UNIVERSIDADE ESTADUAL PAULISTA “JÚLIO DE MESQUITA FILHO” FACULDADE DE MEDICINA Teófilo Augusto Araújo Tiradentes Parada cardíaca por fator anestésico em pacientes pediátricos: revisão sistemática com metanálise proporcional e análise de metarregressão Dissertação apresentada à Faculdade de Medicina, Universidade Estadual Paulista “Júlio de Mesquita Filho”, Campus de Botucatu, para obtenção do título de Mestre em Anestesiologia. Orientador: Prof. Assoc. Leandro Gobbo Braz Botucatu 2023 Teófilo Augusto Araújo Tiradentes Parada cardíaca por fator anestésico em pacientes pediátricos: revisão sistemática com metanálise proporcional e análise de metarregressão Dissertação apresentada à Faculdade de Medicina, Universidade Estadual Paulista “Júlio de Mesquita Filho”, Campus de Botucatu, para obtenção do título de Mestre em Anestesiologia. Orientador: Prof. Assoc. Leandro Gobbo Braz Botucatu 2023 Teófilo Augusto Araújo Tiradentes “Parada cardíaca por fator anestésico em pacientes pediátricos: revisão sistemática com metanálise proporcional e análise de metarregressão” Dissertação apresentada à Faculdade de Medicina, Universidade Estadual Paulista “Júlio de Mesquita Filho”, Campus de Botucatu, para obtenção do título de Mestre. Comissão Examinadora Presidente e Orientador: Prof. Assoc. Leandro Gobbo Braz Departamento de Especialidades Cirúrgicas e Anestesiologia Profa. Assoc. Vânia dos Santos Nunes Nogueira Departamento de Clínica Médica, Faculdade de Medicina de Botucatu, Unesp. Profa. Dra. Karen Santos Braghiroli Grupo de Dor da SMA do Hospital Alemão Osvaldo Cruz, SP. Botucatu, 16 de fevereiro de 2023 Dedicatória À minha filha Yasmin, razão da minha força para seguir em frente. À minha mãe Maria Geralda, que mesmo de longe se faz presente com seu carinho de mãe. Ao meu pai Teófilo de Oliveira, que me ensinou a jamais desistir. À minha irmã Thaís, uma verdadeira luz em minha vida, capaz de iluminar os caminhos mais difíceis. A minha madrinha Maria do Socorro, meu padrinho Macedônio e todos meus familiares que estão me acompanhando de longe a todo momento, sempre me apoiando como podem. Muito obrigado a todos, por sempre estarem ao meu lado até este momento, e ainda estaremos juntos em muitos caminhos que ainda virão! Agradecimento Especial Ao Prof. Assoc. Leandro Gobbo Braz, meu principal incentivador, agradeço imensamente a bondade e generosidade desse grande homem de quem tive a honra de ser escolhido como aluno. Sem ele, esse trabalho não seria possível, além da força e incentivos para seguirmos firmes em nosso objetivo. Muito obrigado Professor! Agradecimentos Ao Prof. Emérito José Reinaldo Cerqueira Braz, pela paciência e pelos ensinamentos. Por ter passado comigo todo o processo desde a seleção dos artigos ao texto final, orientando-me, explicando e guiando tornando o trabalho mais leve. À bibliotecária Dra. Marluci Betini, que com seu amplo conhecimento e experiência nos auxiliou na pesquisa, sendo uma colaboradora fundamental para o trabalho. Ao Prof. Assoc. José E. Corrente, sempre doando seu conhecimento e experiência para que os trabalhos sejam excepcionais. Ao Rafael Ignácio, que me deu a força para seguir tantas vezes quanto foram necessárias. Caminhando comigo em um momento decisivo, apontando sempre o horizonte para eu reconhecer o sucesso do trabalho, não desistir, e lembrando sempre que o melhor ainda está por vir. Meu profundo agradecimento por tanto! RESUMO 1 INTRODUÇÃO As crianças têm um risco maior de parada cardíaca por fator anestésico do que os adultos durante os procedimentos cirúrgicos. Estudos demonstraram que há lacunas no cuidado anestésico em diferentes países. O Índice de Desenvolvimento Humano (IDH) de cada país varia de 0 a 1, representando os menores e os maiores níveis de desenvolvimento, respectivamente. 2 OBJETIVO Avaliou-se em uma população mista de pacientes pediátricos a relação entre a incidência mundial de parada cardíaca por fator anestésico com o tempo e com o IDH. 3 MÉTODO Realizou-se uma revisão sistemática com metarregressão e metanálise de estudos observacionais que reportaram a incidência de parada cardíaca por fator anestésico em crianças. Pesquisou-se nas bases de dados PubMed/Medline, EMBASE, Scopus, Lilacs e Web of Science até julho de 2022. 3.1 Desfecho analisado Incidência de parada cardíaca por fator anestésico na população pediátrica até 24 horas de pós-operatório. 3.2 Variáveis avaliadas Avaliou-se a incidência de parada cardíaca por fator anestésico pelo IDH dos países sendo considerado países em desenvolvimento quando IDH < 0,8 e países desenvolvidos quando IDH ≥ que 0,8 (IDH < 0,8 versus IDH ≥ 0,8) e em dois períodos de tempo (pré-2001 versus de 2001-2022). 4 RESULTADOS Não houve relação entre a incidência de parada cardíaca por fator anestésico com o tempo (p = 0,82); por outro lado, a incidência foi inversamente relacionada ao IDH (p < 0,0001). A incidência de parada cardíaca em crianças não se modificou nos dois diferentes períodos tanto em países em desenvolvimento quanto em países desenvolvidos (p = 0,71 e p = 0,62, respectivamente), porém foi significativamente maior nos países em desenvolvimento em comparação aos países desenvolvidos (9,6 versus 2,0 por 10,000 procedimentos anestésicos; p < 0,0001) no período de 2001-2022. A incidência de parada cardíaca por fator anestésico foi maior em crianças menores de 1 ano de idade do que aquelas maiores ou iguais a 1 ano em países desenvolvidos (10,69 versus 1,48 por 10,000 procedimentos anestésicos; p < 0,0001) e em países em desenvolvimento (36,02 versus 2,86 por 10,000 procedimentos anestésicos; p < 0,0001) no período de 2001-2022. 5 CONCLUSÃO A incidência de parada cardíaca por fator anestésico na população pediátrica não diminuiu nos últimos 60 anos. A elevada incidência de parada cardíaca por fator anestésico em crianças menores de 1 ano é uma situação alarmante tanto em países desenvolvidos quanto em países em desenvolvimento apresentando então um grande desafio aos anestesiologistas. As grandes diferenças entre as incidências de parada cardíaca por fator anestésico em países em desenvolvimento e em desenvolvidos no século atual destacam uma lacuna crescente nos cuidados de segurança anestésica nesses países. Palavras-chave: crianças; países desenvolvidos; países em desenvolvimento; parada cardíaca; revisão sistemática MANUSCRITO1 1 Submetido ao periódico Journal of Clinical Anesthesia SUMÁRIO MANUSCRIPT Anaesthesia-related cardiac arrest rates in children: a systematic review with meta- regression analysis and meta-analysis…………………………….……...…………………….. Abstract…………………………………………………….…………….………………………. 2 Highlights……………………………………………………...………………………………….. 4 1. Introduction ................................................................................................................................ 5 2. Methods....................................................................................................................................... 7 2.1 Outcomes definitions…………………………………………………..………………….. 7 2.2 Search strategy and selection criteria………………………………...