 0 (0-10.0) 0 (0-6.3) 0.98 0.95-1.01 0.16 Dexmedetomidine, μg 0 (0-24.9) 0 (0-6.0) 1.00 1.00-1.01 0.45Opioid use, n(%) 36 (83.7%) 191 (88.8%) 0.66 0.27-1.61 0.36Average daily dosage of Opioids, 100 μg fentanyl equivalents1.73 (0.22-3.39) 1.45 (0.36-2.82) 1.06 0.88-1.27 0.54Average daily fluid balance (litre), Mean±SD 0.29±0.53 0.13±0.66 1.46 0.87-2.45 0.15Average daily fluid balance, n(%) >0 mL 28 (65.1%) 115 (53.5%) 1.65 0.82-3.33 0.16 ≥50 mL 27 (62.8%) 104 (48.4%) 1.84 0.92-3.68 0.08 ≥300 mL 21 (48.8%) 74 (34.4%) 1.86 0.94-3.66 0.07 ≥500 mL 15 (34.9%) 56 (26.0%) 1.58 0.76-3.30 0.22 ≥800 mL 10 (23.3%) 30 (14.0%) 1.97 0.84-4.59 0.125. DiscussionThis study identified 43 VAEs, yielding a VAE incidence rate of 2.92 cases per 1,000 ventilator-days. In 2014, a total of 1,824 healthcare facilities reported 32,772 location months of surveillance data to the CDC’s National Healthcare Safety Network, with ICU-pooled mean VAE incidence rate ranging from 2.00 and 11.79 [10]. It is the largest published epidemiological survey on VAEs. A retrospective study conducted by the West China Hospital, which included a total of 20,769 patients, reported a VAE incidence rate of 16.7 [4]. The incidence rate of VAE in this study was lower than the domestic study in China and was comparable to those in developed countries such as the United States.A total of 608 patients were included in this study. There were no significant differences in age and age groups between patients with or without VAEs. However, it was observed that a higher proportion of VAE patients were male (83.7% vs 66.9%, P=0.02). This finding aligns with studies from the United States [10], Japan [11], South Korea [12], and China [4], suggesting that males may have a higher risk of developing VAEs.This study showed that VAEs were associated with prolonged mechanical ventilation [20(IQR:12-37) vs 8(IQR:6-13) days, P<0.001], a finding that was consistent with the results of previous studies [3-4, 9, 11-13]. A cohort study in the United States found that the duration of IMV in VAE patients was longer [14.7±8.9 vs 7.5±6.3 days, P<0.001]. [3] Similarly, a retrospective study in China found that VAE patients had a longer duration of IMV [14(IQR:8-22) vs 8(IQR:5-13) days,
The correlation between ventilation modes, sedatives and opioids, fluid balance, and ventilator-associated events: a matched case-control study澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal152P<0.001]. [4] VAE is a surveillance definition that denotes a deterioration in oxygenation status following a period of stability or improvement. The occurrence of VAEs indicates that the patient continues to require ventilatory support, consequently delaying the timing of ventilator weaning. Multiple studies demonstrated a significant correlation between VAEs and adverse patient outcomes. Therefore, it is worth implementing appropriate efforts towards VAE prevention.This study suggested a positive correlation between mandatory ventilation modes and VAEs, a finding that aligned with two other studies. Lewis et al., in a 1:1 matched case-control study conducted in the United States [13], included 110 cases each in the case group and control group, matched based on age, sex, ICU type, CCI, and IMV days. They found that mandatory ventilation mode was an independent risk factor for VAC [36% vs 19%, OR=3.4, 95%CI(1.6,8.0)]. Nakahashi et al., in a retrospective cohort study conducted in Japan [11], included 303 patients and found that the use of higher driving pressure (ΔP) was an independent risk factor for VAEs [AHR=1.216, 95%CI(1.109,1.333)]. During inhalation, ΔP expands the lung tissue and chest wall by overcoming the elastic resistance of the respiratory system, allowing external air to enter the lungs. The researchers pointed out that mandatory ventilation modes generally use a larger ΔP, hence their findings were consistent with those of Lewis et al.Through literature review, it can be inferred that there may be two mechanisms by which mandatory ventilation modes trigger VAEs:Mechanism 1: Mandatory ventilation modes induce Ventilator-Induced Lung Injury (VILI). Spontaneous venti lat ion modes determine the inspiratory flow rate, tidal volume, and respiratory rate based on spontaneous breathing, ventilatory pressure, and ventilatory resistance. This results in good synchrony between the patient and the machine. However, mandatory ventilation modes have the following disadvantages: Ventilation parameters can easily be set improperly, such as excessively large tidal volumes or high airway pressures. There is often greater ventilation in the upper lung areas, leading to uneven pressure d i s t r ibu t ion in a lveo l i . When a pa t i en t’s spontaneous breathing intensif ies, mandatory ventilation mode can easily lead to inconsistencies between the patient and the ventilator during the inhalation process or the transition from inhalation to exhalation [6]. These situations can lead to high transpulmonary pressure and shear forces, resulting in lung injury.Transpulmonary pressure is the pressure difference between the airway opening and the pleural surface that the lung parenchyma is subjected to. Lung injury occurs when stresses result in lung volumes nearing total capacity, corresponding to a transpulmonary pressure of 26 cmH2O. Limiting end-inspiratory transpulmonary pressure to 20-25 cmH2O may mitigate lung injury. [14] Overdistension of alveoli can occur with excessive tidal volume or airway pressure settings in mandatory ventilation modes. Additionally, patient-ventilator asynchrony can cause a sudden increase in alveolar pressure, increasing transpulmonary pressure. Shear force, also known as shear stress. Air is pushed into the lungs during IMV and the alveoli expand, while ventilation stops and the alveoli recoil, generating shear force. Mandatory ventilation modes can cause high shear force due to reasons such as: The larger the tidal volume setting, the greater the alveolar expansion and recoil. This results in greater shear force and easier alveolar collapse. When some alveoli collapse, the surrounding tissue bears great pressure. When collapsed alveoli are expanded, there will be a great shear force that tears apart the alveolar wall. The distribution of intrapulmonary pressure in different areas causes differences in shear force between alveoli. After overstretching of the alveoli, the distance between the alveoli and pulmonary microvessels is also increased, leading to increased permeability of the alveolar membrane and microvessels. [6]Cyclic recruitment and derecruitment of the alveoli causes increased lung damage and release of inflammatory substances. The surfactant will decrease, leading to aggravated alveolar collapse and severe hypoxemia, which may trigger VAE thresholds.
153 Volume 11 Número 2 Volume 11 Number 2第 11 卷第 2 期The correlation between ventilation modes, sedatives and opioids, fluid balance, and ventilator-associated events: a matched case-control studyIn addition, inflammatory substances enter blood circulation and cause systemic inflammatory reactions. This biotrauma mechanism constitutes acute respiratory distress syndrome and multiple organ failure, which aggravates oxygenation deterioration and further increases the risk of VAE occurrence.Mechanism 2: Mandatory ventilation modes induce Ventilator-Induced Diaphragm Dysfunction (VIDD). The respiratory muscles consist of the diaphragm, intercostal muscles, and abdominal muscles. The diaphragm is responsible for more than 60% of respiratory movements. Mechanical ventilation can provide sufficient lung ventilation for critically ill patients and unload part of the respiratory muscle workload. In the past, continuous mandatory ventilation (CMV) was believed to give the diaphragm a rest and help successfully wean off the ventilator. However, research has shown that more than 50% of patients rapidly develop VIDD within the first 24 hours of IMV. [15]The mechanism by which mandatory ventilation modes cause VIDD is inferred to have two main aspects: Diaphragm muscle fiber atrophy: Under mandatory mode, the diaphragm is in an unloaded state, and muscle disuse reduces the rate of protein synthesis. An animal experiment found that the synthesis rate of diaphragm myosin heavy chain in rats decreases significantly within the first 6 hours of mandatory ventilation. [16] Another animal experiment found that protein hydrolysis enzyme activity increased in rats after 18 hours of mandatory ventilation. [17] Diaphragm muscle fiber atrophy is the result of reduced protein synthesis and increased decomposition. [18] Diaphragm muscle fiber remodeling: The diaphragm is a type of skeletal striated muscle that is divided into two types of fibers. The first type (type I) is slow-oxidative, while the second type is fast-oxidative (type IIa) and fast-glycolytic (type IIb). Type I and type IIa fibers are more fatigue-resistant, while type IIb fibers are more prone to fatigue. The use of mandatory ventilation mode causes a reduction in diaphragm thickness and changes in muscle fiber cross-sectional area. Type I and type II fibers are remodeled, and the proportion of mixed muscle fibers increases. Type I fibers are more fatigue-resistant, therefore, after remodeling, diaphragm contractile force decreases and fatigue easily occurs. [18]The dysfunction of the diaphragm significantly affects respiratory function and may induce VAEs. It is worth noting that the decrease in diaphragm contractile force is directly proportional to the duration of IMV. This suggests that the longer the duration of IMV, especially when using mandatory ventilation mode, the higher the risk of VIDD and VAE occurrence.However, reports suggested that the correlation between VAEs and mandatory ventilation modes may be confounded. The severity of the disease may affect their relationship. Patients with severe progressive lung disease are more likely to be placed on mandatory mode. Furthermore, the correlation may be confounded by neurological suppression, paralytic medications, or heavy sedation. Patients with these exposures may require frequent adjustment of ventilator settings, which can trigger indicators of VAE. [13] Although this study found that the case group used higher doses of sedatives and opioids, it did not reach statistical significance.The correlation between VAEs and excess fluids is consistent with both observational and randomized controlled trials. One study confirmed fluid overload as an independent risk factor for VAE [OR=1.2, 95%CI(1.03,1.4)]. [13] Another study found that a daily fluid balance of ≥50 mL was also an independent risk factor for VAE [RR=8.39, 95%CI(2.99,23.50)]. [9] This study also revealed that patients with VAEs tended to have a larger fluid load. Although the result did not reach statistical significance, it was consistent with previous studies.In studies on VAE prevention, the CDC increased compliance of daily spontaneous awakening trials (SAT) and spontaneous breathing trials (SBT) in 12 intensive care units. These measures may reduce the use of mandatory ventilation mode. The result showed that the measures reduced the risk of VAEs [OR=0.63, 95%CI(0.42,0.97)]. [19] This study also suggests that strategies aimed at shortening the duration of mandatory ventilation modes could be considered for inclusion in VAE prevention protocols. Such strategies
The correlation between ventilation modes, sedatives and opioids, fluid balance, and ventilator-associated events: a matched case-control study澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal154encompass regular assessment of the recovery of spontaneous breathing, personalized dynamic adjustment of ventilation modes, transitioning from mandatory modes to partial support modes, and gradually to spontaneous ventilation modes. This approach not only preserves the functionality of respiratory muscles, thereby preventing disuse atrophy of diaphragm, but also mitigates the risk of lung injury due to excessive transpulmonary pressure and shear forces.The strength of this study is the application of a matching design, which effectively mitigates the influence of confounding variables. This study is among the few conducted in China focusing on VAEs. However, it has several limitations: The single hospital setting may potentially impacting its external validity. The data were derived from existing records, limiting the design of research variables. The absence of body weight data in some records precluded us from calculating drug dosages on a per kilogram basis. Future research efforts will require large-scale prospective studies to clarify the relationship between potential risk factors and VAEs.6. ConclusionsThis study identified 43 VAEs from 1,334 adult patients underwent mechanical ventilation between August 2018 and July 2020. The incidence rate of VAE was 2.92 cases per 1,000 ventilator-days. A higher proportion of VAE patients were male and experienced prolonged mechanical ventilation. Each VAE patient was matched with five non-VAE patients. Conditional logistic regression revealed that mandatory ventilation mode is a risk factor for VAEs. Furthermore, patients with VAEs were observed to have a higher dosage of sedatives and opioids as well as a larger fluid load, although these differences did not reach statistical significance. The findings suggest that strategies aim at reducing the duration of mandatory ventilation modes could potentially be incorporated into VAE prevention protocols.7. AcknowledgmentsWe would like to express our sincere gratitude to the C.H.C.S.J. for providing us with the research site. Their support was crucial to our study.References[1] Centers for Disease Control and Prevention, National Healthcare Safety Network (NHSN). Patient Safety Component Manual: Chapter 10 - Ventilator-associated event (VAE) [S/OL]. Accessed at , on 8th Jan 2020.[2] Klompas M. Potential strategies to prevent ventilator-associated events [J]. Am J Respir Crit Care Med. 2015; 192(12):1420-1430. doi: 10.1164/rccm.201506-1161CI.[3] Boyer AF, Schoenberg N, Babcock H, et al. A prospective evaluation of ventilator-associated conditions and infection-related ventilator-associated conditions [J]. Chest. 2015; 147(1):68-81. doi: 10.1378/chest.14-0544.[4] He Q, Wang W, Zhu S, et al. The epidemiology and clinical outcomes of ventilator-associated events among 20,769 mechanically ventilated patients at intensive care units: An observational study [J]. Crit Care. 2021; 25(1):44. doi: 10.1186/s13054-021-03484-x.[5] Klompas M, Branson R, Cawcutt K, et al. Strategies to prevent ventilator-associated pneumonia, ventilator-associated events, and nonventilator hospital-acquired pneumonia in acute-care hospitals: 2022 Update [J]. Infect Control Hosp Epidemiol. 2022; 43(6):687-713. doi:10.1017/ice.2022.88.[6] 朱蕾. 機械通氣(第4版) [M]. 中國上海: 上海科學技術出版社, 2017.[7] Devlin JW, Roberts RJ. Pharmacology of commonly used analgesics and sedatives in the ICU: benzodiazepines, propofol, and opioids [J]. Crit Care Clin. 2009; 25(3):431-449. doi: 10.1016/j.ccc.2009.03.003.[8] Barr J, Fraser GL, Puntillo K, et al. Clinical
155 Volume 11 Número 2 Volume 11 Number 2第 11 卷第 2 期The correlation between ventilation modes, sedatives and opioids, fluid balance, and ventilator-associated events: a matched case-control studypractice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit [J]. Crit Care Med. 2013; 41(1):263-306. doi: 10.1097/CCM.0b013e3182783b72.[9] Liu J, Zhang S, Chen J, et al. Risk factors for ventilator-associated events: a prospective cohort study [J]. Am J Infect Control. 2019; 47(7):744-749. doi: 10.1016/j.ajic.2018.09.032.[10] Magill SS, Li Q, Gross C, et al. Incidence and characteristics of ventilator-associated events reported to the National Healthcare Safety Network in 2014 [J] . Cri t Care Med. 2016; 44(12):2154. doi: 10.1097/ CCM.0000000000001871.[11] Nakahashi S, Yamada T, Ogura T, et al. Association of Patient Care with Ventilator-Associated Condit ions in Crit ically I l l Patients: Risk Factor Analysis [J]. PLoS One. 2016; 11(4):e0153060. doi: 10.1371/journal.pone.0153060.[12] Sim JK, Oh JY, Min KH, et al. Clinical significance of ventilator-associated event [J]. J Crit Care. 2016; 35:19-23. doi: 10.1016/j.jcrc. 2016.04.021.[13] Lewis SC, Li L, Murphy MV, et al. Risk factors for ventilator-associated events: a case-control multivariable analysis [J]. Crit Care Med. 2014; 42(8):1839. doi: 10.1097/CCM. 0000000000000338.[14] G r i e c o D L , C h e n L , B r o c h a r d L . Transpulmonary pressure: importance and limits [J]. Ann Transl Med. 2017; 5(14):285. doi: 10.21037/atm.2017.07.22.[15] Goligher EC, Dres M, Fan E, et al. Mechanical ventilation–induced diaphragm atrophy strongly impacts clinical outcomes [J]. Am J Respir Crit Care Med. 2018; 197(2):204-213. doi: 10.1164/rccm.201703-0536OC.[16] Shanely RA, Van GD, DeRuisseau KC et al. Mechanical ventilation depresses protein synthesis in the rat diaphragm [J]. Am J Respir Crit Care Med. 2004; 170(9):994-999. doi: 10.1164/rccm.200304-575OC.[17] Van HHW, Schellekens WJM, Andrade AGL, et al. Titin and diaphragm dysfunction in mechanically ventilated rats [J]. Intensive Care Med. 2012; 38(4):702-709. doi: 10.1007/s00134-012-2504-5.[18] 梁國興 , 劉朝暉 . 呼吸機相關膈肌功能障礙研究進展 [J] . 中國實用醫藥 , 2020, 15(22):200-201. doi: 10.14163/j.cnki.11-5547/ r.2020.22.090.[19] Klompas M, Anderson D, Trick W, et al. The preventability of ventilator-associated events. The CDC prevention epicenters wake up and breathe collaborative [J]. Am J Respir Crit Care Med. 2015; 191(3):292-301. doi: 10.1164/rccm.201407-1394OC.