……………………. 8 2.3 Inclusion and exclusion of studies………………………………..……………………….. 8 2.4 Data extraction…………………………………………………..………………………… 9 2.5 Methodological quality of the included studies……………..…………………………….. 10 2.6 Country Human Development Index………………………..…………………………….. 10 2.7 Statistical analyses…………………………………………..…………………………….. 11 2.7.1 Meta-regression analysis……………………………..……………………………… 11 2.7.2 Proportional meta-analysis………………………...………………………………… 11 3. Results.......................................................................................................................................... 13 3.1 Included studies…………………………………………………………………………… 13 3.2 Meta-regression analysis of anaesthesia-related cardiac arrest rates………………...……. 13 3.3 Proportional meta-analysis of anaesthesia-related cardiac arrest rates………………...….. 14 3.3.1 Anaesthesia-related cardiac arrest rate differences between postnatal age groups (< 1 year versus ≥ 1 year) according to time…………………...………………………..…… 14 3.3.2 Anaesthesia-related cardiac arrest rate differences between postnatal age groups (< 1 year versus ≥ 1 year) according to time and country HDI………………………….....… 14 3.4 Proportional meta-analysis of anaesthesia-related cardiac arrest survival…………….…... 15 3.4.1 Anaesthesia-related cardiac arrest survival differences between postnatal age groups (< 1 year versus ≥ 1 year) according to time and country HDI……………………. 15 3.5 Publication bias………………………………….……………..………………………….. 16 3.5.1 Children (all postnatal age groups).............................................................................. 16 3.5.2 Children younger than 1 year……………...…………………………...……………. 16 3.5.3 Children aged to or older than 1 year………………...……………………………… 17 3.6 Analysing anaesthesia-related cardiac arrest rates in children (all postnatal age groups) according to country HDI and quartile pre-2001……………………………..……………….. 17 3.7 Analysing anaesthesia-related cardiac arrest rates per country HDI and quartile in 2001- 2022……………………………………………………………………………………………. 18 3.8 Anaesthesia-related cardiac arrest survival proportion up to 24 hours postoperative in children (all postnatal age groups) according to country HDI and quartile in studies from 2001 to 2022…………………………………………….……………………………………... 18 4. Discussion.................................................................................................................................... 20 4.1 Anaesthesia-related cardiac arrest rates in children: Implications of the evidence……..… 20 4.2 Survival after anaesthesia-related cardiac arrest in children: Implications of the evidence 24 4.3 Where and how to improve anaesthesia safety in children……………………...………… 26 4.4 Strengths and limitations of this review……………………………………...……………. 28 4.5 Conclusions……………………………………………………………...………………… 29 References........................................................................................................................................ 31 Figure Legends……………………………………………..…………………………………….. 46 Fig. 1. PRISMA flow diagram of study identification, screening, and inclusion process………… 46 Fig. 2. A. Meta-regression analysis of the anaesthesia-related cardiac arrest rates by time; the relationship was not significant (slope: -0.003, 95% CI: -0.035 to 0.028; p = 0.82). B: Meta- regression analysis of the anaesthesia-related cardiac arrest rates by country Human Development Index (HDI) status; the relationship was significant (slope: -5.55, 95% CI: -8.107 to -3.003; p < 0.0001)……………………………………………………………..………………. 48 Table 1. Proportional meta-analysis of cardiac arrest rates (per 10,000 anaesthetic procedures) and survival (%) by time period and by country Human Development Index status in children……………………………………………….…………………………………………... 49 Table 2. Proportional meta-analysis of anaesthesia-related cardiac arrest rates (per 10,000 anaesthetic procedures) according to age group and by time period and by country Human Development Index status……………………………………….………………………………… 50 Table 3. Anaesthesia-related cardiac arrest rates in children (all postnatal age groups; per 10,000 anaesthetic procedures) according to country Human Development Index (HDI) status and quartile in the studies from 2001-2022………………………………………..……………….….. 51 Table 4. Anaesthesia-related cardiac arrest survival up to 24 hours postoperative in children (all postnatal age groups; percentage - %) according to country Human Development Index (HDI) status and quartile in the studies from 2001-2022…………………………………………..…….. 52 eSupplementary Material……………………………..………………………………………… 53 eSupplementary Material A. Search strategy (up to July 30, 2022)……………...…..........……. 53 eSupplementary Material B…………………………………………………..…………………. 57 Table B.1. Standard forms used to extract information from the studies……….....................…… 57 eSupplementary Material C……………………………………………..………………………. 58 Table C.1. Critical appraisal of the results of anaesthesia-related cardiac arrest in children from included studies using the JBI Prevalence Critical Appraisal Checklist….……………………… 58 eSupplementary Material D………………...…………………………...………………………. 60 Fig. D.1. Pooled analysis of proportional random effects from anaesthesia-related cardiac arrest. A. All studies pre-2001: 0.00024 (95% CI: 0.000156-0.000342); B. All studies 2001-2022: 0.000296 (95% CI: 0.000193-0.00042)…………………………………………………………… 60 Fig. D.2. Pooled analysis of proportional random effects from anaesthesia-related cardiac arrest. A. High-Human Development Index (HDI) pre-2001: 0.000229 (95% CI: 0.000142-0.000336); B. Low-HDI pre-2001: 0.000333 (95% CI: 0.000124-0.000643); C. High-HDI 2001-2022: 0.0002 (95% CI: 0.00011-0.000316); D. Low-HDI 2001-2022: 0.00096 (95% CI: 0.000443- 0.001674)……………………………………………………………………………………….. 61 Fig. D.3. Pooled analysis of proportional random effects from anaesthesia-related cardiac arrest survival. A. All studies pre-2001: 0.721116 (95% CI: 0.603-0.825418); B. All studies 2001- 2022: 0.804832 (95% CI: 0.707362-0.886524)……………………………………...……………. 62 Fig. D.4. Pooled analysis of proportional random effects from anaesthesia-related cardiac arrest survival. A. High-Human Development Index (HDI) pre-2001: 0.689933 (95% CI: 0.566313- 0.801113); B. Low-HDI pre-2001: 0.882938 (95% CI: 0.554462-0.998948); C. High-HDI 2001- 2022: 0.899074 (95% CI: 0.825547-0.954193); D. Low-HDI 2001-2022: 0.542649 (95% CI: 0.36694-0.713045)…………………………………………………………………………….….. 63 Fig. D.5. Pooled analysis of proportional random effects from anaesthesia-related cardiac arrest by age group. A. < 1 year pre-2001: 0.000635 (95% CI: 0.00027-0.001152); B. ≥ 1 year pre- 2001: 0.000174 (95% CI: 0.000081-0.000303); C. < 1 year 2001-2022: 0.001364 (95% CI: 0.000781-0.002109); D. ≥ 1 year 2001-2022: 0.00016 (95% CI: 0.000102-0.00023)….………… 64 Fig. D.6. Pooled analysis of proportional random effects from anaesthesia-related cardiac arrest by age group in high-Human Development Index. A. < 1 year pre-2001: 0.000554 (95% CI: 0.00019-0.001107); B. ≥ 1 year pre-2001: 0.000176 (95% CI: 0.000072-0.000326); C. < 1 year 2001-2022: 0.001069 (95% CI: 0.000541-0.001775); D. ≥ 1 year 2001-2022: 0.000148 (95% CI: 0.000097-0.000211)………………………………………………………………………….... 