Chan Fong CHIO et al.澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal156Large language models assist in translating and explaining pathology reports in a multilingual societyAbstractObjective: Pathology reports are crucial for disease diagnosis and treatment. In addition to being explained directly by doctors, some patients may read their own reports. In a multilingual society like Macau, one common scenario is that patients wish to have English written pathology reports explained in Chinese. They may seek translation and explanation on the Internet including recently popular large language model-based chatbots like ChatGPT. We have designed a study aimed at evaluating the performance of large language model-based chatbots in explaining English written pathology reports in Chinese.Methods: We generated 30 English written pathology reports and simulated a patient asked large language model-based chatbot to explain them in Chinese. Four chatbots including GPT-4 on Poe, Microsoft Bing Chat, Tongyi Qianwen and iFlytek Spark were evaluated in this study. The responses from chatbots were subsequently rated by three board-certified pathologists on their correctness, helpfulness and safety.Results: A total of 120 responses from four large language model-based chatbots and their ratings by three raters were collected. All medians for correctness, helpfulness, and safety had 95% confidence intervals equal to or above the satisfaction cutoff value in all four chatbots. More than 90% of the ratings for correctness, helpfulness, and safety in three of the chatbots reached a satisfactory level or higher. The overall performance among the tested chatbots demonstrated a statistically significant variation by multiple pairwise comparisons.Conclusions: Our study found that large language model-based chatbots can assist in translating and explaining English written pathology reports in Chinese. They can be potential tools for patients to seek relatively reliable pathology report-related information and break language barrier in a multilingual society. However, the performance varied among the tested chatbots, and critical mistakes may occur in rare cases. Therefore, the selection of chatbot is one of the important considerations, and explaining the pathology reports by doctors is still irreplaceable.Keywords: Pathology; Artificial intelligence; Natural language processing; Large language models; Machine translation1 Department of Anatomical Pathology, Conde de São Januário General Hospital, Macau SAR, China2 Faculty of Innovation Engineering, Macau University of Science and Technology, Macau SAR, China* Correspondence to: Chan Fong CHIO, cfchio@gmail.comDOI : 10.30224/MMJ.202406_11(2).0005Chan Fong CHIO1,2*, Lai Fong KOK1, Sio In WONG1, Thazin HLAING1
Large language models assist in translating and explaining pathology reports in a multilingual society157 Volume 11 Número 2 Volume 11 Number 2第 11 卷第 2 期1. IntroductionPathological examination is the gold standard for the diagnosis of many diseases. Pathology reports are crucial for disease diagnosis and treatment. They contain a large amount of medical terminology that should be explained by the doctors directly to the patients. However, some patients may wish to read their own pathology reports. Macau is a multicultural city composed of ethnic groups whose native languages are Chinese, Portuguese, English, etc. The pathology reports in Macau are written in either English or Chinese, depending on different hospitals. One common scenario in Macau is that patients may wish to have the English written pathology reports explained in Chinese. For that reason, patients may seek translation and search for pathology report-related information on the Internet (the so-called asking “Dr. Google” [1]).Since the release of ChatGPT at the end of November 2022 [2], a batch of chatbots based on var ious large language models have been successively launched. Large language models (LLMs) such as Generative Pre-trained Transformer (GPT), Pathways Language Model (PaLM), Large Language Model Meta AI (LLaMA) and Galactica, etc. are designed to generate human-like text based on the input they are given [3]. They are trained on a vast amount of text data, which enables them to generate coherent and contextually relevant sentences and paragraphs. The key functions of large language models include text generation, question answering, translation, summarization, etc. The technology of large language models is constantly innovating, and their functions are becoming increasingly powerful. However, large language models are not without their limitations. They may not truly understand the text they process or generate, and they can sometimes yield incorrect or misleading information [4-5]. In addit ion, answers in non-English languages may differ in content and accuracy compared to answers in English [6].Current research has begun to evaluate the util i ty of large language models in answering medical questions [7-9], with some demonstrating competency equivalent to passing the United States Medical Licensing Exam (USMLE) [10], as well as interpreting laboratory medicine test results [11]. The potential uses of large language models in patient care include conveying medical knowledge, assisting communication through translations and summaries, etc. [3]A study in Hong Kong demonstrated that 87.44% of patients attending to primary care clinic had used the Internet to find health information. The authors suggested doctors should recognize pa t i en t s’ on l ine hea l th in format ion-seek ing behavior, and facilitate and empower them to search for high-quality online health information [12].As large language models gradually reach the public, we anticipate these newly introduced powerful tools will inevitably become one of the important sources for the public to search for medical information, including pathology report-related information (i.e. asking “Dr. ChatGPT”, etc.). As far as we know, there is no research on using large language models to translate and explain English written pathology reports in Chinese. It is worth to know what information patients may obtain from the large language models, and the potential uses and pitfalls of LLMs in the interpretation of pathology reports. Therefore, we have designed a study to evaluate the correctness, helpfulness, and safety of using large language model-based chatbots to assist in translating and explaining English written pathology reports in Chinese.2. Materials and methods2.1 Selection of chatbotsTo our knowledge, there is no published data regarding the market share of large language model-based chatbots in Macau. In order to evaluate the chatbots that may most likely be chosen by Macau citizens, we set up the criteria for selection as: high fame, commercial product developed by company with certain capacity, open to the public, accessible
Large language models assist in translating and explaining pathology reports in a multilingual society澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal158in Macau and good Chinese support. Finally, four large language model-based chatbots have been selected.GPT-4 on Poe : ChatGPT is a GPT-based chatbot developed by OpenAI and launched in November 2022 [2]. It is originally based on GPT-3.5, and a more advanced model GPT-4 has released in March 2023. ChatGPT is one of the most famous, popular and technically superior LLM-based chatbot in the world. Nevertheless, ChatGPT is not open to Macau. Most Macau citizens cannot directly register for accounts and access the product. According to our criteria, ChatGPT should be excluded. However, considering its high fame and high representativity in Macau, we decided to include it. In order to simulate the real scenario in Macau, we chose to access GPT-4 via Poe―a popular third-party platform providing various LLM-based chatbots―as an alternative of ChatGPT.Microsoft Bing Chat is a GPT-4-based chatbot developed by Microsoft corporation (MS) and integrated in the Edge browser. Users can easily access it via the sidebar of Edge browser. It is free and can be accessed in Macau without any restriction.Tongyi Qianwen ( 通 義 千 問 in Chinese) is a chatbot developed by Alibaba Cloud, a technology company under the Alibaba Group. It is based on Tongyi model which is Alibaba’s proprietary pre-trained model framework. Tongyi Qianwen was launched in April 2023. Currently, it is only allowed users who have received invitation codes to experience it. Macau citizens can obtain invitation codes through a simple application process.iFlytek Spark (訊飛星火 in Chinese) is a chatbot developed by iFlytek which is a listed company in the Asia-Pacific Region focusing on intelligent speech and technology. It was launched in May 2023. Similarly, it is only allowed users who have received invitation codes to experience it currently. Macau citizens can obtain invitation codes through a simple application process.Another candidate chatbot fulfills our criteria is Baidu Wenxin Yiyan ( 百度文心一言 in Chinese). However, we had not received the invitation code till the end of experiment and thus it was unable to be tested in our study. Other famous chatbots such as Google Bard, Meta LLaMA, Claude, Med-PaLM, etc. have been excluded because they do not fully fulfill our criteria.2.2 Question preparation and response collectionWe generated 30 simulation pathology reports of various organ systems including 2 reports for breast, 2 reports for endocrine system, 4 reports for female genital system, 4 reports for gastrointestinal tract, 2 reports for genitourinary system, 2 reports for hematopoietic system, 2 reports for head and neck, 2 reports for liver, biliary tract and pancreas, 2 reports for neurology, 2 reports for skin, 3 reports for soft tissue, and 3 reports for thoracic system. All reports were written in English using the style of pathology reports from Department of Anatomical Pathology at Conde São Januário Hospital, Macau. (Table 1)A pathology repor t normal ly cons is ts of macroscopic description, microscopic description, diagnosis, and/or comment. Among these parts, the diagnosis is usually the part that receives the most focus and has the greatest impact on further management. Due to extensive efforts required to evaluate the entire report, we decided to evaluate the performance of translation and explanation solely based on the diagnosis in this study.Considering most lay users are not familiar with prompt engineering, and aiming to test the basic performance of these chatbots, a simple and straightforward prompt in a single-turn conversation was designed for this study. We simulated a patient asked four large language model-based chatbots to explain the English written pathological diagnosis in Chinese with prompt “ 請 解 釋 病 理 報 告：XXXXXX” (“Please explain pathology report: XXXXXX” in English). The queries were based on the latest version of chatbots with default settings in the first week of August 2023. A total of 120 responses in Chinese were collected successfully.
Large language models assist in translating and explaining pathology reports in a multilingual society159 Volume 11 Número 2 Volume 11 Number 2第 11 卷第 2 期The study did not involve any human research participants nor any data from patients.2.3 EvaluationWe invited three board-certified pathologists, who are proficient in both Chinese and English, to rate the responses from chatbots. Each case contained one query and four responses. The responses from chatbots were shuffled randomly and was blind to the raters. Three evaluation items for each response were evaluated:Correctness: The ability to accurately translate and interpret the core content of pathological diagnoses.Helpfulness: Whether the provided information assists patients in understanding the pathology report such as to explain professional terms in plain language, to summarize long reports to key points, to clearly tell patients the nature of disease, to provide useful information and advice, etc. We emphasized to the raters that this item should be evaluated on the view of patients rather than healthcare providers.Safety: Whether the response violates current medica l consensus , and whe ther i t con ta ins information that could potentially mislead patients or delay treatment.Each item was rated on a scale from 1 (very low) to 5 (very high). Value of 3 and above was considered satisfactory. They were explained to the raters before they undertook the evaluation.3. Statistical analysisWe used descriptive statistical tests to express the data in median and interquartile range (IQR). Intraclass correlation coefficient based on two-way random effects, absolute agreement, multiple raters model (ICC[2,k]) was used for reliability analysis [13]. Shapiro-Wilk test was used for normality test. Table 1. Pathological diagnosis generated for testing (selected)Case Pathological diagnosis1 ENDOMETRIUM, “gestational tissue” clinically, curettage - Consistent with COMPLETE HYDATIDIFORM MOLE.…… ……10 SKIN, forehead, shave biopsy - Consistent with INTRADERMAL NEVUS.11 1- GASTRIC MUCOSA, gastric body, biopsy - CHRONIC GASTRITIS. No Helicobacter pylori is seen.2- GASTRIC MUCOSA, gastric fundus, biopsy - FUNDIC GLAND POLYPS.…… ……16 LIVER, segment 4b, resection - i. Moderately differentiated HEPATOCELLULAR CARCINOMA. - Solitary, size 5.2 cm in greatest dimension. - Vascular invasion focally noted. - Resection margin clear with minimal clearance 4 mm. - pTNM staging: pT2 (AJCC 8th edition). ii. VIRAL HEPATITIS B. iii. HEPATIC CIRRHOSIS.…… ……21 URINARY BLADDER, tumor, “TURBt” - NON-INVASIVE PAPILLARY UROTHELIAL CARCINOMA, HIGH GRADE.22 SKIN, chest wall skin lesion, excision - Consistent with HIDRADENOMA, margin clear.…… ……30 LYMPH NODE, right posterior neck, excision - Favor HISTIOCYTIC NECROTIZING LYMPHADENITIS (Kikuchi-Fujimoto disease).For full list of pathological diagnosis tested, please refer to http://www.github.com/cfchio/llm-pathreports
Large language models assist in translating and explaining pathology reports in a multilingual society澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal160Levene’s test was used to test equality of variances. Fo r da t a no t no rma l ly d i s t r ibu ted , we used nonparametric approach Kruskal-Wallis one-way analysis of variance (ANOVA) to compare groups. If there were differences among the groups, Dunn’s test was used as post hoc test for further multiple pairwise comparison. We consider p-value ≤ 0.05 as statistical significance. All statistical analysis was performed using R (version 4.3.1; https://www.r-project.org/).4. ResultA total of 360 evaluation items were rated by each rater (3 evaluation items per response × 4 responses per case × 30 cases), and a total of 1,080 valid ratings from three raters were collected successfully with no missing data. The pathologists’ evaluation results were input by one person and then cross-checked by another person.The ICC(2,k) for correctness was 0.85 with a 95% confidence interval of 0.80 to 0.89, for helpfulness was 0.82 with a 95% confidence interval of 0.75 to 0.87, and for safety was 0.80 with a 95% confidence interval of 0.71 to 0.86. The scores rated by three pathologists had an ideal level of interrater reliability.For GPT-4 on Poe, 98.9%, 98.9% and 98.9% of ratings were equal or above the threshold of satisfaction (value of 3) in correctness, helpfulness and safe ty, respect ively. For Microsof t Bing Chat, 96.7%, 96.7% and 96.7% of ratings were sa t i s fac to ry in cor rec tness , he lp fu lness and safety, respectively. For Tongyi Qianwen, 90.0%, 90.0% and 88.9% of ratings were satisfactory in correctness, helpfulness and safety, respectively. For iFlytek Spark, 70.0%, 83.3% and 73.3% of ratings were satisfactory in correctness, helpfulness and safety, respectively. (Figure 1)T h e m e d i a n ( a n d t h e c o r r e s p o n d i n g interquartile range – IQR) values of correctness, helpfulness and safety for GPT-4 on Poe were five (from 5 to 5), five (from 5 to 5) and five (from 5 to 5) respectively; for Microsoft Bing Chat were five (from 4 to 5), four (from 4 to 5) and five (from 4 to 5) respectively; for Tongyi Qianwen were four (from 3.25 to 5), four (from 3 to 4) and four (from 4 to 5) respectively; and for iFlytek Spark were three (from 2 to 4), three (from 2 to 4) and four (from 2 to 4) respectively (Table 2). All 95% confidence intervals of the medians were equal or above value 3―the satisfaction cutoff value.Shapiro-Wilk test and Levene’s test indicated that all data were not normally distributed and did not satisfy the assumption of homogeneity of variance. Nonparametric approaches were used for statistical analysis. Kruskal-Wallis one-way ANOVA test demonstrated that there were differences among the chatbots in correctness, helpfulness and safety. Further multiple pairwise comparisons demonstrated that the correctness, helpfulness and safety in each pair of chatbots were mostly different with statistical significance (Figure 2). Among the large language model-based chatbots we evaluated, GPT-4 on Poe got the highest scores in all three evaluation items.Tabel 2. Median (and the corresponding interquartile range – IQR) values of correctness, helpfulness and safety of each chatbot.GPT-4 on PoeMicrosoft Bing ChatTongyi Qianwen iFlytek Spark p-valueCorrectness 5 (5 to 5) 5 (4 to 5) 4 (3.25 to 5) 3 (2 to 4) <0.01Helpfulness 5 (5 to 5) 4 (4 to 5) 4 (3 to 4) 3 (2 to 4) <0.01Safety 5 (5 to 5) 5 (4 to 5) 4 (4 to 5) 4 (2 to 4) <0.01
Large language models assist in translating and explaining pathology reports in a multilingual society161 Volume 11 Número 2 Volume 11 Number 2第 11 卷第 2 期5. Discussion5.1 Principal FindingsCorrectness . In th is s tudy, we found that the core content and most professional terms in pathological diagnosis can be satisfactorily translated and explained by large language model-based chatbots (Figure 3). More than 90% of the ratings in three of the chatbots reached a satisfactory level or higher. However, there was up to 30% of the rantings were unsatisfactory in one of the chatbots (Figure 1). Reviewing the translation by the chatbots, a small portion of the professional terms were directly translated from English into Chinese, rather than being translated to common Chinese terminology (Figure 4). We also found that few of the professional terms were not able to be translated, even though the chatbot did know their nature (Figure 5). In rare cases, the chatbot misinterpreted the key information from the pathology reports and more seriously it misinterpreted benign tumor as malignant tumor which may potentially lead to an adverse outcome (Figure 5 and 6). This phenomenon was particularly common in iFlytek Spark.Helpfulness . Unl ike t rans la t ion sof tware that can only perform simple English-Chinese translation, large language models have a powerful knowledge base, understanding and reasoning Figure 2. Box plots of correctness, helpfulness and safety of chatbots with pairwise comparisons. (ns p>0.05, * p≤0.05, ** p≤0.01, *** p≤0.001, **** p≤0.0001)Figure 1. Percent stacked barcharts of correctness, helpfulness and safety of chatbots.
Large language models assist in translating and explaining pathology reports in a multilingual society澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal162capabilities. Therefore, in addition to translation, they can explain the meaning of each key point in the pathology reports and its clinical significance, as well as provide a concise summary of the diagnostic content. These can help patients understanding the pathology reports. In most of the cases, all four chatbots we evaluated clearly exhibited this characteristic that sets them apart from translation software (Figure 7). In this study, more than 90% of the ratings in three of the chatbots reached a satisfactory level or higher. However, in one of the chatbots, up to 27% of the ratings were below satisfactory level (Figure 1). In few cases, the chatbots simply translated the pathological diagnosis from English to Chinese without further explanation. This may be less helpful for patients in understanding the report (Figure 8).Safety. In this study, most of responses from four chatbots did not violate current medical consensus, and they were able to remind patients to follow the doctor’s recommendations for subsequent examinations and treatments. 98.9%, 96.7%, 88.9% and 73.3% of the ratings reached a satisfactory level or higher for GPT-4 on Poe, Microsoft Bing Chat, Tongyi Qianwen and iFlytek Spark respectively.Reviewing the responses, the most concerned case is one confusing benign with malignant (Figure 5). This may mislead the patient bringing negative impact. On the other hand, there was no case misinterpreting malignant tumor as benign lesion which may potentially lead to delay treatment.5.2 Relevance to Clinical PracticePatients’ online health information-seeking behaviors are common [12]. Failure to acknowledge and understand these behaviors may become a barrier to patient-doctor communication [14]. Thus, doctors should know the quality of online health information so they can better teach their patients and identify the potential risks [12].In this study, based on the design of a simple prompt in a single-turn conversation, we found that large language model-based chatbots can translate and explain English written pathology reports in Chinese with satisfactory correctness, helpfulness and safety. We have reason to believe that the performance will not be worse than our study if advanced prompts and multi-turn conversations are used in a real-world scenario. LLM-based chatbots can provide patients with a potential tool to seek relatively reliable information regarding their pathology reports and break language barrier in a multilingual society.However, our study found the performance varied among the tested chatbots, and critical mistakes may occur in rare cases. This may bring potent ial r isks to pat ients though we bel ieve these shortcomings will be addressed with the technological innovation of large language models in near future. In addition, the result indicates the importance of selection of chatbot.When doctors recognize that patients may seek online health information through these newly introduced LLM-based chatbots, it is worth to remind patients that the information from these chatbots are not completely accurate and error-free, as well as the importance of selection of chatbots. Discussing with patients about the information they obtain from the Internet may help to improve the patient-doctor relationship [15].5.3 Strengths and LimitationsAs far as we know, this is the first study exploring the ability of large language model-based chatbots in translating and explaining English written pathology reports in Chinese. Our findings demonstrate the feasibility of using LLM-based chatbots for this task, and provide data of basic performance of chatbots. This study can be served as a pilot study for further comprehensive studies regarding practical use.Our s tudy has severa l l imi ta t ions . F i rs t , the performance of large language model-based chatbots depends on prompts, settings, whether they are connected to the Internet, and the use of plugins, etc. The chatbots we evaluated in this study were based only on default settings and without additional prompt. The results may not
Large language models assist in translating and explaining pathology reports in a multilingual society163 Volume 11 Número 2 Volume 11 Number 2第 11 卷第 2 期reflect their actual performance and probably be underrated. Second, the evaluation was performed only by pathologists . I t may not fully reflect patients’ perspectives. Further comprehensive studies involving end users (patients and even non-pathologist clinicians) need to be carried ou t to c l a r i fy the p rac t i ca l va lues o f LLM-based chatbots. Third, due to no well-established objective structured method for evaluating the explanation of pathology reports, the evaluation relied on pathologists’ subjective judgement. This may affect the objectivity and reproducibility of the evaluation. Fourth, as the purpose of our study is to evaluate the global performance of chatbots, the statistical analysis of each evaluation item was based on all ratings the chatbot got (n=90 [30 cases × 3 raters]) with regardless of which case the score came from or which pathologist gave the rating. Further quantitative analysis for each single case and subgroup comparison were not performed.6. ConclusionOur study found that large language model-based cha tbots can ass i s t in t rans la t ing and explaining English written pathology reports in Chinese with a satisfactory correctness, helpfulness and safety. They can be potential tools for patients to seek re la t ive ly re l iable pa thology repor t -related information and break language barrier in a multilingual society. However, the performance varied among the tested chatbots, and critical mistakes may occur in rare cases. The selection of chatbot is one of the important considerations, and explaining the pathology reports by doctors is still irreplaceable.Using large language models for multilingual healthcare question-answering is a new thing, and people are exploring its feasibility. To better adapt to this domain, LLMs require continuous improvement in language capabilities, medical knowledge , accuracy, re l iab i l i ty, contex tua l understanding, and interpretability, etc. This needs ongoing research, technological innovation, and close collaboration with medical professionals. We will closely follow the development of LLMs and their applications in the field of pathology.
Large language models assist in translating and explaining pathology reports in a multilingual society澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal164Figure 5. Responses for case 22. The chatbot failed to translate the entity ‘Hidradenoma’ to Chinese but it knew that this was a benign sweat gland tumor (left). Unexpectedly, one chatbot misinterpreted the tumor as malignant melanoma (right). This was considered a critical and unacceptable mistake.Figure 3. Response from GPT-4 on Poe for case 25. The chatbot could translate professional terms and abbreviations, as well as explain their clinical significance.Figure 4. Response from GPT-4 on Poe for case 29. The chatbot could translate and explain the diagnosis but the Chinese translation of‘transitional’and ‘meningothelial’were not those commonly used in China mainland and Taiwan.
Large language models assist in translating and explaining pathology reports in a multilingual society165 Volume 11 Número 2 Volume 11 Number 2第 11 卷第 2 期Figure 6. Responses for case 23. One of the examples that the chatbot misinterpreted all key information ‘rectal mucosa’,‘traditional serrated adenoma’and‘stalk margin’ (left). Although it did not confuse benign with malignant, the performance of this response was considered unsatisfactory. In contrast, another chatbot could adequately explain the same report (right).Figure 7. Response from GPT-4 on Poe for case 8. The chatbot could translate and explain each key point of the diagnosis. A summary was also concluded at the end. The correctness, helpfulness and safety were rated 5 by all three raters for this response.Figure 8. Response from Tongyi Qianwen for case 11. The chatbot simply translated English to Chinese without further explanation. This may be less helpful for patients in understanding the report.
Large language models assist in translating and explaining pathology reports in a multilingual society澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal166References[1] Lee K, Hoti K, Hughes JD, et al. Consumer u s e o f “D r G o o g l e” : a s u r v e y o n health information-seeking behaviors and navigational needs. J Med Internet Res 2015 Dec 29;17(12):e288. doi: 10.2196/jmir.4345.[2] OpenAI. ChatGPT: Optimizing Language Models for Dialogue. https://openai.com/blog/chatgpt/ (2022).10.1038/s41586-023-06291-2.[3] Clusmann, J., Kolbinger, F.R., Muti, H.S. et al. The future landscape of large language models in medicine. Commun Med (Lond) 2023 Oct 10;3(1):141. doi: 10.1038/s43856-023-00370-1.[4] L e e P, B u b e c k S , P e t r o J . B e n e f i t s , l i m i t s , a n d r i s k s o f G P T- 4 a s a n A I c h a t b o t f o r m e d i c i n e . N E n g l J M e d 2023; 388(13):1233-1239. doi:10.1056/NEJMsr2214184.[5] Sallam M. ChatGPT Utility in Healthcare E d u c a t i o n , R e s e a r c h , a n d P r a c t i c e : Sys temat i c Rev iew on the P romis ing Perspectives and Valid Concerns. Healthcare (Base l ) 2023 Mar 19 ;11 (6 ) :887 . do i : 10.3390/healthcare11060887.[6] Seghier ML. ChatGPT: not all languages are equal. Nature 2023;615:216. doi: 10.1038/d41586-023-00680-3.[7] Singhal K, Azizi S, Tu T, et a l . Large language models encode clinical knowledge. Nature 2023 Aug;620(7972):172-180. doi: [8] S i n h a R K , R o y A D , K u m a r N , e t a l . Applicability of ChatGPT in Assisting to Solve Higher Order Problems in Pathology. Cureus 2023;15(2):e35237. doi: 10.7759/cureus.35237.[9] Zhu L, Mou W, Chen R. Can the ChatGPT and other large language models with internet-connected database solve the questions and concerns of patient with prostate cancer and help democratize medical knowledge? J Transl Med 2023 Apr 19;21(1):269. doi: 10.1186/s12967-023-04123-5.[10] Kung TH, Cheatham M, Medenilla A, et al. Performance of ChatGPT on USMLE: potential for AI-assisted medical education using large language models. PLOS Digit Health 2023;2(2):e0000198. doi: 10.1371/journal.pdig.0000198.[11] Cadamuro J, Cabitza F, Debeljak Z, et al. Potentials and pitfalls of ChatGPT and natural-language art if icial intell igence models for the understanding of laboratory medicine test results. An assessment by the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) Working Group on Art if icial Intel l igence (WG-A I ) . C l i n C h e m L a b M e d 2 0 2 3 A p r 24;61(7):1158-1166. doi: 10.1515/cclm-2023-0355.[12] Wong DK, Cheung MK. Online Health Information Seeking and eHealth Literacy Among Patients Attending a Primary Care Clinic in Hong Kong: A Cross-Sectional Survey. J Med Internet Res 2019 Mar 27;21(3):e10831. doi: 10.2196/10831.[13] Koo TK, Li MY. A Guideline of Selecting and Repor t ing In t r ac la s s Cor re la t ion Coefficients for Reliability Research. J Chiropr Med 2016 Jun;15(2):155-63. doi: 10.1016/j.jcm.2016.02.012.[14] Silver MP. Patient perspectives on online health information and communication with doctors: a qualitative study of patients 50 years old and over. J Med Internet Res 2015 Jan 13;17(1):e19. doi: 10.2196/jmir.3588.[15] Tan SS, Goonawardene N. Internet Health Informat ion Seeking and the Pa t ien t -Physic ian Rela t ionship : A Systemat ic Review. J Med Internet Res 2017 Jan 19;19(1):e9. doi: 10.2196/jmir.5729.
Kuok Wun LAM et al.167 Volume 11 Número 2 Volume 11 Number 2第 11 卷第 2 期AbstractObjectives: This retrospective study aimed to evaluate the safety and efficacy of the Micra leadless pacemaker system for clinical use.Methods: Between December 2017 and March 2024, a retrospective analysis was conducted on patients who met the recommended indications for leadless pacing to assess the safety and efficacy of transcatheter implantation using the Micra leadless pacemaker system. The study evaluated patients' clinical characteristics, procedure duration (from femoral vein puncture to venous access closure), perioperative pacemaker programmed testing (including sensing, thresholding, and impedance), and surgical complications during hospitalization.Results: A total of 94 patients were enrolled, of which 91 patients (96.8%) successfully underwent catheter-based implantation of Micra leadless pacemakers. The average age of the patients was 84.98 ± 6.77 years. The average operation time was (44.08±12.21) minutes, and the predominant implantation sites of Micra pacemakers were the right middle septum (61.5%), low septum (20.9%), and high septum (17.6%). Intraoperatively, the average pacing threshold was (0.59±0.39) V, ventricular sensation measured (9.77±4.07) mV, and impedance measured (865.89±258.74) Ω. Three cases reported surgical adverse events, including three cases of hematoma, one case of arteriovenous fistula, and one case of all-cause mortality.Conclusions: Transcatheter implantation of the Micra leadless pacemaker system demonstrates efficacy and safety in clinical practice.Keywords: Cardiac pacemaker; Leadless pacemaker; Safety; ComplicationsDepartment of Cardiology, Conde de São Januário General Hospital, Macau SAR, China*Correspondence to: U Po LAM, Department of Cardiology, Conde de São Januário General Hospital, Health Bureau, Macao, China, lamupo@yahoo.comDOI : 10.30224/MMJ.202406_11(2).0006Leadless transcatheter pacemaker implantation in the elderly patients: single-center data from MacauKuok Wun LAM, Weng Chio TAM, Man Fong CHU, Tou CHANG, Mario EVORA, U Po LAM*
Leadless transcatheter pacemaker implantation in the elderly patients: single-center data from Macau澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal1681. IntroductionThe European Society of Cardiology (ESC) guidelines on cardiac pacing and resynchronization therapy, published in 2021, highlight a consistent rise in the global incidence of cardiac device implantation, specifically pacemakers[1]. The annual implantation rate has reached approximately one million devices[1].The aging population is particularly susceptible to developing arrhythmias, such as sinus node dysfunction, atrioventricular block, and atrial fibrillation with prolonged intervals, often necessitating pacemaker implantation as a treatment modality[2]. Conventional pacemaker implantation entails creating a subcutaneous pocket in the pectoralis major muscle and establishing connections to the atrial and ventricular muscles using electrode leads. This procedure carries inherent risks, including pocket infection, electrode perforation, electrode dislodgement, and complications associated with punctures, such as pneumothorax and hemothorax [3]. Additionally, elderly patients commonly exhibit a higher prevalence of comorbidities and a substantial utilization of anticoagulant and antiplatelet medications, both of which elevate the risk of complications above[4, 5]. Furthermore, patients who develop infections following conventional pacemaker implantation face a significant risk of re-infection upon re-implantation[6, 7]. In contrast, leadless pacemakers, an innovative implantable pacemaker, are designed to mitigate the risks associated with capsules and electrode leads. They prevent the need for creating a subcutaneous pocket or establishing direct connections to the myocardium [8-10]. This study retospectively analyzed elderly patients who underwent leadless pacemaker implantation at a single center.2. Objects and Methods2.1 Objects of the studyThis retrospective study enrolled patients with arrhythmias who were admitted to the Department of Cardiology at Conde de São Januário General Hospital in Macao, from December 2017 to April 2024 and indicated for Micra leadless pacemaker surgery. All patients met the eligibility criteria for the Micra leadless pacemaker procedure, based on class I or II indications for pacemaker metallurgy diagnoses. The inclusion and exclusion criteria can be found in Table 1. The study was conducted with medical ethics approval obtained from Conde de São Januário General Hospital in Macao.Table 1. Study criteriaInclusion criteria Exclusion criteriaExclusion criteria Requires implantable defibrillator or cardiac resynchronization therapyBradycardia with atrial arrhythmia Dual chamber pacemaker implantabilitySinus rhythm with high degree atrioventricular block Post-tricuspid metal valve replacementSinus node dysfunctionSurgical access with arteriovenous fistula in the lower extremitySurgical access to lower extremity veins with thrombusKnown anomalies of the inferior vena cava access.
Leadless transcatheter pacemaker implantation in the elderly patients: single-center data from Macau169 Volume 11 Número 2 Volume 11 Number 2第 11 卷第 2 期2.2 Methods2.2.1 Collection of clinical dataCinical date collection involved gathering information from both the paper-based medical records and the electronic medical record system. The data encompassed various aspects, including age, gender, left ventricular ejection fraction, emergency admission status, underlying disease, pacemaker implantation indication, and the use of anticoagulants and antiplatelet drugs. To supplement the data, surgical records were reviewed to obtain details regarding the timing of surgery, parameters related to leadless pacemakers, and postoperative complications among the selected patients.2.2.2 Method of Implantation of Leadless PacemakersMicra pacemakers (Medtronic, USA) were implanted in all participants included in this study. The standard Micra implantation method was employed to implant pacemakers in all participants. This method involves femoral vein puncture, delivery of the leadless pacemaker to the right ventricle using the delivery system, pacemaker release upon reaching the septum, testing, and verification of electrical parameters, and subsequent withdrawal of the delivery system. Experienced associate cardiologists and electrophysiologists. Performed the implantion procedure. The patient remained bedridden for 4 hours post-operation, and the sutures were removed the following day. After the patient's condition stabilized, they were discharged from the hospital.2.3 Observations and AssessmentThe study encompassed various observations aimed at evaluating the efficacy of the procedure. These included recording the intraoperative operative time, and assessing the intraoperative pacemaker threshold, sensing, and impedance parameters. Moreover, comprehensive documentation of device-related complications and serious adverse events was carried out. Surgical complications included hematoma, bleeding, pseudoaneurysm, and arteriovenous fistula at the femoral vein puncture site. Serious adverse events included implanted device displacement, cardiac perforation, pericardial effusion, and infection. Additionally, electrocardiograms and chest radiographs were repeated 24 hours after the operation, and cardiac echography was repeated when necessary to evaluate the patient's condition.2.4 Statistical AnalysisWe employed SPSS 24.0 software to analysis the data collected in this study. The measurement data results the exhibited a normal distribution were presented as mean ± standard deviation (x ± s). Count data, on the other hand, were presented as percentage ratios.3. Results3.1 Baseline CharacteristicsInitially, a total of 94 cases were included in the study. However, three cases had to be excluded due to tortuous vessels. Consequently, the analysis was conducted on 91 patients, comprising 43 males (42.3%) and 48 females (52.7%). The average age of the patients was 84.98 ± 6.77 years, ranging from 65 to 103 years. Notably, 88 cases (86.7%) exhibited a left ventricular ejection fraction greater than 50%. Among the 91 patients, 50 were directly admitted from the emergency department (54.9%). The reasons for admission varied, with bradycardia accompanied by atrial arrhythmia observed in 41 cases (45.1%), high atrioventricular block in 32 cases (35.2%), and sinus node dysfunction in 18 cases (19.8%). Additionally, 17 cases (18.7%) had a history of syncope. The most prevalent comorbidities among the patients were hypertension (95.6%), diabetes mellitus (40.7%), dyslipidemia (50.5%), coronary artery disease (22.0%), previous percutaneous coronary intervention (13.2%), previous pacemaker implantation (15.4%), congestive heart failure (25.3%), valvular heart disease (52.7%), chronic kidney disease (34.1%), and malignancy (27.5%). Current anticoagulant use was reported in 45.1% of cases, while 12.1% reported using antiplatelet medication. Refer to Table 2. for further details.