65 Fig. D.7. Pooled analysis of proportional random effects from anaesthesia-related cardiac arrest by age group in low-Human Development Index. A. < 1 year pre-2001: 0,001046 (95% CI: 0.000441-0.001909); B. ≥ 1 year pre-2001: 0.000167 (95% CI: 0.000033-0.000402); C. < 1 year 2001-2022: 0.003602 (95% CI: 0.000934-0.007996); D. ≥ 1 year 2001-2022: 0.000286 (95% CI 0.000039-0.00076)…………………………………………………………………………...…..... 66 eSupplementary Material E……………………………………..………………………………. 67 Table E.1. Description of the included studies on anaesthesia-related cardiac arrest and survival in children…………………………………………………………………………………………. 67 References……………………………..………………………………………………………….. 72 eSupplementary Material F…………………………..…………………………………………. 78 Table F.1. Anaesthesia-related cardiac arrest rates (per 10,000 anaesthetic procedures) according to age group by time period and by country Human Development Index (HDI) status (raw event rates provided)…………………………………………………………………….………………. 78 eSupplementary Material G…………………………..………………………………………… 79 Table G.1. Anaesthesia-related cardiac arrest rates in children (all postnatal age groups; per 10,000 anaesthetic procedures) according to country Human Development Index (HDI) status and quartile in the studies from pre-2001…………………………………………………………. 79 Normas de submissão do periódico Journal of Clinical Anesthesia 1 Anaesthesia-related cardiac arrest rates in children: a systematic review with meta- regression analysis and meta-analysis Running title: Anaesthesia-related cardiac arrest in children Teófilo Augusto A. Tiradentes (M.D.)1; José R. C. Braz (M.D., Ph.D.)1; Marluci Betini (Ph.D.)2; José E. Corrente (Ph.D.)3; Leandro G. Braz (M.D., Ph.D.)1* 1Anaesthesia Cardiac Arrest and Mortality Study Commission, Department of Surgical Specialties and Anaesthesiology, Botucatu Medical School, Sao Paulo State University - UNESP, Botucatu, SP, Brazil 2 Technical Division of Library and Documentation, Sao Paulo State University - UNESP, Botucatu, SP, Brazil 3Department of Biostatistics, Institute of Biosciences, Sao Paulo State University - UNESP, Botucatu, SP, Brazil Funding disclosure Leandro G. Braz received a fellowship from the National Council for Scientific and Technological Development – (CNPq) [grant number 307966/2021-6]. CNPq is a Brazilian governmental agency dedicated to promoting scientific research. No other external funding or other competing interests are declared. *Corresponding author: Department of Surgical Specialties and Anesthesiology, Botucatu Medical School, Sao Paulo State University - UNESP Professor Mario Rubens G. Montenegro Av., Botucatu, Sao Paulo State, Brazil E-mail address: leandro.braz@unesp.br Zip code: 18618-687; Phone: +55 14 3880 1412 2 Abstract Study objective: Children have a higher risk of anaesthesia-related cardiac arrest (CA) than adults undergoing surgeries. Studies have demonstrated gaps among countries in the quality of anaesthesia care. The Human Development Index (HDI) ranges from 0 to 1, representing the lowest and highest levels of development, respectively. We examined in mixed paediatric patients the relationship between the global anaesthesia-related CA rates with time and country HDI. Design: This was a systematic review with meta-regression and meta-analysis of observational studies that reported anaesthesia-related CA rates in children. We searched the PubMed/Medline, EMBASE, Scopus, LILACS, and Web of Science databases from inception to July 2022. Setting: 24-hour anaesthesia-related CA rates. Measurements: Anaesthesia-related CA rates were analysed by time and country HDI status in low-HDI (HDI<0.8) versus high-HDI countries (HDI≥0.8) in two periods (pre- 2001 versus 2001-2022). Main results: There was no relationship between anaesthesia-related CA rates and time (p=0.82), while the rates were inversely correlated with country HDI (p<0.0001). The rates in children did not change between the periods in either high- or low-HDI countries (p=0.71 and p=0.62, respectively) but were significantly higher in low-HDI than in high- HDI countries (9.6 versus 2.0 per 10,000 anaesthetic procedures; p<0.0001) in 2001- 2022. The anaesthesia-related CA rates were higher in children <1 year than ≥1 year in high-HDI countries (10.69 versus 1.48 per 10,000 anaesthetic procedures; p<0.0001) and in low-HDI countries (36.02 versus 2.86 per 10,000 anaesthetic procedures; p<0.0001) in 2001-2022. 3 Conclusion: Anaesthesia-related CA rate did not decline over the past 60 years. High and alarming anaesthesia-related CA rates among children younger than 1 year in high- and low-HDI countries, respectively, pose challenges for anaesthesiologists. The great differences in the anaesthesia-related CA rates between low- and high-HDI countries in the present century highlight a need to close a widening gap in anaesthesia safety care in these countries. Keywords: cardiac arrest; children; developed countries; developing countries; systematic review 4 Highlights Anaesthesia-related cardiac arrest rates have not declined over the past 60 years Anaesthesia-related cardiac arrest rates are associated with country HDI status These rates are higher in low-HDI than in high-HDI countries in the present century These rates in high- and low-HDI countries were higher in < 1 year than ≥ 1 year The survival proportions increased in high-HDI but decreased in low-HDI countries 5 1. Introduction Anaesthetic procedures in children are a large part of the daily clinical practice of anaesthesiologists [1]. A study in the USA demonstrated that approximately one in seven children are exposed to at least one anaesthetic procedure before the age of three years [2]. Cardiac arrest is one of the most catastrophic complications of paediatric anaesthesia and can lead to severe neurologic sequalae in survivors and death [3]. Children, mainly neonates and infants, have a higher risk of cardiac arrest and mortality than adults undergoing surgeries [4-10]. Children, parents, and anaesthesiologists fear paediatric anaesthesia because of the risk of acute morbidity, cardiac arrest, and mortality [11]. Intraoperative cardiac arrest is related not only to the patient’s condition/disease but also to factors such as inadequate risk assessment, inappropriate anaesthesia and surgery management, and human factor breakdown [12,13]. These factors reflect the quality of surgical and anaesthesia care provided, which stem from the level of socioeconomic and health development of each country [14]. Three studies in high- income countries demonstrated high perioperative cardiac arrest proportions attributed to anaesthesia-related causes in children in different time periods: 52% in 1994-1997 [15], 49% in 1998-2004 [16] and 48% in 2008-2016 [17]. The Human Development Index (HDI), which was defined by the United Nations Development Programme, is calculated based on rates of enrolment in higher education, literacy, per capita income, and life expectancy [18]. The HDI ranges from 0 to 1, representing the lowest and highest levels of development, respectively. The relation of surgery and anaesthesia safety to the country HDI has been described in previous studies [19-25]. 