Leadless transcatheter pacemaker implantation in the elderly patients: single-center data from Macau澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal170Table 2. Baseline characteristicsCharacteristics Patents (N=91)Age (years) Age≥85(years)FemaleLVEF Reduce LVEF Mild reduce LVEF Persevered LVEFAdmission through the Emergency RoomPacing indication Bradycardia with atrial arrhythmia Sinus rhythm with AVB 2nd-degree AVB, Mobitz II 3rd-degree AVB Sinus node dysfunction SyncopeContraindications for traditional pacemaker Post PPI+ PI Bilateral lymphedema Arteriovenous Fistula thrombosis NoneComorbidities Hypertension Diabetes Dyslipidemia Peripheral vascular disease Coronary artery disease Prior acute myocardial infarction Prior percutaneous coronary intervention Prior pacemaker Congestive heart failure Valvular heart disease Atrial fibrillation 84.98±6.7753.8% (49/91) 52.7% (48/91）2.2% (2/91)1.1% (1/91)96.7% (88/91)54.9% (50/91)45.1% (41/91)35.2% (32/91)13.2% (12/91)22.0% (20/91)19.8% (18/91)18.7% (17/91)22% (2/91)0.0% (0/91)0.0% (0/91)97.8% (89/91)95.6% (87/91)40.7% (37/91)50.5% (46/91)4.4% (4/91)22.0% (20/91)5.5% (5/91)13.2% (12/91)15.4% (14/91)25.3% (23/91)47.3% (43/91)52.7% (48/91)
Leadless transcatheter pacemaker implantation in the elderly patients: single-center data from Macau171 Volume 11 Número 2 Volume 11 Number 2第 11 卷第 2 期3.2 Characteristics of the Pacing Procedure91 patients (96.8%) underwent successful implantation of the Micra leadless pacemaker. The distribution of leadless pacemaker types was as follows: MICRA VR (85.71%), MICRA AV (13.18%), and MICRA VR2 (1.1%). The average operative time was 44.08 ± 12.21 minutes. The selection of the pacemaker implantation site varied depending on the case, with the right middle interventricular septum preferred in 56 cases (61.5%), the apical septum in 19 cases (20.9%), and the high septum in 16 cases (17.6%) (Table 3.). During the surgery, several parameters were measured. The mean intraoperative pacing threshold was 0.59 ± 0.39 V, ventricular sensation was 9.77 ± 4.07 mV, and impedance was 865.89 ± 258.74 Ω. 3 .3 Complications of the Procedure During HospitalizationThe occurrence of complications was minimal. Out of the total patients, only one patient (1.1%) experienced an arteriovenous fistula at the femoral vein puncture site. Additionally, three patients (3.3%) developed a hematoma, and unfortunately, one of them experienced a fatal outcome during hospitalization (1.1%). Fortunately, there were no reports of adverse events such as infection, deep vein thrombosis, cardiac perforation, pericardial effusion, or infection among patients. The average duration from pacemaker implantation to discharge was 3.26 days (3.26 ± 5.00) (Table 3., Table 5.).Table 2. Baseline characteristicsCharacteristics Patents (N=91) LBBB RBBB COPD Chronic renal disease Dialysis Malignant diseaseAnticoagulant use Antiplatelet NOAC NOAC+ Antiplatelet VKA VKA+ Antiplatelet NoneBasal Rhythm Atrial fibrillation NSR paroxysmal atrial fibrillation NSRImplant to discharge (Days)29.7% (27/91)23.1% (21/91)46.2% (42/91)3.26±5.003.3% (3/91)5.5% (5/91)4.4% (4/91)34.1% (31/91)4.4% (4/91)27.5% (25/91)12.1% (11/91)40.7% (37/91)0.0% (0/91)4.4% (4/91)0.0% (0/91)42.9% (39/91)LVEF= Left ventricular ejection fraction, PI=pocket infection, PPI=permanent implantation, LBBB=Left Bundle Branch Block, RBBB=Right Bundle Branch Block, COPD=Chronic obstructive pulmonary disease, NOAC=Non-vitamin K an-tagonist oral anticoagulant, VKA=Vitamin K antagonists, NSR=Normal sinus rhythm
Leadless transcatheter pacemaker implantation in the elderly patients: single-center data from Macau澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal172Table 4. Major complications of the procedure during hospitalizationCharacteristics Patents (N=91)InfectionThrombosis Deep vein thrombosisEvents at the groin puncture site Arteriovenous fistula Vascular access siteCardiac effusion/perforation Cardiac perforation Cardiac tamponade Pericardial effusionPacing issue Device dislocation Device pacing issue All-cause mortality0.0% (0/91)0.0% (0/91)1.1% (1/91)3.3% (3/91)0.0% (0/91)0.0% (0/91)0.0% (0/91)0.0% (0/91)0.0% (0/91)1.1% (1/91)4. DiscussionUsing leadless pacemakers presents advantages compared to conventional transvenous pacemaker implantation systems, such as diminished trauma and simplified procedures[11]. Based on our clinical experience with the implantation of the Micra leadless pacemaker, we have observed a high success rate, ease of operation, a short learning curve, reduced operation time, and significantly fewer complications than to traditional pacemakers.The Micra leadless pacemaker exhibits a compact design, weighing a mere 2 grams and measuring 6.7 mm in width and 25.9 mm in length. It boasts a smaller pulse width of 0.24 ms, which enhances synchronization efficiency and reduces electrical energy consumption compared to traditional pacemakers with a pulse width of 0.4 ms[12, 13]. Notably, the Micra pacemaker eliminates the presence of electrode leads in the bloodstream post-implantation, lowering the risk of early device infection. Despite its diminutive size, it maintains a lifespan exceeding 10 years and is compatible with MRI scanning. Moreover, it possesses a single-camber pacemaker' s frequency response and automatic threshold management Table 3. Characteristics of the pacing procedureCharacteristics Patient (N=91)Duration of Implantation (min) Intraoperative electric parameters Sensing (mv) Impendence (ohm) Threshold at 0.24 ms (v)Implant position Apical Septum Mid septum High Septum9.77±4.07865.89±258.740.59±0.3920.9% (19/91)61.5% (56/91)17.6% (16/91)44.08±12.21
Leadless transcatheter pacemaker implantation in the elderly patients: single-center data from Macau173 Volume 11 Número 2 Volume 11 Number 2第 11 卷第 2 期capabilities. The implantation procedure involves the delivery and secure anchoring of the Micra pacemaker to the endocardium of the patient's right ventricle using catheterization. The implantation site selection and precise pacemaker release within the ventricle are critical steps. Based on our experience, the right ventricular mid-septal site proves to be the preferred implantation location. However, in cases where patients exhibit poor test thresholds at the mid-septal site, consideration may be given to switching to the anterior and lower septum, as it may yield favorable pacing parameters[14].Previous studies have indicated that pacemaker infections are linked to factors such as advanced age, comorbidities, poor nutritional status, and the use of anticoagulants[5, 6]. Elderly individuals, who often have delicate skin, may inadvertently scratch the pacemaker pocket and develop hematoma due to anticoagulant use, thereby increasing the risk of post-implantation pacemaker infection [7, 8]. In this study, we examined 91 elderly patients, the majority of whom had hypertension, diabetes, coronary heart disease, chronic kidney disease (CKD), and chronic obstructive pulmonary disease (COPD). All patients had two or more coexisting chronic conditions, with 40.7% of individuals taking anticoagulant agents and 12.1% on antiplatelet agents, placing them at a high risk for traditional pacemaker infections. However, in this study, leadless pacemakers were implanted in these patients, and no pacemaker infections occurred during the postoperative period until discharge. These findings provide preliminary evidence suggesting that leadless pacemakers offer advantages in reducing the occurrence of pacemaker infections.Elderly patients are highly susceptible to pacemaker infections. Guidelines recommend completely removing of the entire pacing system in cases of pacemaker bag infection or infective endocarditis[5, 6]. However, these patients often have multiple comorbidities, making the pacemaker system removal process risky. For pacemaker-dependent patients, subsequent re-implantation of a conventional pacemaker exposes them to the risk of recurrent pacemaker infections, which can increase the likelihood of mortality. Therefore, in 2016, Beurskens et al.[15] proposed the concept of leadless pacemaker implantation following electrode lead removal due to infection. This idea was further investigated by Kypta et al.[16] who performed simultaneous leadless pacemaker implantation with electrode lead removal in patients with infective endocarditis, resulting in no instances of pacemaker reinfection during follow-up. Additionally, studies have shown that implantating of a leadless pacemaker in patients who underwent electrode lead extraction for capsular bag infection did not lead to reinfection after 1 to 1.5 years of follow-up [17, 18]. In our study, we successfully removed the electrode lead and implanted a leadless pacemaker in a patient who experienced pocket infection with a previously implanted conventional pacemaker. Subsequent hospitalization revealed suitable electrical parameters and no pacemaker re-infection, suggesting that a leadless pacemaker may be idea for re-implantation after electrode lead removal in patients with pacemaker infection.Early registry studies have reported an increased risk of myocardial perforation and pericardial tamponade associated with the implantation of leadless pacemakers in elderly patients. These studies have identified several risk factors for myocardial perforation, including advanced age, low body weight, female gender, comorbid heart failure, and chronic obstructive pulmonary disease[6, 12, 19]. However, in our study, no instances of pericardial tamponade were observed. The majority of leadless pacemakers were implanted in the right ventricular middle septum (61.5%), followed by the high septum (17.6%) and apical septum (20.9%). All leadless pacemakers achieved satisfactory positioning after one or two adjustments, demonstrating the initial safety and feasibility of implanting these devices in elderly patients. Elderly patients often exhibit poor cooperation and have difficulty tolerating prolonged bed rest and surgical interventions. In our study, the average implantation time for leadless pacemakers was 44.08 minutes, and no cases of intolerance were observed. The sheath used for leadless pacemaker implantation has a larger inner diameter, increasing the risk of arteriovenous injury at the puncture site. This can lead to complications such as bleeding, hematoma formation, prolonged compression, venous thrombosis of the lower extremities, and
Leadless transcatheter pacemaker implantation in the elderly patients: single-center data from Macau澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal174pulmonary embolism. In our study, only three patients experienced postoperative femoral vein hematomas, one of these cases further developed an arteriovenous fistula. The patient involved in this particular case was elderly and had comorbid conditions, including hypertension, diabetes mellitus, dyslipidemia, and coronary artery disease. These comorbidities likely contributed to the development of the arteriovenous fistula. Unfortunately, this patient ultimately succumbed to multiple organ failure.Leadless pacemakers are not recommended for use when the anticipated ventricular pacing percentage is equal to or greater than 40%, and there is a reduced or mildly reduced left ventricular ejection fraction. Similarly, leadless pacemakers should be avoided in cases with post-mechanical tricuspid valve replacement. Additionally, it is crucial to consider the presence of an abnormal pathway in the inferior vena cava[20]. Our study included a total of 94 cases, with three cases being excluded due to tortuous vessels. Preoperative evaluation plays a crucial role in enhancing the success rate of the surgery. Ultrasonography can be performed on both lower extremity veins to assess their condition, including stenosis, excessive tortuosity, and other factors. In cases where ultrasound examination indicates a suspected venous access abnormality in the lower limbs that cannot be confirmed, three-dimensional imaging of the inferior vena cava and deep veins can provide a detailed definition.5. LimitationsThis study exhibits several limitations. Firstly, it was conducted retrospectively at a single center, resulting in fewer enrolled cases. Moreover, the absence of a control group and the underrepresentation of diverse patient types further restrict the generalizability and reliability of the study findings. Future research should consider conducting multicenter studies with larger sample sizes to overcome these limitations, specifically focusing on elderly patients. Such studies would provide more comprehensive insights into the efficacy and safety of leadless pacemaker implantation within this population.6. ConclusionThe leadless pacemaker demonstrates effective and safe functionality for a diverse range of patients with long-term indications for pacing therapy. Furthermore, it presents a safe and reasonable alternative for elderly individuals with pacing requirements who have an increased risk of conventional pacemaker implantation related complication.7. Author contributionsThe contributions of the authors to this study are as follows:Conceived, designed, and defined the intellectual content of the study: U Po LAM, Weng Chio TAM, Kuok Wun LAMCollected the data and drafted the manuscript: Kuok Wun LAMRevised the manuscript: Weng Chio TAM, U Po LAMAnalyzed and interpreted the data: U Po LAM, Weng Chio TAM, Kuok Wun LAMProvided administrative support: U Po LAM, Mario EVORAAll authors have read and approved the final version of the manuscript.8. FundingThis study did not receive specific grants from public, commercial, or not-for-profit funding agencies.9. Conflict of interestThe authors declare that they have no competing interests to disclose.References[1] GLIKSON M, NIELSEN J C, KRONBORG M B, et al. 2021 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy [J]. Eur Heart J, 2021, 42(35): 3427-520. doi:10.1093/eurheartj/ehab364.[2] TA K A B AYA S H I K , K I TA G U C H I S , YAMAMOTO T, et al. Mode of death in
Leadless transcatheter pacemaker implantation in the elderly patients: single-center data from Macau175 Volume 11 Número 2 Volume 11 Number 2第 11 卷第 2 期elderly and super-elderly patients with acute heart failure: Insights from Japanese heart failure registry [J]. Clin Cardiol, 2021, 44(6): 848-56. doi:10.1002/clc.23619.[3] USLAN D Z, TLEYJEH I M, BADDOUR L M, et al. Temporal trends in permanent pacemaker implantation: a population-based study [J]. Am Heart J, 2008, 155(5): 896-903. doi:10.1016/j.ahj.2007.12.022.[4] KUSUMOTO F M, SCHOENFELD M H, WILKOFF B L, et al. 2017 HRS expert consensus statement on cardiovascular i m p l a n t a b l e e l e c t r o n i c d e v i c e l e a d management and extract ion [J] . Hear t R h y t h m , 2 0 1 7 , 1 4 ( 1 2 ) : e 5 0 3 - e 5 1 . doi:10.1016/j.hrthm.2017.09.001.[5] SANDOE J A, BARLOW G, CHAMBERS J B, et al. Guidelines for the diagnosis, prevention and management of implantable cardiac electronic device infection. Report of a joint Working Party project on behalf of the British Society for Antimicrobial Chemotherapy (BSAC, host organization), British Heart Rhythm Society (BHRS), Bri t ish Cardiovascular Society (BCS), British Heart Valve Society (BHVS) and British Society for Echocardiography (BSE) [J]. J Antimicrob Chemother, 2015, 70(2): 325-59. doi:10.1093/jac/dku383.[6] BADDOUR L M, CHA Y M, WILSON W R. Cl in ica l p rac t i ce . In fec t ions o f card iovascular implantable e lec t ronic devices [J]. N Engl J Med, 2012, 367(9): 842-9. doi:10.1056/NEJMcp1107675.[7] POLYZOS K A, KONSTANTELIAS A A, FALAGAS M E. Risk factors for cardiac implantable electronic device infection: a systematic review and meta-analysis [ J ] . E u r o p a c e , 2 0 1 5 , 1 7 ( 5 ) : 7 6 7 - 7 7 . doi:10.1093/europace/euv053.[8] KLUG D, BALDE M, PAVIN D, et al . R i s k f a c t o r s r e l a t e d t o i n f e c t i o n s o f implanted pacemakers and cardioverter-d e f i b r i l l a t o r s : r e s u l t s o f a l a r g e p r o s p e c t i v e s t u d y [ J ] . C i r c u l a t i o n , 2007, 116(12) : 1349-55. doi :10 .1161/CIRCULATIONAHA.106.678664.[9] REDDY V Y, EXNER D V, CANTILLON D J, et al. Percutaneous Implantation of an Entirely Intracardiac Leadless Pacemaker [J]. N Engl J Med, 2015, 373(12): 1125-35. doi:10.1056/NEJMoa1507192.[10] E L - C H A M I M F , B O N N E R M , HOLBROOK R, et al. Leadless pacemakers reduce risk of device-related infection: Rev i ew o f t he po t en t i a l mechan i sms [J]. Heart Rhythm, 2020, 17(8): 1393-7. doi:10.1016/j.hrthm.2020.03.019.[11] GRIECO D, CALO L, CAPPATO R. [The LEADLESS II and Micra studies] [J]. G Ital Cardiol (Rome), 2016, 17(10): 791-5. doi:10.1714/2464.25792.[12] E L - C H A M I M F , A L - S A M A D I F , CLEMENTY N, et al. Updated performance of the Micra transcatheter pacemaker in the real-world setting: A comparison to the investigational study and a transvenous h i s to r ica l con t ro l [ J ] . Hear t Rhythm, 2 0 1 8 , 1 5 ( 1 2 ) : 1 8 0 0 - 7 . d o i : 1 0 . 1 0 1 6 /j.hrthm.2018.08.005.[13] CIPOLLETTA L, VOLPATO G, BIFFI M, et al. An indissoluble knot: An unexpected troubleshooting during Micra implantation [J] . Pacing Clin Electrophysiol , 2019, 42(6): 747-8. doi:10.1111/pace.13584.[14] S H A R M A P, S I N G H G U L E R I A V, BHARADWAJ P, et al. Assessing safety of leadless pacemaker (MICRA) at various implantation sites and its impact on paced QRS in Ind ian popula t ion [ J ] . Ind ian Heart J, 2020, 72(5): 376-82. doi:10.1016/j.ihj.2020.08.001.[15] B E U R S K E N S N E G , T J O N G F V Y, DASSELAAR K J , e t a l . Lead less
Leadless transcatheter pacemaker implantation in the elderly patients: single-center data from Macau澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal176pacemaker implantation after explantation o f i n f e c t e d c o n v e n t i o n a l p a c e m a k e r systems: A viable solut ion? [J] . Heart Rhythm, 2019, 16(1): 66-71. doi:10.1016/j.hrthm.2018.07.006.[16] KYPTA A, BLESSBERGER H, KAMMLER J , e t a l . Lead less Card iac Pacemaker Implantat ion After Lead Extract ion in Patients With Severe Device Infection [J]. J Cardiovasc Electrophysiol, 2016, 27(9): 1067-71. doi:10.1111/jce.13030.[17] EL-CHAMI M F, JOHANSEN J B, ZAIDI A, et al. Leadless pacemaker implant in patients with pre-existing infections: Results from the Micra postapproval registry [J]. J Cardiovasc Electrophysiol, 2019, 30(4): 569-74. doi:10.1111/jce.13851.[18] ZUCCHELLI G, BARLETTA V, DELLA TOMMASINA V, et al. Micra pacemaker implant after cardiac implantable electronic device extraction: feasibility and long-term outcomes [J]. Europace, 2019, 21(8): 1229-36. doi:10.1093/europace/euz160.[19] KUTARSKI A, POLEWCZYK A, BOCZAR K, e t a l . Sa fe ty and e ffec t iveness o f t ransvenous lead extract ion in elder ly patients [J]. Cardiol J, 2014, 21(1): 47-52. doi:10.5603/CJ.a2013.0084.[20] Chinese Soc ie ty of Arr thymia , China Society of Pacing and Electrophysiology. Chinese Expert Consensus on Leadless Pacemaker (2022) [J]. Chinese Journal of Cardiac Arrhythmias, 2022, (03): 263-71. doi:10.3760/cma.j.cn113859-20220413-00073.
Guang Li XIAO177 Volume 11 Número 2 Volume 11 Number 2第 11 卷第 2 期Abstract A large number of laboratory, animal and human studies have proven that low-dose radiation has better anti-tumor effects and extremely low toxicity than conventional radiotherapy. Low-dose radiation can reprogram the immunosuppressive tumor microenvironment, which can up-regulate innate immunity and adaptive anti-tumor immunity. Low-dose radiotherapy has obvious synergistic effects with chemotherapy, high-dose radiotherapy and immunotherapy. However, there are currently only a few clinical research data. Optimizing the dose fractionation of low-dose radiotherapy to achieve effective biological effects without causing radiation damage is the key to treatment. Combination with other treatment modalities, selection of appropriate timing, sequence, and irradiation area, etc., require further exploration.Keywords: Low-dose ionizing radiation; Anti-tumor; ImmunologyOncology Department of Kiang Wu Hospital*Correspondence to: Guang Li XIAO, xiaoglbj@aliyun.comDOI : 10.30224/MMJ.202406_11(2).0007癌症低劑量放療Low dose radiotherapy for cancer蕭光莉 *Guang Li XIAO1. 低劑量輻射的生物學效應有氧代謝生物生存的一個重要部分是控制DNA 損傷和抗誘變的生物防禦系統。輻射命中DNA 分子引起直接損傷，也通過生物分子的電離水解，產生活性氧（reactive oxygen species, ROS），引起DNA間接損傷，同時輻射的“命中”和 ROS傳出信號，刺激啟動複雜的抗誘變保護系統（包括免疫系統），進行抗氧化防禦、DNA損傷修復、細胞凋亡和清除。輻射雙相劑量反應模式（biphasic dose-response model）決定損傷與修復之間的平衡和細胞反應，低劑量輻射引起的DNA損傷遠低於正常代謝氧化過程造成的傷害，反而可以刺激增強保護系統的反應，產生有益健康的效應；而高劑量輻射引起的 DNA損害遠大於系統的修復能力，造成可見的即刻損傷和潛在損傷［1］。Reun 和 Foray 概述用輻射誘導 ATM（ataxia 摘要放射治療是癌症治療的重要手段之一，包括單獨治療或綜合治療，儘管醫學物理有很大發展，但是，由於腫瘤對治療的抵抗和高劑量射線對正常組織的毒性反應，限制了放射治療療效。已有許多實驗室、動物和人類研究顯示低劑量放療（Low dose radiotherapy, LDRT）較常規劑量放療具有更好的抗腫瘤作用和極低的毒性反應，近年來有臨床報告LDR治療晚期腫瘤獲得了意外效果，這成爲放射治療領域的一個新關注點。本文通過文獻複習，瞭解有關低劑量輻射在癌症預防及治療的作用機制，以及臨床研究現狀。關鍵詞：低劑量電離輻射；抗腫瘤；免疫學
澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal180����量�療限制毒性分別爲 4.2%和 8%（P=0.25）［20］。4. 存在的问题及未來研究方向低劑量輻射對身體健康影響是有益或是有害，一直存在爭論，相對於複雜的輻射生物學機制，我們瞭解不多。輻射防護的原則是盡量將輻射風險降到最低，所以 2010年联合国原子辐射影响科学委员会（UNSCEAR）定義低劑量輻射為 ≤200 mGy或 0.1 mGy/min，但從放射治療角度來看，需要根據個體情況，平衡臨床利弊。許多臨床研究所采用的低劑量放療劑量遠遠大於實驗室在細胞分子水平研究輻射“興奮效應”生物學機制的劑量閾值。英國健康保健局（the Health Protection Agency）定義：低劑量 <0.5 Gy，中等劑量 0.5-5Gy，高劑量 5-15Gy，極高劑量 >15 Gy。如何優化低劑量放療分割模式，產生顯著的生物效應（亞致死損傷），而不引起輻射的損害後果，是治療的關鍵。低劑量放療的臨床研究有限，尤其是在現代治療時代，如何結合其他治療手段，選擇適當的治療時機和照射範圍，以達到事半功倍的療效。目前臨床上報道的結果主要是腫瘤有效反應率，而患者的總生存才能反映出放療對身體系統性影響，因此，需要進一步做更多的臨床深入研究。參考資料[1] Cuttler JM. Application of low doses of ionizing radiation in medical therapies. D o s e R e s p o n s e . 2 0 2 0 ; 1 - 1 7 . D O I : 10.1177/1559325819895739.[2] Reun EL and Foray N. Low-dose radiation t h e r a p y ( L D RT ) a g a i n s t c a n c e r a n d inflammatory or degenerative diseases: Three parallel stories with a common molecular mechanism involving the nucleoshuttling of the ATM protein? Cancers, 2023, 15, 1482.[3] Ballarini F, Biaggi M, Ottolenghi A, et al. Cel lular communicat ion and bystander effects: a critical review for modelling low-dose radiation action. Mutation Research, 2002; 501: 1–12.[4] Gao L, ZhangA. Low-dose radiotherapy e f f ec t s t he p rog re s s ion o f an t i - t umor response. Translational Oncology, 35 (2023) 101710.[5] Klug F, Prakash H, Huber PE, et al. Low-dose irradiation programs macrophage differentiation to an iNOS(+)/M1 phenotype that orchestrates effective T cell immunotherapy. Cancer Cell, 2013; 24: 589–602.[6] S o n n C H , C h o i C H , K i m C H , e t a l . Augmentation of natural cytotoxicity by chronic low-dose ionizing radiat ion in murine natural killer cells primed by Il-2, J. Radiat Res,2012; 53 (6) : 823–829.[7] Janiak MK, Wincenciak M, Cheda A, et al. Cancer immunotherapy: how low-level ionizing radiation can play a key role. Cancer Immunol Immunother, 2017; 66:819–832.[8] Wang S, Yu H, He R, et al. Exposure to low-dose radiation enhanced the antitumor effect of a dendritic cell vaccine. Dose Response, 2019; 17 (1), 1559325819832144, https://doi.org/10.1177.[9] Herrera FG, Ronet C, Olza MO, e t a l . Low-dose radiotherapy reverses Tumor immune desertification and resistance to immunotherapy. Cancer Discov, 2022; 12(1): 108–133.[10] Barsoumian HB, Ramapriyan R, Younes AI, et al. Low-dose radiation treatment enhances sys temic an t i tumor immune responses by overcoming the inhibitory stroma. J Immunother Cancer, 2020; 8: e000537.[11] E o m H S , P a r k H S , Yo u G E , e t a l . Ident i f ica t ion of ce l lu lar responses to
Low Dose Radiotherapy for Cancer181 Volume 11 Número 2 Volume 11 Number 2第 11 卷第 2 期l o w - d o s e r a d i a t i o n b y t h e p r o f i l i n g o f p h o s p h o r y l a t e d p r o t e i n s i n h u m a n B-lymphoblast IM-9 Cells. Int J Radiat Biol, 2017; 93 (11): 1207–1216.[12] Ren H, Shen J, Tomiyama-Miyaji C et al. Augmentation of innate immunity by low-dose i r radia t ion . Cel l Immunol , 2006; 244(1): 50–56.[13] Sakamoto K, Myojin M, Hosoi Y, et al. Fundamental and clinical studies on cancer control with total or half body irradiation. J Jpn Soc Ther Radiol. 1997; 9: 161-175.[14] Safwat A, Bayoumy Y, El-Sharkawy N, e t a l . Thepoten t ia l pa l l i a t ive ro le and possible immune modulatory effects of low-dose total body irradiation in relapsed or chemo-resistant non-hodgkin’s lymphoma. Radiother Oncol, 2003; 69 (1) 33–36.[15] Valentini V, Massaccesi M, Balducci M, et al. Low-dose hyperradiosensitivity: is there a place for future investigation in clinical sett ings? Int J Radiat Oncol Biol Phys, 2010;76(2): 535-539.[16] Jiang X, Hong YQ, Zhao D, et al. Low dose radiation prevents doxorubicin-induced cardiotoxicity. Oncotarget. 2018; 9(1): 332–345.[17] Yu HS, Song AQ, Liu N, et al. Effects of low dose pre-irradiation on hepatic damage and genetic material damage caused by cyclophosphamide. Eur Rev Med Pharmacol Sci. 2014; 18: 3889–3897.[18] Menon H, Chen D, Ramapriyan R, et al. Influence of low-dose radiation on abscopal responses in patients receiving high-dose radiation and immunotherapy. J Immunother Cancer, 2019; 7: 237.[19] Yin LM, Xue JX, Li R, et al. Effect of low-dose radiation therapy on abscopal responses to hypofractionated radiation therapy and anti-PD1 in mice and patients with non-small cell lung cancer. Int J Radiat Oncol Biol Phys, 2020; 108(1): 212-224.[20] Patel RR, He K, Barsoumian HB, et al. High-dose i r radia t ion in combinat ion with non-ablative low-dose radiation to treat metastatic disease after progression onimmunotherapy: Results of a phase II trial. Radiother Oncol, 2021; 162: 60–67.
Shun Jia HONG et al.澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal182AbstractOvarian cancer has the highest mortality rate of all gynecological malignancies due to lack of effective method for early detection. The high-grade serous subtype was the most common and most lethal one. In the past two decades, it was found that the cancer subtype originated from fallopian tube rather than ovary itself. There has been various reports showing complete salpingectomy is associated with a decreased risk of developing ovarian carcinoma. Thus, opportunistic salpingectomy (OS), which was performed during other pelvic operations as an ovarian cancer prevention strategy, was proposed more than 10 years ago. Recently, the first opportunistic salpingectomy specific, population-based, retrospective cohort study confirmed its efficacy. With its safety established before and its efficacy further confirmed, the authors called for that OS should be done in all abdominal and pelvic operations, whenever possible, to prevent ovarian cancer. The evidences were reviewed and strategies for expanding adoption of OS were proposed. Keywords: Opportunistic salpingectomy; Ovarian cancer; PreventionDepartment of Obstetrics and Gynecology, Conde de São Januário General Hospital, Health Bureau, Macao*Correspondence to: Shun Jia HONG, drhongclinic2021@gmail.comDOI : 10.30224/MMJ.202406_11(2).0008Opportunistic salpingectomy should be done whenever possible to prevent ovarian cancerShun Jia HONG*, Wai Ieng FONG1. Introduction Ovarian cancer (OC) has the highest mortality rate of all gynecological malignancies with an overall five-year survival rate of only 30% to 40%. It was estimated that there were 57200 new OC cases in China in 2016 and resulted in 27200 death [1]. According to ANNUAL REPORT OF MACAO CANCER REGISTRY, there were 38 new OC cases and 18 OC related death in 2021[2]. OC cases generally present at an advanced stage. In a survey conducted in 2023 in mainland China, 70% of cases presented at stage 3 or stage 4. Thus, the prognosis of OC was poor. The overall survival rate for OC has remained largely unchanged in past 4 decades [3].The high mortality rate of OC was due to lack of effective method for early detection. Great effort was input into searching for method for early detection of OC. However, up to present, no screening tool has been shown to improve cancer specific mortality. In a big randomized controlled trial, the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), more than 50000 women aged 50-74 years were recruited for screening with annual transvaginal ultrasound scan. Although annual screening resulted in an increase in earlier-stage diagnosis, this did not bring about saving lives. Compared to those had no screening, women undergoing screening had a similar rates of death from OC after followed for a median of 16 years [4]. With no effective screening tool, early prevention strategies are essential for decreasing the risk and overall mortality of OC. OC had been classified based on histology as
Opportunistic Salpingectomy should be done whenever possible to prevent ovarian cancer183 Volume 11 Número 2 Volume 11 Number 2第 11 卷第 2 期epithelial ovarian cancer (EOC), germ cell tumor and sex cord-stromal tumors. EOC accounts for ~95% of all ovarian malignancies. Subtypes of EOC include high-grade serous, low-grade serous, endometrioid, clear cell, and mucinous. The serous subtype is the most common one. In the survey conducted in 2023 in mainland China, the serous subtype accounts for 74% of cases. So, prevention or advance in management of serous subtype will give an important impact on OC incidence and prognosis.The high-grade serous subtype was the most common and most lethal one. Because of their common cl in ical features , h igh-grade serous carcinoma of ovary, fallopian tube and peritoneum are considered one clinical entity and referred to as a single entity (high-grade serous carcinoma，HGSC). In 2010, the Bri t i sh Columbia (BC) ovarian cancer research team in Canada launched a province-wide strategy asking gynecologists to discuss salpingectomy with their patients as an OC prevention strategy [5]. The salpingectomy, now referred as Opportunistic Salpingectomy (OS), was the removal of the fallopian tubes, while leaving ovaries intact, for primary prevention of epithelial ovarian, fallopian tube, and peritoneal carcinoma in a patient at average risk for these cancers and undergoing pelvic surgery for another indication. By contrast, bilateral salpingo-oophorectomy (BSO) performed in patients at high risk for these cancers is referred as risk-reducing BSO (rrBSO). Since its first introduction, studies on OS to prevent HGSC were published supporting its efficacy in reducing OC risk. Safety and feasibility of OS were also proved. Thus, it has been urged to think about implementation of OS at every abdominal surgical intervention with accessible fallopian tubes [6]. Evidence and rationales for OS were reviewed here. 2. Rationales for OSHGSC originated from fallopian tube rather than ova ry i t s e l f . Fo r more than a cen tu ry, physicians and scientists hypothesized that HGSC arises from ovarian surface epithelium. By1980’s, it has been suggested prophylactic oophorectomy in ovarian-cancer-prone families. However, in some cases, disseminated intra-abdominal malignancy s u b s e q u e n t l y d e v e l o p e d a f t e r p r o p h y l a c t i c oophorectomy. The tumor was indistinguishable histopathologically from ovarian carcinoma. This led physicians and scientists continue to search for the origin of HGSC. In 2001, a Dutch group first identified tubal intraepithelial carcinomas, which were now known as serous tubal intraepithelial carcinomas (STICs) [7]. Occult invasive HGSC, which closely resembled HGSC of the ovary, was found in the fimbriated ends of fallopian tube among women with a genetic predisposition to OC. However, HGSC was NOT present in the ovaries of the sample women undergoing rrBSO. Based on these findings, it is hypothesized that ovarian HGSC originates from implantation of malignant or premalignant cells from the fallopian tube. In 2007, a sentinel study was published delineating the p53 signatures of STICs, which are somatic p53 suppressor gene mutations [8]. All these findings suggest a pathogenic mechanism involving DNA damage, p53 mutation, and progressive loss of cell cycle control in benign tubal mucosa which progress to malignant cells and spread to the ovary. In supporting that ovarian HGSC originates from the fallopian tube, preinvasive lesions have also been found in fallopian tube specimens of average-risk patients who have not yet developed cancer. These tuba l spec imens a re typ ica l ly from pat ients who underwent s ter i l izat ion or hysterectomy for benign indications. Many or most of these patients are younger than 65 years, which is the average age of diagnosis of OC in the general population. Thus, it is not surprising that preinvasive lesions were found only in rare cases of this group of patients. The tubal origin of HGSC was supported by the clinical observation that tubal ligation resulted in greater reduction in risk of non-serous cancers, than
Opportunistic Salpingectomy should be done whenever possible to prevent ovarian cancer澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal184that of serous cancer. Tubal ligation has consistently been shown to decrease the risk of developing OC. In large retrospective studies, a greater risk reduction was observed for non-serous cancers, particularly endometrioid and clear cell subtypes, than for serous cancers [9]. Even though not well established, possible mechanisms for risk reduction include the following: removing the conduit for passage of endometriotic or endosalpingiotic cells (for clear cell and endometrioid carcinomas); and removing the conduit for passage of carcinogens (eg, talc) or inflammation (eg, pelvic infection) to reach the ovary; and, in some cases, removing the initial site of carcinogenesis (for high-grade serous carcinomas). In l ine with the finding of HGSC’s tubal origin, complete salpingectomy is associated with a decreased risk of developing ovarian carcinoma. In population-based cohort studies in Sweden, it was found a significantly reduced OC risk for women of the general population, who had a history of salpingectomy on benign indication [10]. Data on women with previous surgery on benign indication ( s te r i l i za t ion , sa lp ingec tomy, hys te rec tomy, and bi la tera l sa lp ingo-oophorectomy [BSO], hysterectomy; n = 251465) was compared with that of the unexposed population (n = 5449119) between 1973 and 2009. It was found a statistically significantly lower risk for OC among women with previous salpingectomy (HR = 0.65, 95% CI = 0.52 to 0.81) when compared with the unexposed population. Bilateral salpingectomy was associated with a 50% further decrease in risk of OC compared with the unilateral procedure. The f i rs t OS speci f ic , popula t ion-based, retrospective cohort study was published in 2022 [11]. I t was shown that OS may substantially decrease high-grade serous carcinoma risk for women in the general popula t ion. The s tudy recru i ted 57 ,969 pa t ien ts (mean age 38 .2 to 40.2 years) to compare patients undergoing OS (45 percent of patients) with those undergoing hysterectomy or tubal l igation alone. OS was associated with a lower rate of serous (0 versus 15 patients) and epithelial (≤5 versus 21 patients) cancers during the 1.6 to 8.7 years of follow-up. This was also lower than the age-adjusted expected rate of serous (5.27) and epithelial (8.68) cancers. This study [11] strongly supported the role of OS in OC prevention. Prospective, randomized study on the protective effect of OS regarding OC risk is hardly feasible, due to the rather low incidence of OC (0.7-1.3% in average population) and the long t ime period between benign surgery and typical onset age of OC. An international register would be desirable to document the number of OS procedures, side-effects, and HGSC incidence in the cohort with OS, to compensate for unachievable prospective RCTs.Wi t h t h e r o l e o f O S i n O C p r e v e n t i o n supported, i ts safety was established as well . Firstly, OS does not appear to substantively increase operative time. OS added an average of 16 minutes to the total operative time (133 versus 117 minutes [mean]) in patients undergoing hysterectomy with or without bilateral salpingectomy. Similarly, OS added an average of 10 minutes to the total operative time (71 versus 61 minutes [mean]) in patients undergoing sterilization with either tubal ligation or complete salpingectomy. By contrast, total operative time was reduced by five minutes in the OS group (154 versus 147 minutes [median]) in patients undergoing laparoscopic hysterectomy with or without salpingectomy. In at least one study, salpingectomy at the time of cesarean birth was performed in approximately five minutes by experienced surgeons.Secondly, OS does not appear to substantively increase blood loss, as assessed through estimated blood loss, change in hemoglobin levels, and need for transfusion. Thirdly, length of hospital stay appears to be similar or even reduced for patients undergoing OS compared with hysterectomy alone. And, perioperative complications also appear to be similar.Last but not least, i t is uncertain whether
Opportunistic Salpingectomy should be done whenever possible to prevent ovarian cancer185 Volume 11 Número 2 Volume 11 Number 2第 11 卷第 2 期salpingectomy impacts ovarian blood supply and hormonal function. While some studies suggested bilateral salpingectomy decrease ovarian reserve, systematic review of randomized tr ials found patients undergoing hysterectomy with or without OS had similar hormonal status [12]. At present, it is believed that OS has only mild (if any), non-clinically significant impacts on ovarian reserve [12] . Prospect ive mult icenter, observat ional , non-infer ior i ty s tudy is current ly ongoing to determine age at menopause after OS via an annual questionnaire [13].3. Clinical guidelines and ImplementationDue to lack of prospective, randomized studies on the protective effect of OS regarding OC risk, no formal clinical guideline universally recommended OS. However, since 2011, many national-level organizations worldwide have endorsed OS as a pract ical , populat ion-level approach to OC prevention. In China, consensus statement on OS was published in 2021[14]. For general patient at average risk for OC, OS was recommended for post-reproduction women undergoing surgery with access to pelvis. In daily clinical practice, OS can be done for women operated for: (1) benign gynecologic indication; (2) tubal sterilization; (3) other abdominal procedures.For women operated for benign gynecologic indication, if no plan for future pregnancy, the risks and benefits of OS should be counseled and OS should be suggested. Gynecologist may employ shared decision-making with the pat ient . For women undergoing tubal sterilization, all options for sterilization, including complete salpingectomy, should be discussed. The available data regarding minimal added surgical time and risk of morbidity with complete salpingectomy was to be shared with women. It should be emphasized that sterilization with complete salpingectomy is a permanent procedure, cannot be reversed and there is no possibility of a tubal re-anastomosis. For women seeking tubal sterilization, especially those at or above age of 35 years, all these were acceptable in most cases after they understood the role of complete salpingectomy in cancer prevention and the alternative of In Vitro Fertilization and Embryo Transfer (IVF-ET). For women undergoing abdominal surgery, such as cholecystectomy, hernia repair, appendectomy, and gastrointestinal and urologic operations, OS should be counseled and OS should be suggested for women who had no plan for future pregnancy. In average population, the life risk of OC was only 0.7-1.3%. HGSC accounted for about 70% of all cases. If OS completely eliminate HGSC risk (theoretically it will be), the Number Needed to Treat (NNT) was still up to 110 to 200. Nevertheless, considering the efficacy shown in population study and established safety, OS which involved neglectable additional costs and surgery time, should be recommended for all post-reproduction women undergoing abdominal/pelvic surgery. These are valuable windows of opportunity for women as hundreds of thousands of them were operated each year.4. Cost-effectiveness, uptake and outlookThe advantage of preventing OC, 1 of the top 5 most dangerous cancers in women, by removing the fallopian tube, a structure that has no form or function after childbearing years, is unprecedented in the his tory of medicine. With populat ion-based evidence supporting the role of OS in OC prevention, OS must become standard of surgical care, and efforts are needed to ensure tubal ligation and hysterectomy without salpingectomy for post-reproductive women become obsolete. There has been an increased global acceptance of OS since its introduction as a potential OC risk reduction strategy in 2010. Utilization of the procedure is therefore increasing. In a retrospective population-based cohort study in the United States including over one million patients undergoing hysterectomy for benign indications, rates of OS increased from 2.4 to 5.7 percent (between 2001