6 An estimated 1.7 billion children lacked access to safe and adequate quality surgical care worldwide in 2017 [26]. Most of these children were from low-income countries and made up a disproportionately large fraction of the population undergoing anaesthesia [11]. Three prior systematic reviews of global studies covering surgical patients of all age groups demonstrated that the anaesthesia-related cardiac arrest rates were inversely related to a country’s HDI and decreased over time only in high-HDI countries [20,21,23]. Therefore, there is still a lack of strong evidence regarding whether the rates of anaesthesia-related cardiac arrest in children have decreased over time and are related to a country’s HDI status. Considering the emergence of measures related to pharmacological and technological advances designed to improve anaesthesia safety in the last two decades and the early 2020s [27,28], we tested the hypothesis that the anaesthesia-related cardiac arrest rates in children have decreased in the present century (2001-2022) compared with the last century (pre-2001) and assumed that this decrease may be dissimilar in countries with different HDI values. In the present review, we aimed to examine in mixed paediatric surgical patients the relationship between the global rates of anaesthesia-related cardiac arrest and time and the HDI. 7 2. Methods We performed a systematic review (PROSPERO-CRD42021229919) using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [29]. The Cochrane Handbook for Systematic Reviews of Interventions guided our choice of methods [30]. 2.1 Outcomes definitions The primary outcomes of interest were the rates of anaesthesia-related cardiac arrest up to 24 hours postoperative in children separately by postnatal age group: younger than 1 year, aged or older than 1 year, and overall (all postnatal age groups). Most of the studies that described anaesthesia-related cardiac arrest events did not subdivide anaesthesia-related cardiac arrest events into entirely and partially anaesthesia-related cardiac arrests. However, some studies have subdivided anaesthesia-related cardiac arrest events. Entirely anaesthesia-related cardiac arrests were events exclusively attributed to anaesthesia personnel or the anaesthetic process (e.g., ventilatory depression with resultant hypoxemic cardiac arrest after intravenous opioid injection in a stable child patient without comorbidities). Partially anaesthesia-related cardiac arrests were events in which anaesthesia personnel or the anaesthetic process clearly played some role, but other factors related to the patient’s disease/condition or surgical procedure were reported that may have also played a role in the sequence of events (e.g., cardiac arrest immediately after the induction of anaesthesia in an unstable, hypovolemic child patient). In our review, we always included these arrest events as the sum of entirely and partially anaesthesia-related cardiac arrests. Anaesthesia-related cardiac arrests were classified by the authors of the studies included in this review. 8 The secondary outcomes were the anaesthesia-related cardiac arrest survival proportions up to 24 hours postoperative in children. 2.2 Search strategy and selection criteria The search strategy was developed (TAAT and LGB) in consultation with a research librarian (MB) with systematic review expertise. We systematically searched the medical literature to identify all studies that reported perioperative and/or anaesthesia- related cardiac arrest rates. We searched the PubMed/Medline, EMBASE, Scopus, LILACS, and Web of Science databases from inception to July 30th, 2022. The search was conducted using index terms (e.g., Medical Subject Headings [MeSH] and Emtree) and text words as well as word variants for “an(a)esthesia”, “cardiac arrest” and “mortality”, including an exhaustive list of synonyms. The search strategy was adapted to each database to retrieve related studies (eSupplementary Material A, which outlines our full search strategies). Two independent authors (TAAT and JRCB) screened the resulting list of titles and abstracts to identify whether the studies contained relevant information. Duplicate studies were excluded using EndNote (X9.2/2019 version, Clarivate Analytics, Philadelphia, PA, USA). Those studies deemed relevant were downloaded, and the full- text articles were reviewed by three independent authors (TAAT, JRCB, and LGB). These authors also reviewed the references of the included studies to identify additional relevant papers. No language restrictions were imposed, and translation services were used when necessary. 2.3 Inclusion and exclusion of studies Full-text studies were included if they fulfilled the following criteria: (1) observational studies; (2) studies that described anaesthesia-related cardiac arrest rates in 9 mixed paediatric surgical patients; and (3) studies with sufficient information to calculate the required variables. The following types of studies were excluded to ensure the reports represented a mixed paediatric patients: (1) those focused on specific age groups (e.g., only neonates); (2) those that had specific surgical procedures (e.g., only gastrointestinal surgery); (3) those that had a specific condition/disease (e.g., only cardiac patients) and (4) those that had a specific nature of surgery (e.g., only emergency surgery). These exclusion criteria prohibited a specific condition/disease, age group, nature of surgery or type of surgery from influencing the findings of this review. We included published full- text articles. Stand-alone abstracts and unpublished studies were excluded from this review. We did not impose a large sample size requirement that would exclude published studies from the smallest centres with lower paediatric surgical volumes. If more than one study reported data derived from the same population sampled during the period being studied, data were extracted from only the most recent and/or complete study. 2.4 Data extraction Two of the authors (TAAT and LGB) independently and in duplicate identified the studies to be included in the review based on the prespecified inclusion criteria. We used standard forms to extract relevant information in duplicate by two of the authors (TAAT and LGB) (see Table B.1 in eSupplementary Material B, which shows the standard forms used to extract information from the studies). Any discrepancies were resolved after a discussion between the two authors. In case of ongoing controversy, discrepancies were adjudicated by a third author (JRCB). If eligible articles had missing data, the authors were contacted for clarification. 