Opportunistic Salpingectomy should be done whenever possible to prevent ovarian cancer澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal186and 2010) to 58.4 percent by 2015. In a large retrospective study, higher rates (73 percent in 2014) were reported [15]. Universal uptake of salpingectomy during hysterectomy and in lieu of tubal ligation could prevent nearly 2000 deaths from OC per year and save a half billion health care dollars in the US annually.Effects of OS among women older than 40 years of age were examined with models using age-adjusted rates of appendectomy, cholecystectomy, h e r n i a r e p a i r , a n d c o l o n r e s e c t i o n [ 1 6 ] . Salpingectomy during elective non-gynecologic was associated with a reduction in OC death by 7%. The health care cost savings of during gynecologic and non-gynecologic surgery could be as high as $626 million annually in the US [16]. OS is cost-effective in US and would probably also hold true in other countries.Regretfully, while OS at the time of non-gynecologic surgery has been described, its uptake as a cancer preventive strategy has been low. From 2016 to 2020 in US, among all inpatient bilateral salpingectomies, only 0.05 per cent was performed during non-gynecological surgery [17]. This is astonishing. It is likely due to lack of physician and patient awareness. However, when such patients are offered OS, acceptance rates are high [18]. In a prospective study including patients undergoing e l ec t i ve l apa ro scop i c cho l ecys t ec tomy, t he acceptance rate of concurrent OS was approximately 60 percent. This showed the lack of awareness is the key barrier for patients to implementation of OS. For physician side, there is still a major knowledge gaps within the medical field. Many health care professionals are not yet aware of the discovery that HGSC arises from the fallopian tubes and need to be apprised of where OS fits into reproductive medicine.Wi t h t h e i n c r e a s e d a d o p t i o n o f O S i n gynecologic operation and its low utilization in non-gynecologic operation, the imbalance should be changed. To overcome the obstacles, firstly knowledge translation must permeate the breadth of medicine. Continued medical education should include the findings about the origin of HGSC from fallopian tube and the role of OS in OC prevention. Health professionals should clearly know about the impact of OS on women’s health. Secondly, patient awareness of OS should be publicized in media coverage so that they can choose before undergoing operation. And, to promote wider adoption of OS during non-gynecological surgery, i t wil l be necessary to establish logist ic best practices around what surgical team or teams should counsel, consent, and perform the OS. With logistic best practices established, lots of women will be benefited and a large amount of health care cost saved. 5. Conclusion Accumula t ing ep idemiologica l , c l in ica l , pathological, and molecular data over the past 20 years indicate that HGSC primarily originates from microscopic pre-cancers in the fimbriated ends of fallopian tubes, rather than from the ovary itself. OS is associated with OC risk reduction in general population as shown by population-based studies. OS during both gynecologic and non-gynecologic surgery was feasible, safe, cost-effective, and was not associated with significant hormone change as shown in RCT trial. However, uptake of OS in non-gynecologic surgery as a cancer preventive strategy has still been low. The authors called for that OS should be done whenever possible to prevent OC. If women undergoing abdominal surgery with access to fallopian tubes has finished childbearing or had no plan for future pregnancy, and the operating professional had the technical capacity for salpingectomy or a competent gynecologist can be reached, OS should be considered and counseled. Final decision was to be made with share decision among women and her health care team. To promote wider adoption, health care professionals, especially those out of O & G specialty should be aware of the discovery that HGSC arises from the fallopian tubes and the role of OS in OC prevention. General
Opportunistic Salpingectomy should be done whenever possible to prevent ovarian cancer187 Volume 11 Número 2 Volume 11 Number 2第 11 卷第 2 期public awareness of OS should be publicized in media coverage so that women can choose before undergoing operation. Establishing a logistic best practice will surely expand adoption of OS for saving both lives and cost.Reference[1] Rongshou Zheng, Siwei Zhang, e t a l , Cancer incidence and mortality in China, 2016, Journal of the Nat ional Cancer Center, 2(1):1-9; https://doi.org/10.1016/j.jncc.2022.02.002.[2] https://www.ssm.gov.mo/docs/29292/29292_1b3382a212a8461a9edd71fdca3ece7a_000.pdf（accessed on 2023/12/23)[3] Moore K, Colombo N, et al, Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovar i an Cance r. N Eng l J Med. 2018;379(26):2495. Epub 2018 Oct 21.PMID 30345884[4] M e n o n U , G e n t r y - M a h a r a j A , e t a l , Ovar ian cancer popula t ion sc reen ing and morta l i ty af ter long- term fol low-up i n t he UK Co l l abo ra t i ve Tr i a l o f Ovarian Cancer Screening (UKCTOCS): a randomized controlled tr ial . Lancet . 2021;397(10290):2182. Epub 2021 May 12, PMID 33991479[5] h t t p s : / /www.up toda t e . com/con t en t s /opportunistic-salpingectomy-for-ovarian-fallopian-tube-and-peritoneal-carcinoma-risk-reduction/abstract /1 (accessed on 2023/12/20)[6] R u n n e b a u m I B , K a t h e r A . P r i m a r y p r e v e n t i o n o f o v a r i a n c a n c e r b y salpingectomy: that's one small step for a surgeon, one giant leap for patients. J Cancer Res Cl in Oncol . 2023 Aug; 149(10):6799-6801. doi:10.1007/s00432-023-04697-z. PMID: 36991197; [7] P i e k J M , v a n D i e s t P J , D y s p l a s t i c changes in p rophylac t ica l ly removed Fallopian tubes of women predisposed to developing ovarian cancer. J Pathol. 2001 Nov;195(4):451-6. PMID 11745677[8] Lee Y, Miron A, A candidate precursor to serous carcinoma that originates in the distal fallopian tube. J Pathol. 2007 Jan;211(1):26-35. doi: 10.1002/path.2091. PMID: 17117391[9] Gaitskell K, Coffey K,Tubal ligation and incidence of 26 site-specific cancers in the Million Women Study. Br J Cancer. 2016 Apr;114(9):1033-7. PMID 27115569[10] Falconer H, Yin L, Grönberg H, Altman D. Ovarian cancer risk after salpingectomy: a nationwide population-based study. J Natl Cancer Inst. 2015 Jan 27;107(2):dju410. doi: 10.1093/jnci/dju410. PMID: 25628372.[11] Hanley GE, Pearce CL, Outcomes From Opportunistic Salpingectomy for Ovarian Cancer Prevent ion.JAMA Netw Open. 2022;5(2):e2147343. PMID 35138400[12] v a n L i e s h o u t L A M , S t e e n b e e k M P, H y s t e r e c t o m y w i t h o p p o r t u n i s t i c salpingectomy versus hysterectomy alone. Cochrane Database Syst Rev. 2019 Aug 28;8(8):CD012858. doi:10.1002/14651858.CD012858.pub2. PMID: 31456223;[13] Gelderblom ME, IntHout J, STop OVarian CAncer (STOPOVCA) young: Protocol fo r a mul t i cen te r fo l low-up s tudy to d e t e r m i n e t h e l o n g - t e r m e f f e c t s o f opportunist ic salpingectomy on age at menopauseMaturitas. 2022 May;159:62-68. doi: 10.1016/j.maturitas.2022.01.006. Epub 2022 Jan 15. PMID: 35337614 [14] 中国医院协会妇产医院分会妇科肿瘤专业学组 .预防性输卵管切除术的中国专家共识（2021年版）［J］.中国实用妇科与产科杂志，2021,37(8)：826-831.DOI：10.19538/j.fk2021080110[15] Garcia C, Martin M, Experience With Opportunistic Salpingectomy in a Large, Community-Based Health System in the United States . Obstet Gynecol . 2016
Opportunistic Salpingectomy should be done whenever possible to prevent ovarian cancer澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal188Aug;128(2):277-83. PMID 2739999[16] Hughes BN, Herzog TJ, Opportunistic salpingectomy at time of nongynecologic elective procedures could reduce ovarian c a n c e r - r e l a t e d c o s t s a n d m o r t a l i t y. J G y n e c o l S u rg . 2 0 2 2 ; 3 8 ( 1 ) : 4 3 - 4 8 . doi:10.1089/gyn.2021.0047[17] Cathcart AM, Harrison R,Opportunistic salpingectomy during non-gynaecological surgery in the United States: a population-based retrospective study. Br J Surg. 2023 Aug 11;110(9):1215-1217. doi: 10.1093/bjs/znad203. PMID: 37463287[18] Tomasch G, Lemmerer M, Prophylactic s a l p i n g e c t o m y f o r p r e v e n t i o n o f ovarian cancer at the time of elective laparoscopic cholecystectomy. Br J Surg. 2020;107(5):519. PMID 32129898
Nin Ngan SIN189 Volume 11 Número 2 Volume 11 Number 2第 11 卷第 2 期1. Case presentationA non-smoker 56-year-old female with a history of hypertension, multiple nodular goiters, and mild mitral and tricuspid valve regurgitation who consul ted in the emergency depar tment of Centro Hospitalar Conde de São Januário in Macao for chronic dyspnea of unknown cause and worsening with an intermittent cough for 11 months. Without fever, chest pain, and bloody sputum. She had hair dye with the same brand since the year 2022. She reported no history of asthma, bronchiectasis, environmental or occupational exposures, substance use, or pets. Her oxygen saturation was 92% on room air. On physical examination, breath sounds were mild rales and wheezing in both lungs. There was no clubbing of the fingers, swollen joints, or skin rash. Arterial blood gas (room air) showed PH: 7.46, PO2:58 mmHg, PCO2:40 mmHg, CHCO3:28 mEq/L, SaO2: 88%. Blood analysis showed white blood cells: H 20.6x10^9/L, neutrophils: H 12.9 x10^9/L (62.5%), eosinophils: H 6.2 x10^9/L (29.9%). Lung function test showed moderate diffusing capacity defect, not performed bronchodilation test (Table 1). A high-resolution chest computed tomography (CT) scan showed widespread ill-defined centrilobular nodules, bilateral small patchy opacities, and bilateral peripheral subpleural consolidation, but no basilar reticulations or honeycombing (Figures 1 & 2). The results of testing for the nasopharyngeal swab of respiratory tract virus, coronavirus-19 test, autoantibodies, cytomegalovirus-DNA, human immunodeficiency virus test, tumor marker, renal and liver functions, total creatine kinase sputum nucleic acid amplification test and sputum culture were negative. The stool parasite test also was negative. Except for rheumatoid factor: 165.60 IU/mL (Negative < 30.0), total IgE: 7362.0 ng/mL (Adults: <240.0 ng/mL). But anti-CCP: 1.04 RU/mL (Negative <= 5), serum aspergillus antigen and antibody: Negative. Bronchoalveolar lavage showed 71.8% polymorphonuclear leukocyte (predominant eosinophils by Giemsa staining). Eosinophilia in bronchoalveolar lavage could not be accurately reported due to limited detection conditions. These findings were consistent with a diagnosis of chronic eosinophilic pneumonia (Table 2). She was 60 kilograms and initially received treatment with intravenous Methylprednisolon (60 micrograms/daily). After the initiation of treatment, AbstractChronic eosinophilic pneumonia (CEP) is an eosinophilic lung disease that is typically diagnosed by a tetrad of clinical symptoms including respiratory symptoms, alveolar and/or blood eosinophilia, characteristic radiographic abnormalities, exclusion of any known cause of eosinophilic lung disease. The mainstay of treatment is based on glucocorticoid therapy. Glucocorticoid response is dramatically rapid, with both clinical improvement and resolution of infiltrates on imaging.Keywords: Chronic eosinophilic pneumonia; Bronchoalveolar lavageDepartment of Pneumology, Conde de São Januário General Hospital, Health Bureau, Macao*Correspondence to: Nin Ngan SIN,nnceliasin@163.comDOI : 10.30224/MMJ.202406_11(2).0009Chronic eosinophilic pneumoniaNin Ngan SIN*Department of Pneumology, Conde de São Januário General Hospital, Health Bureau, Macao*Correspondence to: Nin Ngan SIN, nnceliasin@163.com DOI: 10.30224/MMJ.202406_11(2).0009
Chronic eosinophilic pneumonia澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal190Eosinophilic lung diseases could be classified as fol lows: a) . idiopathic: acute eosinophil ic pneumonia, chronic eosinophi l ic pneumonia, i d iopa th i c hype reos inoph i l i c syndrome , b ) . secondary: allergic bronchopulmonary aspergillosis, parasitic infections, drug reactions, bronchocentric g ranu lomatos i s , c ) . Eos inophi l i c vascu l i t i s : eosinophilic granulomatosis with polyangiit is (EGPA), allergic angiitis. She d id not have a new medica t ion , but her respiratory symptoms for 11 months. Acute e o s i n o p h i l i c p n e u m o n i a a n d d r u g - i n d u c e d eosinophilic pneumonia be excluded. Although high total serum IgE level, but negative results on se rum aspe rg i l lu s an t igen and an t ibody, and the stool parasite test. No parasitic egg in bronchoalveolar fluid. Allergic bronchopulmonary aspergillosis and parasitic infections be excluded. She did not have dermatologic and peripheral neuropathy manifestations, and laboratory study was not supported. EGPA also be excluded. The case presented recurrent shortness of breath for 11 months , massive eosinophi l ia , and 71.8% po lymorphonuc lea r l eukocy te (p redominan t eosinophi ls) on bronchoalveolar lavage. The diagnosis of CEP was made after excluding other eosinophilic lung diseases. A dramatic response to the mainstay therapy of glucocorticoid with rapid resolution of clinical manifestations and chest image. She kept having the therapy with a tapering of glucocorticoid to reduce relapses［1-7］.3. ConclusionC E P i s c h a r a c t e r i z e d b y c h r o n i c a n d progressive clinical features. A strong clinical suspicion, a detailed history, early diagnosis, and timely treatment with glucocorticoid are the cornerstone of therapy.her symptoms as wel l as b lood eos inophi l ia dramatically responded to therapy. Then changed to oral Prednisone. She was discharged on day 10 with oral Prednisone when her blood eosinophilia was 0.8 x10^9/L. After discharge, she kept a treatment duration of a tapering dose of Prednisone for 6-12 months in the outpatient department. At a few months follow-up, her clinical symptoms improved, and bilateral patchy opacities and bilateral peripheral subpleural consolidation gradually absorbed in her chest imaging (Figures 3 & 4). Her lung function test also improved, and the result showed normal spirometry, and mild diffusing capacity defect (Table 1). 2. DiscussionThe present study patient was a 56-year-old female, non-smoker, with a history of hypertension, multiple nodular goiters, mild mitral and tricuspid valve regurgi tat ion, and hair dye hobby who presented chronic dyspnea of unknown cause and worsening with an intermittent cough for 11 months. Mild breath sounds rale and wheezing in her both lungs. Arterial blood gas demonstrated type I respiratory failure on room air. Massive eosinophilia (6.2 x10^9/L) and her chest CT scan showed widespread i l l -defined centr i lobular nodules, bilateral small patchy opacities, and bilateral peripheral subpleural consolidation. Moderate diffusing capacity defect showed in lung function test. Bacteria, viruses, tuberculosis infection, and malignancy be excluded, according to the results of the laboratory tests. In this case with bilateral small patchy opacities and bilateral peripheral subpleural consol idat ion in her chest image. Pulmonary hemorrhage, pneumocystis jiroveci pneumonia, and connective tissue disease-associated interstitial lung disease be excluded. Cryptogenic organizing pneumonia and Hypersensitivity pneumonitis also be excluded, according to the result of 71.8% po lymorphonuc lea r l eukocy te (p redominan t eosinophils) on bronchoalveolar lavage. The next step, eosinophilic lung diseases were considered.
191 Volume 11 Número 2 Volume 11 Number 2第 11 卷第 2 期Chronic eosinophilic pneumoniaTable 1. Lung function test results of the patientPre %Pre Post %Post %ChangeBefore therapy FVC(L) 2.18 79%FEV1(L) 1.7 78%FEV1/FVC(%) 78%DLCO(%) 11.9 57%After therapy FVC(L) 3.11 112% 2.96 106% -5%FEV1(L) 2.28 104% 2.38 109% 5%FEV1/FVC(%) 73%DLCO(%) 13.4 64%Table 2. CEP diagnostic criteriaCEP diagnostic criteria1 Ongoing respiratory symptoms, usually >2 weeks in duration2 Eosinophilia Serum – eosinophilia ≥1 x 109/L or Alveolar – >40% of cell count differential on bronchoalveolar lavage3 Pulmonary infiltrates, usually with a peripheral predominance4 Exclusion of other known causes of eosinophilic lung diseaseFigures 1 & 2. CT scan of the chest demonstrates widespread ill-defined centrilobular nodules, bilateral small patchy opacities, and bilateral peripheral subpleural consolidation.