10 2.5 Methodological quality of the included studies The methodological quality of the retrieved studies was assessed by two independent reviewers (TAAT and JRCB) before inclusion in the review. We used the Joanna Briggs Institute Critical Appraisal Checklist for Prevalence Studies, which assesses nine domains: target population; sampling; sample size; description of participants and setting; coverage of identified sample; methods for identifying the outcome; reliability of the outcome measurement; and appropriate statistical analysis and response rate [31]. The cut-off for study inclusion/exclusion in the qualitative analysis was determined through consensus between the reviewers. The cut-off point for the inclusion of a study in the review was a ‘yes’ answer to at least five questions (more than 50%). Any discrepancies were resolved by discussion between the two authors and adjudicated by a third author (LGB) in case of an ongoing disagreement. 2.6 Country Human Development Index To classify country HDI status, we used a cut-off of 0.8, which is widely accepted [18]. Similar to previous studies, countries with an HDI ≥ 0.8 were categorized as high, and those with an HDI < 0.8 were categorized as low [20-24]. Since the HDI of a country may change over time and studies often report data spanning several years, the HDI of each study was calculated as the mean of the HDI values in the first and last years studied [21-25]. If the HDI was not reported in the study for the period covered, the HDI on the closest available date was used. Considering that the interest of this study was the identification of changes in the rates of anaesthesia-related cardiac arrest in the current century in relation to the last century, we divided the study into two periods: pre-2001 (last century) and 2001-2022 11 (present century). Studies were allocated to one of the periods based on their median patient recruitment interval [21-25,32]. Additionally, we analysed anaesthesia-related cardiac arrest rates and the survival proportions up to 24 hours postoperative per quartile to detect possible regional differences in these rates and proportions and for further comparisons for country HDI. 2.7 Statistical analyses 2.7.1 Meta-regression analysis We conducted a meta-regression analysis with a fixed effects model, restricted estimated maximum likelihood, and an observed log-odds ratio to investigate whether the anaesthesia-related cardiac arrest rates changed significantly in relation to HDI and time, considering all studies together and separately from countries with low- and high-HDI values. HDI and time were evaluated as continuous variables. Stata 16 software (StataCorp LP, College Station, TX, USA) was used to perform the meta-regression analysis. The data were reported with their 95% confidence intervals (CIs). Statistical significance was defined as p < 0.05. 2.7.2 Proportional meta-analysis Using StatsDirect software (StatsDirect Ltd., Altrincham, Cheshire, UK), we applied a random effects model, with the inverse of the double arcsine square root method to stabilize variants [33], to calculate weighted event rates across all the studies included in the proportional meta-analysis [34]. For these analyses of anaesthesia-related cardiac arrest rates and survival proportions, both HDI (low- versus high-HDI) and time periods were dichotomized. 12 We subgrouped aggregate event rates per 10,000 anaesthetic procedures for each period (pre-2001 versus 2001-2022) and for each country HDI to calculate event rates for each period and by low- versus high-HDI. For the subgroup analyses, we tested for an interaction by fitting a generalized linear model with a binomial distribution adjusted by overdispersion [35] to assess whether effect sizes differed significantly across subgroups. The data were analysed using a multivariate forward stepwise logistic regression model and are reported as the odds ratios and 95% CIs to represent anaesthesia-related cardiac arrest rates and survival proportions separately by postnatal age group (younger than 1 year and aged or older than 1 year) in low- and high-HDI countries, and by time period. Publication bias was assessed using Egger’s test, which estimates the risk of bias using a linear regression approach [36]. The I2 statistic was used to quantify the degree of heterogeneity between studies [37]. Values greater than 40% suggest meaningful heterogeneity [38]. All procedures were performed using SAS for Windows v.9.4 (SAS Institute, Cary, NC, USA). A value of p < 0.05 was considered statistically significant. 13 3. Results Our search strategy identified 81,018 citations. After reviewing the titles and abstracts, we excluded 54,838 duplicate studies and 25,950 irrelevant studies. We retrieved 230 potentially relevant full-text articles for a detailed evaluation and identified 38 potentially relevant studies in the search of reference lists of related papers. Of these articles, 38 met the inclusion criteria. We assessed the methodological quality of the 38 studies. Five or more “yes” answers to nine questions were recorded for all studies (see Table C.1 in eSupplementary Material C). Thus, all 38 studies were included in the review (Fig. 1). 3.1 Included studies The earliest study included was published in 1961 [39] and the most recent was published in 2022 [40]. The studies originated from 23 countries on four continents. The studies included in the review covered a total of 5,493,489 anaesthetic procedures in children. The studies reported 1,001 anaesthesia-related cardiac arrests (eSupplementary Material D, Figs. D.1 to D.7, which show the forest plots summarizing the data; eSupplementary Material E, Table E.1, which describes the characteristics and designs of the studies included). Significant heterogeneity (> 40%) was observed in most of the event rates and proportions. 3.2 Meta-regression analysis of anaesthesia-related cardiac arrest rates Analysis of data from all studies, regardless of country HDI status, revealed no relationship between anaesthesia-related cardiac arrest rates and time (p = 0.82; Fig. 2A). Analysis of data from all studies revealed that anaesthesia-related cardiac arrest rates in 14 children (all postnatal age groups) were inversely correlated with country HDI (p < 0.0001; Fig. 2B). 3.3 Proportional meta-analysis of anaesthesia-related cardiac arrest rates Regardless of HDI status, anaesthesia-related cardiac arrest rates in children (all postnatal age groups) did not change significantly between the two periods (p = 0.59), and these rates did not differ significantly between high- and low-HDI countries in pre- 2001 (p = 0.76) but were significantly higher in low-HDI countries than in high-HDI countries (9.6 versus 2.0 per 10,000 anaesthetic procedures; p < 0.0001) in 2001-2022. Anaesthesia-related cardiac arrest rates did not change between the time periods in either high- or low-HDI countries (p = 0.71 and p = 0.62, respectively) (Table 1). 3.3.1 Anaesthesia-related cardiac arrest rate differences between postnatal age groups (< 1 year versus ≥ 1 year) according to time When the children were analysed according to postnatal age group, the odds ratios of anaesthesia-related cardiac arrest rates of all studies were 3.4-fold and 8.2-fold higher among children younger than 1 year than ≥ 1 year old in the pre-2001 (6.35 versus 1.74 per 10,000 anaesthetic procedures; p < 0.0001) and 2001-2021 periods (13.64 versus 1.60 per 10,000 anaesthetic procedures; p < 0.0001), respectively (Table 2; Table F.1 in eSupplementary Material F). 3.3.2 Anaesthesia-related cardiac arrest rate differences between postnatal age groups (< 1 year versus ≥ 1 year) according to time and country HDI The odds ratios of anaesthesia-related cardiac arrest rates in high-HDI countries was 3.1-fold and 8-fold higher among children younger than 1 year than among those ≥ 15 1 year of age in pre-2001 (5.54 versus 1.76 per 10,000 anaesthetic procedures ; p < 0.0001) and in 2001-2022 (10.69 versus 1.48 per 10,000 anaesthetic procedures; p < 0.0001), respectively, while the odds ratios in low-HDI countries of these rates were 6.6- fold and 7.3-fold higher among children younger than1 year than among those ≥ 1 year of age in pre-2001 (10.46 versus 1.67 per 10,000 anaesthetic procedures; p = 0.002) and in 2001-2022 (36.02 versus 2.86 per 10,000 anaesthetic procedures; p < 0.0001), respectively (Table 2; Table F.1 in eSupplementary Material F). 3.4 Proportional meta-analysis of anaesthesia-related cardiac arrest survival Regardless of HDI status, anaesthesia-related cardiac arrest survival proportions in children (all postnatal age groups) did not change significantly between the two periods (72.1% versus 80.4%; p = 0.32), but the survival proportions significantly increased in high-HDI countries (69.0% versus 89.9%; p = 0.003) while decreased significantly in low-HDI countries (88.3% versus 54.3%; p = 0.020) between the time periods (Table 1). The anaesthesia-related cardiac arrest survival proportions did not differ in the pre-2001 period between low- and high-HDI countries (p = 0.09) but were lower in low-HDI countries than in high-HDI countries in the 2001-2022 period (54.3% versus 89.9%; p < 0.0002) (Table 1). 3.4.1 Anaesthesia-related cardiac arrest survival differences between postnatal age groups (< 1 year versus ≥ 1 year) according to time and country HDI When the children were analysed according to postnatal age group, the odds ratios of anaesthesia-related cardiac arrest survival proportions in high- and low-HDI countries were similar between children younger than 1 year and children ≥ 1 year of age in high- 16 HDI countries pre-2001 (p = 0.43 and p = 0.95, respectively) and in 2001-2022 (p = 0.54 and p = 0.34, respectively). 3.5 Publication bias 3.5.1 Children (all postnatal age groups) In studies published before 2001, no publication bias was observed for rates of anaesthesia-related cardiac arrest (1.40, 95% CI: -0.08-2.89; p = 0.06) or survival proportions (-0.50, 95% CI: -2.44-1.43; p = 0.57). In studies published from 2001 to 2022, publication bias was observed for rates of anaesthesia-related cardiac arrest (2.11, 95% CI: 0.37-3.85; p = 0.02) and survival proportions (-1.91, 95% CI: -3.15-0.68; p = 0.005). Studies published before 2001 from high-HDI countries showed no publication bias for rates of anaesthesia-related cardiac arrest (1.38, 95% CI: -0.42-3.18; p = 0.12) or survival proportions (-0.78, 95% CI: -2.86-1.30; p = 0.40). Studies from high-HDI countries published in 2001-2022 showed no risk of publication bias for rates of anaesthesia-related cardiac arrest (2.20, 95% CI: -0.76-5.17; p = 0.13) or survival proportions (-1.37, 95% CI: -3.12-0.38; p = 0.11). Studies from low-HDI countries published in 2001-2022 showed publication bias for rates of anaesthesia-related cardiac arrest (2.22, 95% CI: 1.08-3.36; p = 0.003) and no publication bias for survival proportions (-2.76, 95% CI: -15.23-9.71; p = 0.57). 3.5.2 Children younger than 1 year Publication bias was observed for rates of anaesthesia-related cardiac arrest in studies published before 2001 (2.13, 95% CI: 1.33-2.93; p = 0.0003) and 2001-2022 (1.92, 95% CI: 0.16-3.68; p = 0.035). 17 There was publication bias for rates of anaesthesia-related cardiac arrest in studies published before 2001 from high-HDI countries (2.31, 95% CI: 1.17-3.44; p = 0.002). Studies from high-HDI countries published in 2001-2022 showed no risk of publication bias for rates of anaesthesia-related cardiac arrest (1.90, 95% CI: -1.16-4.95 = 0.18). 3.5.3 Children aged to or older than 1 year Publication bias was observed for rates of anaesthesia-related cardiac arrest in studies published before 2001 (2.05, 95% CI: 0.60-3.49; p = 0.011), but no publication bias was observed in studies published in 2001-2022 (0.17, 95% CI: -1.05-1.40; p = 0.76). There was publication bias for rates of anaesthesia-related cardiac arrest in studies published before 2001 from high-HDI countries (2.47, 95% CI: 0.62-4.32; p = 0.017). Studies from high-HDI countries in 2001-2022 showed no risk of publication bias for rates of anaesthesia-related cardiac arrest (-0.28, 95% CI: -2.22-1.65 = 0.76). We did not study publication bias in relation to other outcomes because few studies addressed each outcome in the proportion meta-analysis. The small number of studies would have rendered the findings unreliable [41]. 3.6 Analysing anaesthesia-related cardiac arrest rates in children (all postnatal age groups) according to country HDI and quartile pre-2001 Anaesthesia-related cardiac arrest rates according to country HDI and quartile in the pre-2001 period are shown in Table G.1 in eSupplementary Material G. A total of 100% of the reports (4) contained in the first quartile were based on data (1990s) from high-HDI countries in North America (the USA), Europe (France), and Asia (Japan) that described low anaesthesia-related cardiac arrest rates, ranging from 0.42 to 0.65 per 10,000 anaesthetic procedures [42-45]. The median anaesthesia-related cardiac arrest rate 18 was 2.88 per 10,000 anaesthetic procedures. In the fourth quartile, a total of 100% of the reports (4) were based on data (1950s-1980s) from high-HDI countries in North America (the USA), South America (Argentina), and Europe (Sweden) that described high anaesthesia-related cardiac arrest rates, ranging from 4.72 to 13.92 per 10,000 anaesthetic procedures [5,7,39,52]. 3.7 Analysing anaesthesia-related cardiac arrest rates per country HDI and quartile in 2001-2022 In the first quartile, with low anaesthesia-related cardiac arrest rates ranging from 0 to 0.71 per 10,000 anaesthetic procedures [53-58], a total of 100% of the reports (6) were based on data from high-HDI countries in North America (the USA), Asia (South Korea), and Europe (Scandinavian countries, Italy, the Netherlands, and England). The median anaesthesia-related cardiac arrest rate was 2.66 per 10,000 anaesthetic procedures. In the fourth quartile, with rates equal to or higher than 5.18 per 10,000 anaesthetic procedures [9,40,68-71], 83.3% of the reports (6) were based on data from low-HDI countries in Asia (Thailand and India) and Africa (South Africa, Nigeria, and Benin), while 16.7% were based on data from a high-HDI country in North America (the USA) (Table 3). 