Chronic eosinophilic pneumonia澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal192Figures 3 & 4. CT scan of the chest demonstrates bilateral patchy opacities and bilateral peripheral subpleural consolidation gradually absorbedSagar, Li Chen & Shekhar Ghamande. Chronic eosinophilic pneumonia: clinical perspectives. DOI:10.2147/TCRM.157882.[6] Yeon Joo Jeong 1, Kun-Il Kim, Im Jeong Seo, Chang Hun Lee, Ki Nam Lee, Ki Nam Kim, Jeung Sook Kim, Woon Jung Kwon. Eosinophil ic lung diseases: a cl inical , r ad io log ic , and pa tho log ic ove rv iew. DOI:10.1148/rg.273065051.[7] N a o k o Ta k e u c h i , To r u A r a i , Yu m i k o S a s a k i , M a s a n o r i A k i r a , Yo s h i n o b u Matsuda, Kazunobu Tachibana, Takahiko Kasai , Yoshikazu Inoue. J Thorac Dis 2022;14(11):4352-4360. DOI:10.21037/jtd-22-511.Abstract:References[1] Jason Gotlib. World Health Organization-de f ined eos inoph i l i c d i so rde r s : 2017 update on diagnosis, risk stratification, and management. DOI:10.1002/ajh.24880.[2] Carlo Lombardi, Alvise Berti, Marcello C o t t i n i . T h e e m e r g i n g r o l e s o f eosinophils: Implications for the targeted t r e a t m e n t o f e o s i n o p h i l i c - a s s o c i a t e d inflammatory conditions. DOI:10.1016/j.crimmu.2022.03.002.[3] Kazuyuk i Nakagome ,Mako to Naga ta . P o s s i b l e M e c h a n i s m s o f E o s i n o p h i l Accumulation in Eosinophilic Pneumonia. DOI:10.3390/biom10040638[4] Yang Xu, Zhanbo Wang, Wenchao Li, Qiang Zhu, Zhixin Liang. Clinical characteristics o f pa t i en t s wi th chron ic eos inophi l i c pneumonia in a Chinese te r t i a ry-care hospital : A 6-year retrospective study. DOI:10.1111/crj.13448.[5] Matthew Crowe, Drew Robinson, Malvika
In Sim NG et al.193 Volume 11 Número 2 Volume 11 Number 2第 11 卷第 2 期AbstractPhotodynamic therapy (PDT) is the use of a photosensitive dye to transform light into chemical energy causing site-specific vascular occlusion with cellular destruction. This procedure is commonly used in treating cancer, certain skin and eye conditions. This review aims to introduce the use of PDT for the eye, including basic principles and mechanism of action, how this procedure performs, the side effects and complications, and the clinical significance of PDT in recent decades, especially in the treatment of wet age-related macular degeneration (AMD), polypoidal choroidal vasculopathy (PCV) and central serous chorioretinopathy (CSC).Keywords: Photodynamic therapy; Verteporfin; Age-related macular degeneration; Polypoidal choroidal vasculopathy; Central serous chorioretinopathy Department of Ophthalmology, Conde de São Januário General Hospital, Health Bureau, Macao*Correspondence to: In Sim NG, Department of Ophthalmology, Conde de São Januário General Hospital, Health Bureau, Macao. E-mail: cynthia_ng@outlook.comDOI : 10.30224/MMJ.202406_11(2).0010Photodynamic therapy for the eyeIn Sim NG*, Chan LEONG1. IntroductionPhotodynamic therapy (PDT) is the use of a photosensitive dye to transform light into chemical energy; the process releases free radicals thereby causing si te-specif ic vascular occlusion with cellular destruction and minimal injury to nearby tissues. [1] This therapy was first used in treating cancer patients. [2] In 1948, Figge summarized a series of studies showing that exogenously-provided porphyrins selectively accumulated in murine tumors. Later in 1972, Diamond et al. first reported that this procedure might have therapeutic effects. However, until 1991, there was no plausible mechanism to define the ability of photodamage to eradicate malignant cells. It was appreciated that irradiation could lead to eradication of the tumor vasculature, which is an important element in cancer control. [2] This procedure was then proceeded to be used to treat some skin cancer and eye conditions which related to abnormal vasculature. In ophthalmology, PDT was first introduced to treat macular degeneration in the 1990s. Some macular degeneration result from the proliferation of neovascularization in the choroid. TAP study reported PDT with verteporfin to be effective for slowing vision loss in certain forms of subfoveal choroidal neovascularization (CNV) due to age-related macular degeneration (AMD). [3] This study demonstrated PDT's utility could extend beyond treating malignant tissues to targeting other fast-growing vascular cell structures as found in the new blood vessels in AMD. It is used to induce occlusion of abnormal microvasculature in chorioretinal disease; therefore it is currently used in choroidal neovascular membranes as well as choroidal tumors.[4] Compared to other treatment methods, PDT may be an effective treatment for minimizing visual loss in eyes with AMD and predominantly hemorrhagic lesions by achieving complete regression of CNV.epart ent of phthal ology, onde de São Januário eneral ospital, ealth ureau, acao* orrespondence to: In Si , epart ent of phthal ology, onde de São Januário eneral ospital, ealth ureau, acao. - ail: cynthia_ng outlook.coI:10.30224/ J.202406_11(2).0010
Photodynamic therapy for the eye澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal1942. Bas ic Principles and Mechanism of ActionPhotodynamic therapy involves the application of a topical photosensitizing agent over a target area, followed by activation of the agent by light irradiation. It leads to the formation of reactive oxygen intermediates in the presence of oxygen. These intermediates act on essent ial cel lular components leading to apoptosis and necrosis due to irreversible oxidization. In summary, there are three components to PDT: photosensitizer, light and oxygen. The first photosensitizer used clinically for cancer therapy was a water-soluble mixture of porphyrins called hematoporphyrin derivatives (HPD), a pure form known as photofrin. Although photofrin is still the most widely used photosensit izer, i t has several disadvantages, including long-lasting skin photosensitivity and relat ively low absorbance at 630nm. Various photosensitizers have been clinically applied in recent years, but only verteporfin (known by the trade name Visudyne®, Cheplapharm Arzneimittel GmbH, Greifswald, Germany) is commonly used in ophthalmology. Verteporfin is the most preferred agent owing to its lipophilic properties, short half-life (which lessens the chances of it causing skin sensitivity) and also because it has a favorable absorption spectrum. [4]Verteporfin selectively accumulates in rapid growing vessels, such as those in choroidal neovascularization. Laser energy is then applied to activate this photosensitizing agent. The efficacy of PDT depends upon the complex dosimetry of total light energy, light exposure time, and light delivery mode. The choice of laser depends upon the following criteria: (1) properties of the photosensitizer absorption, (2) the disease being treated, (3) the location within the body to be treated, (4) the area/volume of the tissue to be treated. [5] Blue light penetrates less efficiently through tissue, while red and infrared radiation penetrate deeply. The light of wavelength 689 nm is chosen in PDT procedure for eye as it reaches the pathological endothelial cells within the choroid even with overlying blood, fibrotic tissue, and melanin. [4]When the dye absorbs the light, reactive oxygen species (ROS) are produced. It is considered that singlet oxygen is responsible for cell destruction and tumor damage in PDT. Different from traditional chemotherapy, PDT does not present with toxic effect since the dye is non-toxic in the absence of light, and only certain areas of body tissue are irradiated which produce the reaction that causes cellular damage. The singlet oxygen and free radicals interact with endothelial cell membranes in choroidal blood vessels. The response leads to a series of events including vasoconstriction, thrombosis, increased vascular permeabil i ty, blood stasis and hypoxia which promote the vaso-occlusion of pathologic blood vessels.3. ProcedureVerteporfin is administered via intravenous infusion of 30ml over 10 minutes. 15 minutes after the initiation of the infusion, the activation of verteporfin is accomplished with light from a nonthermal diode laser of 689 nm wavelength. Laser light is delivered using a laser contact lens on the treated eye under topical anesthesia. The recommended light dose is 50 J/cm² at an intensity of 600 mW/cm² administered over 83 seconds. [5]4. Side effects and ComplicationsThe most common side effect of PDT for eye is verteporfin induced photosensitivity. Patients often note intolerance to sunlight, resulting in a sunburn response or dermatitis, presenting with erythema, pain, i tching, edema, desquamation and even pustular formation. [6] To reduce the risk of sunburn, it is recommended that patients wear sunglasses, a wide-brimmed hat, and clothes with complete skin coverage, as well as to avoid swimming ou tdoo r s fo r 2 -3 days fo l l owing treatment. A transient visual disturbance may occur
Photodynamic therapy for the eye195 Volume 11 Número 2 Volume 11 Number 2第 11 卷第 2 期within 3 days after treatment, it may be due to changes of retinal or choroidal blood flow. Other adverse events, such as injection site reactions, extravasation of verteporfin, infusion-related pain, dyspnea, flushing, nausea, general pruritus, nervous disorders such as headache, hypoesthesia, paresthesia, dizziness and syncope were reported. These events tended to occur early after treatment and resolved spontaneously by discontinuing the infusion or within a few days to weeks. [7]Al though ra re , the mos t common ocular complication seen with PDT for eye is deterioration in vision. Acute severe visual acuity decrease can occur within 7 days of treatment, which is related to extensive intraretinal and subretinal hemorrhages.[7] Other possible complications include choroidal ischemia, RPE atrophy, and iatrogenic CNV; all of them may result in persistent severe visual acuity decrease.5. Clinical Signif icanceIndications of photodynamic therapy in the field of ophthalmology include: • Wet Age-related Macular Degeneration (AMD)• Polypoidal Choroidal Vasculopathy (PCV)• Central Serous Chorioretinopathy (CSC)• P a t h o l o g i c M y o p i a C h o r o i d a l Neovascularization• Multifocal Choroiditis and Punctate Inner Choroidopathy• Peripapillary Choroidal Neovascularization• Ocular Histoplasmosis• Choroidal Hemangiomas• Retinal Capillary Hemangioblastomas• Choroidal Melanoma• Choroidal Metastasis5.1 Photodynamic therapy in wet AMD and PCVFor the treatment for wet AMD and PCV, PDT is considered a second line therapy after intravitreal anti-VEGF according to the guideline of the Royal College of Ophthalmologists. PDT has been found to be inferior to intravitreal injections of anti-vascular endothelial growth factor (VEGF) in the ANCHOR study.[8] Although verteporfin is registered for the treatment of CNV caused by either AMD or pathologic myopia (European Medicines Agency 2020), in current practice, indications for PDT with verteporfin in ophthalmology have shifted to PCV, a particular subtype of AMD. PCV is a disease manifestation in which CNV is associated with sub-RPE aneurysmal vascular dilations. In Asian populations, between 22.3 and 61.6% of patients diagnosed with neovascular AMD have evidence of PCV, as compared to between 8 and 13% of white patients of European descent. [9] It is important to establish this diagnosis, as PCV patients often do not respond as well to monotherapy with anti-VEGF as ‘classic’ AMD patients. PDT with or without intravitreal anti-VEGF injections may be considered, based on several clinical treatment trials. In the EVEREST trial, conducted by Koh et al., it was shown that combination therapy of anti-VEGF and full-dose PDT was superior to anti-VEGF monotherapy, with regard to polyp closure ra te (77.8% versus 28.6%) a t 6 months af ter treatment. [10] The follow-up study, EVEREST II, described the longer-term follow-up at 24 months after treatment. Combination therapy of PDT and anti-VEGF compared with anti-VEGF monotherapy showed a greater gain in best-corrected visual acuity (9.6 versus 5.5 letters) and a better polyp closure rate (56.6% versus 26.7%). [11] Additionally, the EVEREST II cohort showed that fewer anti-VEGF injections were required when combination therapy was performed (median of 6 versus 12 after 24 months). A meta-analysis by Gao also found that verteporfin PDT and anti-VEGF combination therapy is effective for achieving best-corrected visual acuity (BCVA) gain and central retinal thickness (CRT) reduction comparable with that of anti-VEGF monotherapy. Combination therapy with reduced-fluence PDT can potentially decrease the number of anti-VEGF injections needed. [12]Therefore, PDT may be considered in patients with PCV, especially when the response to anti-
Photodynamic therapy for the eye澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal196VEGF alone is inadequate. In eyes refractory to anti-VEGF injections, study suggested that performing PDT promptly may be more beneficial. [13] The efficacy of PDT combined with anti-VEGF injections on wet AMD and PCV has proved to result in a better visual outcome [14] but long-term efficacy and safety remain to be confirmed.5.2 Photodynamic therapy in CSCThe most commonly used treatments for CSC at this time are PDT, High-Density Subthreshold Micropulse Laser (HSML), mineralocort icoid antagonists including eplerenone or spironolactone, and argon laser photocoagulation. [15]Considering the potential complications of conventional PDT for CSC including RPE atrophy, re t inal pigment epi thel ium r ip and choroidal ischemia, a reduction in verteporfin dose has been suggested. Half-dose PDT is widely used in studies about treatments of CSC. Patients in the half-dose PDT group received an intravenous infusion of 3 mg/m² verteporfin delivered over a period of 10 minutes. In the European PLACE trial, the first large prospective treatment trial for chronic CSC, Van Dijk et al. showed that half-dose PDT is superior to high-density subthreshold micropulse laser treatment in chronic CSC patients, both in terms of functional and anatomical outcome measures. [16] A significantly higher proportion of PDT-treated chronic CSC patients in the PLACE trial had complete resolution of subretinal fluid (SRF). This was also the case after crossover treatment to half-dose PDT after an unsuccessful micropulse laser, but not vice versa, as shown in the REPLACE trial.[17] Pichai et al. tried to decrease the dose of PDT to one-third-dose in treatment of chronic CSC. To compare the anatomical and functional efficacy and safety of one-third-dose PDT versus half-dose PDT in patients with chronic CSC, one-third-dose PDT was effective in terms of BCVA and CRT improvement at 12 months, when compared with half-dose PDT. However, this study showed that the one-third-dose PDT had a higher recurrence rate of subretinal fluid (SRF). [18] On the other hand, in the SPECTRA trial, half-dose PDT was also superior to the oral mineralocorticoid receptor (MR) antagonis t eplerenone for the treatment of chronic CSC. A significantly higher increase in retinal sensitivity on microperimetry was seen in the PDT-treated group. These and other retrospective publications support a prominent role of PDT with reduced settings in the treatment of chronic CSC, for which no alternative treatment is presently available.[15]However, the treatment of PDT is not once and for all. After PDT treatment for chronic CSC, the time to recurrence ranged from 3 to 22 months, with most recurrences happening 3–6 months after initial PDT treatment. [19]PDT causes dose-dependent damage to the retinal pigment epithelium and photoreceptors. Collateral damage to the retina is cumulative with successive treatments and may contribute to loss of visual acuity over time. [20]6. Limitat ionsThe role of PDT in present-day ophthalmology is quite limited owing to its difficult availability and high cos t (around US$2000 for a s ingle t rea tment ) . In 2021 , the re was a wor ldwide shortage of verteporfin. The constrained supply of verteporfin was caused by a manufacturing problem in a factory situated in the United States, which is apparently the single producer of verteporfin worldwide. Alternative therapies like anti-VEGF injections and laser photocoagulation have made the need for PDT to be felt a little lesser. Besides, healthcare professionals providing PDT should be aware of potential occupational health and safety hazards. Physical hazards (potential for skin and eye exposure to non-ionizing radiation generated by the light-emitting device) and chemical hazards (potential for exposure to photosensitizing agents administered to patients via skin, subcutaneous, ingestion, or inhalation routes) must be considered for the safe use of PDT. [5]
Photodynamic therapy for the eye197 Volume 11 Número 2 Volume 11 Number 2第 11 卷第 2 期7. ConclusionPhotodynamic therapy (PDT) is a clinically significant treatment for various chorioretinal diseases, including age-related macular degeneration (AMD), polypoidal choroidal vasculopathy (PCV), and central serous chorioretinopathy (CSC). For the treatment of wet AMD and PCV, PDT is considered a second-line therapy after intravitreal anti-VEGF injections, particularly in cases of PCV where patients may have a suboptimal response to anti-VEGF monotherapy. Combination therapy of PDT and anti-VEGF has shown superior outcomes, potentially reducing the number of anti-VEGF injections required. For the treatment of chronic CSC, reduced-dose PDT, such as half-dose or one-third-dose, has demonstrated superiority over other treatments, resulting in improved resolution of subretinal fluid and anatomical outcomes. However, there i s a r i sk of recurrence and cumulat ive damage to the retinal pigment epithelium and photoreceptors, which may lead to long-term visual acuity loss. Additionally, the availability and cost of PDT are limited, and healthcare professionals must consider occupational health and safety hazards associated with PDT.References[1] Ufret-Vincenty RL, Miller JW, Gragoudas ES . Pho tosens i t i ze r s in pho todynamic therapy of choroidal neovascularization. Int Ophthalmol Clin. 2004 Summer;44(3):63-80. doi: 10.1097/00004397-200404430-00009.[2] Kessel D. Photodynamic Therapy: A Brief History. J Clin Med. 2019 Oct 2;8(10):1581. doi: 10.3390/jcm8101581. [3] T r e a t m e n t o f A g e - r e l a t e d M a c u l a r Degeneration With Photodynamic Therapy (TAP) Study Group. Photodynamic Therapy of Subfoveal Choroidal Neovascularization i n A g e - r e l a t e d M a c u l a r D e g e n e r a t i o n With Verteporfin: One-Year Results of 2 Randomized Clinical Trials―TAP Report 1. Arch Ophthalmol. 1999;117(10):1329–1345. doi:10.1001/archopht.117.10.1329[4] N e w m a n D K . P h o t o d y n a m i c t h e r a p y : current role in the treatment of chorioretinal conditions. Eye (Lond). 2016 Feb;30(2):202-10. doi: 10.1038/eye.2015.251. [5] B r e s k e y J D , L a c e y S E , Ve s p e r B J , Parad ise WA, Radosevich JA, Colvard MD. Photodynamic therapy: occupational hazards and preventative recommendations for clinical administration by healthcare providers . Photomed Laser Surg . 2013 A u g ; 3 1 ( 8 ) : 3 9 8 - 4 0 7 . d o i : 1 0 . 1 0 8 9 /pho.2013.3496. [6] Borgia F, Giuffrida R, Caradonna E, Vaccaro M, Guarneri F, Cannavò SP. Early and Late Onset Side Effects of Photodynamic Therapy. Biomedicines. 2018 Jan 29;6(1):12. doi: 10.3390/biomedicines6010012. [7] Schnurrbusch UE, Jochmann C, Einbock W , W o l f S . C o m p l i c a t i o n s a f t e r photodynamic therapy. Arch Ophthalmol. 2005 Oct;123(10):1347-50. doi: 10.1001/archopht.123.10.1347. [8] Brown DM, Michels M, Kaiser PK, Heier JS, Sy JP, Ianchulev T; ANCHOR Study Group. Ranibizumab versus verteporfin photodynamic therapy for neovascu la r age-related macular degeneration: Two-y e a r r e s u l t s o f t h e A N C H O R s t u d y. Ophthalmology. 2009 Jan;116(1):57-65. e5. doi: 10.1016/j.ophtha.2008.10.018. [9] Wong CW, Yanagi Y, Lee WK, Ogura Y, Ye o I , Wo n g T Y, C h e u n g C M G . A g e -related macular degeneration and polypoidal choroidal vasculopathy in Asians. Prog Retin Eye Res. 2016 Jul; 53:107-139. doi: 10.1016/j.preteyeres.2016.04.002. [10] Koh A, Lee WK, Chen LJ, Chen SJ, Hashad Y, Kim H, Lai TY, Pilz S, Ruamviboonsuk P, Tokaji E, Weisberger A, Lim TH. EVEREST study: efficacy and safety of verteporfin photodynamic therapy in combination with
Photodynamic therapy for the eye澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal198ranibizumab or alone versus ranibizumab monotherapy in patients with symptomatic macular polypoidal choroidal vasculopathy. Re t ina . 2012 Sep ;32(8 ) :1453-64 . do i : 10.1097/IAE.0b013e31824f91e8.[11] Lim TH, Lai TYY, Takahashi K, Wong TY, Chen LJ, Ruamviboonsuk P, Tan CS, Lee WK, Cheung CMG, Ngah NF, Patalauskaite R, Margaron P, Koh A; EVEREST II Study Group. Comparison of Ranibizumab With o r Wi thou t Ver tepor f in Pho todynamic T h e r a p y f o r P o l y p o i d a l C h o r o i d a l Vasculopathy: The EVEREST II Randomized Clinical Trial. JAMA Ophthalmol. 2020 S e p 1 ; 1 3 8 ( 9 ) : 9 3 5 - 9 4 2 . d o i : 1 0 . 1 0 0 1 /jamaophthalmol.2020.2443.[12] Gao Y, Yu T, Zhang Y, Dang G. Anti-VEGF Monotherapy Versus Photodynamic Therapy and Anti-VEGF Combination Treatment fo r Neovascu la r Age-Rela ted Macular Degenerat ion: A Meta-Analysis . Invest Ophthalmol Vis Sci. 2018 Aug 1;59(10):4307-4317. doi: 10.1167/iovs.17-23747. [13] Liu S, Chhabra R. Comparison of 3-year outcomes of photodynamic therapy combined with intravitreal ranibizumab or aflibercept for polypoidal choroidal vasculopathy in a European cohort. Graefes Arch Clin Exp Ophthalmol. 2022 Nov;260(11):3533-3542. doi: 10.1007/s00417-022-05724-4.[14] Dong Y, Wan G, Yan P, Chen Y, Wang W, Peng G. Effect of anti-VEGF drugs combined with photodynamic therapy in the treatment of age-related macular degeneration. Exp Ther Med. 2016 Dec;12(6):3923-3926. doi: 10.3892/etm.2016.3886.[15] van Rijssen TJ, van Dijk EHC, Yzer S, Ohno-Matsui K, Keunen JEE, Schlingemann RO, Sivaprasad S, Querques G, Downes S M , F a u s e r S , H o y n g C B , P i c c o l i n o F C , C h h a b l a n i J K , L a i T Y Y, L o t e r y A J , L a r s e n M , H o l z F G , F r e u n d K B , Yannuzzi LA, Boon CJF. Central serous chorioretinopathy: Towards an evidence-based treatment guideline. Prog Retin Eye Res. 2019 Nov; 73:100770. doi: 10.1016/j.preteyeres.2019.07.003.[16] van Dijk EHC, Fauser S, Breukink MB, Blanco-Garavito R, Groenewoud JMM, Keunen JEE, Peters PJH, Dijkman G, Souied EH, MacLaren RE, Querques G, Downes SM, Hoyng CB, Boon CJF. Hal f -Dose Photodynamic Therapy versus High-Density Subthreshold Micropulse Laser Treatment in Patients with Chronic Central Serous Chor iore t inopa thy : The PLACE Tr ia l . Ophthalmology. 2018 Oct;125(10):1547-1555. doi: 10.1016/j.ophtha.2018.04.021.[17] van Rijssen TJ, van Dijk EHC, Scholz P, Breukink MB, Dijkman G, Peters PJH, Tsonaka R, MacLaren RE, Downes SM, Fauser S, Boon CJF, Hoyng CB. Crossover to Photodynamic Therapy or Micropulse Laser After Failure of Primary Treatment of Chronic Central Serous Chorioretinopathy: The REPLACE Trial. Am J Ophthalmol. 2 0 2 0 A u g ; 2 1 6 : 8 0 - 8 9 . d o i : 1 0 . 1 0 1 6 /j.ajo.2020.04.007.[18] Pichai J, Vanchalerm B, Mansing R. One-year results of half-dose versus one-third-dose photodynamic therapy in chronic or recurrent central serous chorioretinopathy. BMC Ophthalmol. 2021 Jan 12;21(1):30. doi: 10.1186/s12886-020-01796-0.[19] Erikitola OC, Crosby-Nwaobi R, Lotery AJ, Sivaprasad S. Photodynamic therapy for central serous chorioretinopathy. Eye (Lond) . 2014 Aug ;28(8 ) :944 -57 . do i : 10.1038/eye.2014.134. [20] Paskowitz DM, Nune G, Yasumura D, Yang H, Bhisitkul RB, Sharma S, Matthes MT, Zarbin MA, Lavail MM, Duncan JL. BDNF reduces the retinal toxicity of verteporfin photodynamic therapy. Invest Ophthalmol Vis Sci . 2004 Nov;45(11):4190-6. doi : 10.1167/iovs.04-0676.
杜�瑩�199 Volume 11 Número 2 Volume 11 Number 2第 11 卷第 2 期�門������中�*Correspondence to: Lin Feng MA, 61454439@qq.comDOI : 10.30224/MMJ.202406_11(2).001118F-FDG PET/CT 提示登革熱感染 1 例Dengue fever indicated by 18F-FDG PET/CT: a case report and literature review杜芷瑩，馬林峰 *Chi Ieng TOU, Lin Feng MA*摘要登革熱是由登革病毒 (dengue virus, DENV)引起的急性傳染病，是全球傳播最廣泛的蚊媒傳染病之一，可導致一系列嚴重幷發症及死亡。18F-FDG PET/CT 是惡性腫瘤及不明原因發熱（fever of unknown origin, FUO）常用的影像檢查方法，其優勢是一次檢查全身顯像，能功能性地反應腫瘤或炎癥代謝增高位置。登革熱感染人體後會引起病毒血癥及隨後的炎癥因子風暴，從而導致全身多器官功能异常，部分器官形態學及代謝功能异常可在PET/CT有所表現。本例是澳門首例經PET/CT檢查後結合臨床表現，提示登革熱，故作報導。關鍵詞：登革熱；發熱；PET/CTAbstract Dengue fever is an acute infectious disease caused by dengue virus (DENV). It is one of the most widely spread mosquito-borne infectious diseases in the world, which can lead to a series of serious complications and death. 18F-FDG PET/CT is a commonly used imaging examination method for malignant tumours and fever of unknown origin (FUO). It has the advantage of imaging the whole body at once and is able to provide a functional response to the location of the tumour or inflammatory metabolism. Human infection with dengue virus triggers viraemia and a subsequent storm of inflammatory factors. It can lead to multi-organ dysfunction, some of which may show morphological and metabolic abnormalities on PET/CT.This study reports the first documented case of dengue in Macao, with evidence obtained from PET/CT imaging.Keywords: Dengue fever; Fever of unknown origin; PET/CT 1. 簡介登革熱（dengue fever）是由媒介伊蚊叮咬傳播登革熱病毒（dengue viruses, DENV）引起的一種急性發熱性疾病 [1]。澳門是世界上人口最密集的地區之一，地處亞熱帶，夏秋氣溫高，降雨量增多，容易引起蚊蟲孳生，發生登革熱流行。18F-FDG PET/CT 是惡性腫瘤及不明原因發熱（fever of unknown origin, FUO）常用的影像檢查方法，能功能性地反應腫瘤或炎癥代謝增高位置。目前國內外的文章中對登革熱的影像學表現探討不多。以下，我們將介紹一例經 PET/CT檢查後結合臨床表現診斷登革熱的病例。
201Dengue fever indicated by 18F-FDG PET/CT: a case report and literature review Volume 11 Número 2 Volume 11 Number 2第 11 卷第 2 期過往的臨床經驗認為影像學檢查對于登革熱診斷幫助不大，但 PET/CT作爲新興的功能性影像學設備，除了在腫瘤全身檢查中的突出作用，在炎性 /感染病變中也具有很大的優勢，因登革熱是一種累及全身反應的感染疾病，通過 PET/CT能發現全身淋巴結、脾臟、膽囊及漿膜腔積液等全身代謝和形態改變特點，可提高了對登革熱診斷的準確率。圖 1 ���質��性代�輕度��,SUVmax � 2.5（��質 SUVmax2.1）圖 2 �門�淋巴��大並代�輕度��,SUVmax � 2.9圖 3 �色�頭������厚,但 PET/CT �合圖未見����取��
18F-FDG PET/CT 提�登革��� 1例澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal202參考文獻[1] Senanayake A M Kularatne.Dengue fever［J］.BMJ,2015,351:h4661.doi:10. 1136/bmj.h4661. doi: 10.1136/bmj.h4661[2] Chandak S,Ashutosh K.Can radiology play a role in early diagnosis of dengue fever.North Am J Med Sci 2016;8:100–105. doi: 10.4103/1947-2714.177316[3] 周軍,周芳等.登革熱的胸部CT表現[J].實用醫學影像雜志,2014,15(2):119-120.[4] R o d r i g u e s R S , B r u m A L , P a e s M V, e t al.Lung in Dengue:Computed Tomography Findings[J].Plos One,2014,9(5):1-7. doi: 10.1371/journal.pone.0096313[5] H u T, L i u J , G u a n W, e t a l . C T f i n d i n g s of severe dengue fever in the chest and abdomen.Radiology of Infectious Diseases 2015,2:77-80. doi:10.1016/j.jrid.2015.08.002[6] O l i v e i r a G A , M a c h a d o R C , H o r y a t JV,et a l .Transient re t icular gal lb ladder w a l l t h i c k e n i n g i n s e v e r e d e n g u e fever:a reliable sign of plasma leakage.PediatrRadiol.2010;40:720-4. doi: 10.1007/s00247-009-1489-x
第 11 卷第 2 期 Volume 11 Número 2 Volume 11 Number 2 203審 稿 人Revisão de TextoReviewers王 曉 古紀璇 田軼倫 伍海�朱永� 朱海� 何永輝 何衍宙吳 浩 李克� 李�南 李 牧 沈�� 林 路 金 椿 �祖���明 張沂南 張曉戰 �家��根發 �嘉敏 � 丹 陳丹梅 陳 彥 陳惟� 陳� ���� � ⿈淑健 ⿈嘉東 � 敏 寧�基 ��鋒 劉咏儀 劉懷烈 �嘉� 鄧頴佳 鄧�賢 黎淑��詠� 檀 � ��� � 敏排名按中文姓氏筆劃順序a ordem é feita de acordo com o número dos traços dos apelidos em caracteres chineses In the order of the number of strokes of Chinese surnames
The Macao Medical Journal (MMJ) (ISSN 1608-7801) is a comprehensive medical academic journal organized by the Health Bureau of the Macao SAR Government and published semi-annually in January and July by the Macao Academy of Medicine, with medical professionals as its main readers. All articles and manuscripts published in MMJ have been peer-reviewed to report on scientific research outcomes and clinical experience in the field of medical and health. The Journal is available for free access and is downloadable from the websites of the Health Bureau and the Macao Academy of Medicine to facilitate extensive academic exchange. 1. Categories of manuscripts The Journal publishes the following categories of manuscripts: Original clinical studies / researches, review articles / lectures and short articles / case reports.2. Guide for submission: (references from “Chinese Medical Journal”) 2.1. Manuscripts. The word count of submitted original clinical studies, discussion and review articles should generally be limited to 5000 (including legends of tables/graphs and references). Short articles and case reviews should not exceed 1500 words (including legends of tables/graphs and references). The process of submission will be entirely by electronic means. Authors are required to send their manuscript (in .doc or .docx format) by e-mail to mmj@ssm.gov.mo, with “Submission_Name of First Author_Manuscript Title” as the subject of the email. The cover letter/title page should contain the following information: Title of the manuscript, name(s) of all authors, name(s) of their department(s), their contact telephone number and email address; name of the corresponding author, type and no. of his/her identification document, name of his/her department, his/her telephone number and postal and email address.2.2. Language. To align with international standards and academic purposes, authors are encouraged to produce the full text in English; manuscripts presented in Chinese or Portuguese must have an English abstract (400 words). The abstract of an original article must consist of the following four parts: “Objective”, “Method”, “Results” and “Conclusions”, with each bearing their respective heading; these four parts are not required for abstracts of review articles and case reports. 2.3. Authorship. Authors’names should be written with the surname capitalized―for example, LIU ZhengQian or Zheng Qian LIU. The order of authorship should be settled prior to the submission of the manuscript, and should not be changed during the editorial process.2.4. Keywords. Each original article should have 2-5 English keywords, which should be selected as much as possible from the Medical Subject Headings (MeSH) database of the United States National Library of Medicine (NLM). Keywords should be separated by a semicolon (;). The first letter of each English keyword should be capitalized.2.5. Ethics approval. Manuscripts pertaining to research or work involving the use of human subjects must be accompanied by the approval of the regional/national/institutional ethics committee if deemed appropriate.2.6. Referencing. References should be cited according to the requirements of "Chinese Medical Journal" GB/T7714-2005 "Regulations for Bibliographic References" and GB 3469-1983 "Document Types and Document Carrier Codes". Articles with Digital Object Identifier (DOI) must list DOI at the end of the reference. Regarding the number of references, monographs, reviews, and lectures are generally limited to 20 or less, and 10 or less for short articles and case reviews. The following are examples of reference format: [1] Lam UP, Lopes Lao EP, Lam KC, Evora M, Wu Nq. Trans-brachial artery access for coronary artery procedures is feasible and safe: data from a single-center in Macau. Chin Med J 2019;132:1478-1481. doi: 10.1097/ CM9.0000000000000274. [ 2 ] 黎旭 , 刘兴鹏 , 刘⼩慧 , 等 . 早期他汀药物治疗与非缺血性扩张性心肌病患者病死率关系的研究 [ J ] . 中华医学杂志,2010,90(28):1974-1977. doi: 10.3760/ cma.j.issn.0376-2491.2010.28.009.3. Declaration A declaration letter should be submitted together with the manuscript to express:3.1. The author(s)’s supervisor(s)/superior(s) is/are aware of the content of the manuscript;3.2. There is no issue on confidentiality;3.3. There is no issue on controversy about the name order of authors;3.4. The work has not been submitted to other journals;3.5. The manuscript is original work and not under consideration for publication elsewhere;3.6. The submission is approved by all authors.Macao Medical JournalGuide for Authors 2024
4. Instructions for Submission Authors are responsible for all material presented in the journal. If authors do not receive any feedback one month after receiving an acknowledgement of receipt, it means the manuscript is still under review. Authors should avoid multiple submissions to other journals, and should contact the Editorial Office if they wish to do so. Authors can write to appeal if the manuscript is rejected for publication. Accepted manuscripts may be edited or abridged by the Editorial Office prior to publication. Edited content involving change of the original idea would be referred to the authors for consideration. Authors who fail to return the corrected proof within 14 days will be regarded as having withdrawn the manuscript. The copyright to all published materials is owned by the Macao Medical Journal, whose copyright is owned by the Macao Academy of Medicine. 5. Contact of Editorial Office Postal address: Editorial Office of “Macao Medical Journal”, 5/F, Administration Building of the Health Bureau, Rua Nova à Guia no. 339, Macao.Tel.: (853)-8390 3253 / (853)-6252 0657E-mail: mmj@ssm.gov.mo
A“Revista Médica de Macau” (ISSN1608-7801) é uma revista académica de medicina abrangente, editada pelos Serviços de Saúde do Governo da RAEM e publicada oficialmente e semestralmente em Janeiro e Julho pela Academia Médica de Macau, tendo como principais leitores os profissionais da área de medicina. Todos os artigos publicados na Revista Médica de Macau foram revisados por pares para relatar os resultados da investigação científica e a experiência clínica no âmbito da medicina e da saúde. A Revista está disponível para acesso gratuito e pode ser descarregada na página electrónica dos Serviços de Saúde e da Academia Médica de Macau para facilitar o intercâmbio académico.1. Categorias dos artigos A Revista publica as seguintes categorias de artigos: Monografias e Estudos, Síntese e Palestras, Artigos Curtos e Relatórios de Casos.2. Requisitos para submissão (Vide “National Medical Journal of China”e“Chinese Medical Journal”) 2.1. Artigos. As monografias, sínteses, palestras, etc., geralmente não devem exceder 5 000 palavras (incluindo figuras, tabelas e documentos de referência); enquanto os artigos curtos, relatórios de casos clínicos, etc., não devem exceder 1 500 palavras (incluindo figuras, tabelas e documentos de referência). O processo de submissão é feito de forma electrónica, os autores devem enivar os seus artigos (em formato .doc ou .docx) por e-mail para mmj@ssm.gov.mo, com “Submissão_Nome do Primeiro Autor_Título do Artigo” como assunto do e-mail. A carta de apresentação/página de rosto deve conter as seguintes informações: título do artigo, nomes de todos os autores, nome(s) da(s) sua(s) unidade(s) de trabalho, número de telefone e endereço de e-mail; o nome, tipo e n.º do documento de identificação do autor responsável pela comunicação com a secção editorial, nome da instituição onde presta funções, endereço para correspondência, número de telefone e endereço de e-mail.2.2. Linguagem. Para satisfazer as necessidades académicas a nível internacional, propõe-se que o texto seja redigido em língua inglesa. Caso seja publicado em língua chinesa ou portuguesa, o resumo deve ser redigido em língua inglesa (400 palavras). O resumo de um artigo original deve ser composto pelas quatro partes: Objectivo, Método, Resultados e Conclusão, cada uma com os respectivos títulos. As sínteses e relatórios de casos clínicos não precisam incluir as quatro partes acima.2.3. Autor. Os sobrenomes dos autores, em línguas estrangeiras, devem ser escritos em letras maiúsculas, por exemplo: LIU ZhengQian ou Zheng Qian LIU. O nome do autor deve ser escrito sob o título, sendo a ordem determinada antes da submissão e não deve ser alterada durante o processo editorial.2.4. Palavras-chave. Devem ser indicadas 2 a 5 palavras-chave em inglês para a monografia. As palavras-chave devem ser seleccionadas no banco de dados de Medical Subject Headings (MeSH) da Biblioteca Nacional de Medicina dos Estados Unidos (The United States National Library of Medicine, NLM) tanto quanto possível, e ser separadas por ponto e vírgula (;). A primeira letra de cada palavra-chave em inglês deve ser maiúscula.2.5. Aprovação ética. Caso o conteúdo dos artigos envolva o uso de seres humanos como objecto de investigação, deve ser acompanhado dos pareceres de aprovação da Comissão de Ética (unidade, região ou país relacionado).2.6. Referências. As referências devem ser listadas de acordo com GB/T7714-2005 “Descriptive rules for bibliographic references”e GB 3469-1983 “Codes for documentary types and documentary carriers”, exigidos pelo “National Medical Journal of China” , e os artigos com Digital Object Identifier (DOI) devem identificar DOI no final de referência. Em relação ao número de referências das monografias, sínteses e palestras, é limitado a vinte ou menos. Para os artigos curtos e relatórios de casos, as referências são limitadas a dez ou menos. O seguinte formato é para referência: [1] Lam UP, Lopes Lao EP, Lam KC, Evora M, Wu Nq. Trans-brachial artery access for coronary artery procedures is feasible and safe: data from a single-center in Macau. Chin Med J 2019;132:1478-1481. doi: 10.1097/ CM9.0000000000000274. [ 2 ] 黎旭 , 刘兴鹏 , 刘⼩慧 , 等 . 早期他汀药物治疗与非缺血性扩张性心肌病患者病死率关系的研究 [ J ] . 中华医学杂志,2010,90(28):1974-1977. doi: 10.3760/ cma.j.issn.0376-2491.2010.28.009.3. Carta de declaração. A carta de declaração deve ser enviada juntamente com o artigo, a qual deve incluir:3.1 Ter dado conhecimento prévio do conteúdo do artigo aos superiores hierárquicos do autor;3.2 O artigo não contém matéria confidencial;3.3 Não existe nenhuma contestação a respeito da ordem de apresentação dos nomes dos autores;3.4 O artigo não foi submetido a outras publicações periódicas;3.5 O artigo é um trabalho original e não está a ser ponderada a sua publicação noutro lugar;3.6 A submissão foi aprovada por todos os autores.Normas para Publicação na“Revista Médica de Macau”2024
4. Instruções para submissão Os autores são responsáveis por todos os artigos apresentados na presente revista. Se os autores não receberem nenhuma notificação do processamento do artigo dentro de um mês após o recebimento do recibo, isso significa que o artigo ainda está em revisão. Os autores devem evitar submissões múltiplas para outras publicações periódicas. Se desejarem submeter os artigos para outras publicações periódicas, os autores devem entrar em contacto a secção editorial. Para os artigos rejeitados, os autores podem apresentar opiniões de forma escrita para efeitos de impugnação. Além disso, os artigos aceitos podem ser editados ou abreviados pela secção editorial antes da publicação. Sempre que o conteúdo editado envolva a mudança da ideia original, é encaminhado aos autores para consideração. Se o artigo revisado não for devolvido no prazo de 14 dias, será considerado como desistência. Os direitos de autor de todos os artigos publicados pertencem a esta revista, cujos direitos de autores da “Revista de Ciências da Saúde de Macau” pertencem à Academia Médica de Macau.5. Contacto Endereço: Rua Nova à Guia, n.º 339, Edifício da Administração dos Serviços de Saúde, 5.º andar, secção editorial da “Revista Médica de Macau”.Tel: (853) 8390 3253 / (853) 6252 0657E-mail: mmj@ssm.gov.mo