3.8 Anaesthesia-related cardiac arrest survival proportion up to 24 hours postoperative in children (all postnatal age groups) according to country HDI and quartile in studies from 2001 to 2022 In the first quartile, with low anaesthesia-related cardiac arrest survival proportions ranging from 0% to 53.8% [56,57,60,68,71], a total of 60% of the reports (5) were based on data from low-HDI countries in Asia (China and Thailand) and Africa 19 (Benin), while 40% of the reports were based on data from high-HDI countries in Europe (England and the Netherlands). The high median anaesthesia-related cardiac arrest survival proportion in 2001-2022 was 89.1%. In the third and fourth quartiles, with high anaesthesia-related cardiac arrest survival proportions ranging from 92.3% to 100% [17,55,58,59,61-63,65,69], 88.9% of the reports (8) were based on data from high-HDI countries in North America (the USA), Europe (France, Italy, and Germany), and Asia (South Korea), while 11.1% of the reports were based on data from a low-HDI country in South America (Brazil) (Table 4). 20 4. Discussion 4.1 Anaesthesia-related cardiac arrest rates in children: Implications of the evidence We demonstrated that the anaesthesia-related cardiac arrest rates were inversely related to country HDI and did not change over time in children. When comparing the period before 2001 with the period from 2001 to 2022, no significant change in the anaesthesia-related cardiac arrest rates was observed in high- or low-HDI countries. The anaesthesia-related cardiac arrest rates were higher in low-HDI countries than in high- HDI countries in 2001-2022 and were higher in children younger than 1 year than in older children in each period and in high- and low-HDI countries in both time periods. Comparing the results of our review with the findings from a previous worldwide systematic review of studies on anaesthesia-related cardiac arrest rates according to country HDI and two time periods (pre-1990 versus 1990-2020) in patients of all ages [23], we observed no important differences (95% CIs overlapped) between the reviews regarding the anaesthesia-related cardiac arrest rates among patients of all ages compared with those among children in similar time periods (1990-2020 versus 2001-2022) in high- HDI countries (1.12, 95% CI: 0.59-1.81 versus 2.00, 95% CI: 1.10-3.16, respectively) or low-HDI countries (5.56, 95% CI: 2.81-9.15 versus 9.60, 95% CI: 4.43-16.74, respectively). However, the anaesthesia-related cardiac arrest rates, in similar time periods (1990-2020 versus 2001-2022) were 9.5-fold higher in children younger than 1 year than in patients of all ages in high-HDI countries (10.69, 95% CI: 5.41-17.75 versus 1.12, 95% CI: 0.59-1.81, respectively) and 6.5-fold higher in low-HDI countries (36.02, 95% CI: 9.34-79.96 versus 5.56, 95% CI: 2.81-9.15, respectively), with 95% CIs that did not overlap, while apparent similar anaesthesia-related cardiac arrest rates were observed between children equal to or older than 1 year and patients of all ages in high-HDI countries (1.48, 95% CI: 0.97-2.11 versus 1.12, 95% CI: 0.59-1.81, respectively) and 21 low-HDI countries (2.86, 95% CI: 0.39-7.60 versus 5.56, 95% CI: 2.81-9.15, respectively), with overlapping 95% CIs. Our review demonstrated that anaesthesia for children equal to or older than 1 year of age in high-HDI countries has reached an adequate level of safety in the present century comparable to that of anaesthesia safety in patients of all ages in high-HDI countries, with an anaesthesia-related cardiac arrest rate of approximately 1 per 10,000 anaesthetic procedures [23]. This progress is due to advances in pharmacology, intensive education, expansion of neonatal and paediatric intensive care units, training, and centralization of care [11]. Data from the paediatric perioperative cardiac arrest (POCA) registry show that medication-related causes of anaesthesia-related cardiac arrests in children were decreased significantly by the discontinuation of halothane as the primary anaesthetic and the use of newer anaesthetics (sevoflurane and propofol) [15,16]. Studies from high-HDI countries [3,17,62,63,67,69] and low-HDI countries [9,51,60,65,71] in 2001-2022 demonstrated that the major mechanisms of anaesthesia- related cardiac arrest in children were respiratory and cardiovascular followed in a lesser proportion by medication-related and equipment-related mechanisms. However, in some low-HDI countries in Asia [68] and Africa [70], medication-related was still an important mechanism of anaesthesia-related cardiac arrest. Unfortunately, the decrease in anaesthesia-related cardiac arrests in children is not universal. Thus, high anaesthesia-related cardiac arrest rates were demonstrated in children younger than 1 year in high-and low-HDI countries in 2001-2020. These findings, in conjunction with the similar anaesthesia-related cardiac arrest rates in high- and low-HDI countries between the time periods, indicated no improvement in anaesthesia safety in children younger than 1 year in recent decades. The high anaesthesia-related cardiac arrest rate in children younger than 1 year, even in very high- 22 HDI countries, may be due to the increase in the number of surgical patients with a poorer ASA physical status, as demonstrated in a global systematic review of studies [20]. In addition, a study from a high-HDI country [72] reported that the total proportion of children aged less than 1 year, and the proportion of children aged less than 1 year with an ASA physical status of III to V were higher in 2014 to 2016 than in 2008 to 2013, confirming increases in underlying risks and complexity among paediatric surgical patients. In addition, studies have indicated increases in the numbers of preterm neonates with low and very low birth weights who were treated with surgical interventions, which were associated with high morbidity and mortality rates [67,73]. Analysis of anaesthesia-related cardiac arrest rates per quartile in children provided additional insights. We were able to detect regional differences in these event rates in the 2001-2022 period. The lowest anaesthesia-related cardiac arrest rates were reported in studies from high-HDI countries, while the highest rates were reported in studies from low-HDI countries. Reports from African countries have demonstrated alarmingly high rates, ranging from 29.64 to 156.25 per 10,000 anaesthetic procedures [40,70,71]. The highest anaesthesia-related cardiac arrest rate reported in a high-HDI country in the 2001-2022 period was documented in an American study [69]. The study was conducted in a tertiary paediatric hospital that performs surgical services in all areas. According to the authors, two of the major factors contributing to anaesthesia-related cardiac arrest events were present in large proportions in the surgical paediatric population: ASA physical status ≥ III and postnatal age ≤ 180 days. Anaesthesia for neonates and infants poses challenges even for experienced paediatric anaesthesiologists, especially if the neonate or infant was born prematurely or has comorbidities [67]. Neonates and infants differ from adults in their anatomy, 23 physiology, metabolism, and clearance of drugs. A small body size, limited cardiovascular reserves, organ system immaturity and underlying diseases determine marginal safety in perioperative management of neonates and infants, and not all anaesthesiologists have suitable training and experience in neonatal anaesthesia [11]. Neonates and infants are at increased risk of hypoxemia because of a smaller functional residual capacity, an increased heart rate and metabolic requirements compared with adults; additionally, the proportionally large head and tongue, restricted submandibular space, high location of the larynx in the neck, and a flaccid epiglottis present special challenges in airway management [74]. Studies have highlighted a high incidence of respiratory complications followed by cardiac arrest during airway management in neonates and infants, which is related to the high incidence of difficult tracheal intubation [17,75,76]. However, recent studies have demonstrated two major advances regarding this issue: the use of the videolaryngoscope, which has improved the first-attempt success rate of tracheal intubation and decreased the rate of airway complications [77], and apnoeic oxygenation, which has been shown to significantly prolong the safe apnoea time until desaturation in neonates and infants, and depends on adequate preoxygenation and the implementation of high-flow nasal oxygen during endotracheal intubation, which ensure adequate oxygenation during prolonged airway manipulation or difficult intubation [78]. Studies from high-HDI countries in the present century have demonstrated by univariable and multivariable analyses that an ASA physical status III-V is strongly associated with high anaesthesia-related cardiac arrest rates in children [3,16,17,63,69]. However, anaesthesia-related cardiac arrest still occurred in children with an ASA I physical status in 2001-2022 as demonstrated in reports from low-HDI countries [60,71] and high-HDI countries [16,59,63]. 24 Studies from high-HDI countries demonstrated higher anaesthesia-related cardiac arrest rates in cardiac surgeries than in noncardiac surgeries in children [3,17,69,79]. Children with heart disease have an increased frequency of anaesthesia-related cardiac arrest when undergoing cardiac surgery [79,80] and noncardiac surgery [79], with a higher risk in neonates and infants. Fortunately, these cardiac arrests were associated with high survival proportions [80]. Some studies showed by univariate analyses a significantly higher rate of anaesthesia-related cardiac arrest during emergency surgeries than in nonemergency surgeries [3,17,69]. However, after adjustment for ASA physical status ≥ III and age ≤ 6 months, a study demonstrated no significant correlation between anaesthesia-related cardiac arrest and emergency surgery [69]. As patients, surgical procedures and interventional techniques become more complex, more children are presenting for and receiving anaesthetic care outside of traditional operating room settings. Challenges related to patient safety in these locations include a remote location, limited and ergonomically inefficient anaesthesia workspace, poor lighting (because of the need for fluoroscopy), unfamiliar procedures and equipment, and lack of regular interactions with personnel in these areas [81]. A study in Spain demonstrated that 27% of anaesthesia-related cardiac arrests in children occurred in procedures performed outside of the operating room [3]. 4.2 Survival after anaesthesia-related cardiac arrest in children: Implications of the evidence Our review also demonstrated that the survival proportions after anaesthesia- related cardiac arrests were lower in low-HDI countries than in high-HDI countries in 2001-2022, and survival showed an opposite behaviour according to the country HDI 25 between the periods, with an increase in survival proportions in high-HDI countries and a decrease in low-HDI countries. Analysis of survival proportions per country HDI and quartile in children provided additional insights, showing regional differences in these event rates in the 2001-2022 period. The lowest survival proportions (less than 70%) were reported in studies from low-HDI countries, with a proportion of 71.4%, in Asia (China, Thailand, and Pakistan) and Africa (Benin and Nigeria), and in studies from high-HDI countries, with a proportion of 28.6%, in Europe (England and the Netherlands) [56,57,60,64,68,70,71]. The highest survival proportions (100%) were reported in studies from high-HDI countries, with a proportion of 83.3%, in Europe (France, Italy, and Germany) and Asia (South Korea), and in a study from a low-HDI country in South America (Brazil), with a proportion of 16.7% [17,55,59,61,62,65]. Anaesthesia-related cardiac arrest is distinct from other in-hospital cardiac arrests because it is witnessed by the anaesthesia and surgical teams; it also has special characteristics because the causal factors are, in most cases, already known. Patients are in an ideal environment for the management of cardiac arrest, with monitoring and venous access, and often already have a secured airway; additionally, a defibrillator and resuscitative drugs are often readily available. These factors allow the rapid commencement of resuscitative efforts, with greater possibilities of an increased rate of return of spontaneous circulation. The surgical theatre environment offers access to treatments that are not readily available outside the operating room, such as resuscitative thoracotomy, internal chest compressions, extracorporeal life support, cardiac catheterization, and massive transfusion. Location-specific differences in process-of-care measures were observed, suggesting variability in response times that may contribute to survival and neurological outcomes for anaesthesia-related cardiac arrest patients [82]. 26 The high rates of anaesthesia-related cardiac arrest and low proportions of survival in low-HDI countries likely reflect the poor quality of surgical and anaesthesia care in these countries. Indeed, these rates and proportions have not improved over time. The most complete study related to the neurological conditions of survivors after anaesthesia-related cardiac arrest in children was carried out in a high-HDI country (Spain) [3]. The authors of the study reported 15 anaesthesia-related cardiac arrests, with four deaths (27%), five survivors without neurological sequelae (33%) and six survivors with neurological sequelae (40%), of which three died within three months, and three survived, two of whom had transient neurological damage and recovered with physiotherapy and one of whom remained in a vegetative state. 4.3 Where and how to improve anaesthesia safety in children Our review findings indicated a large gap in the anaesthesia safety of children, mainly among neonates and infants, between low-HDI countries, especially in Africa, and high-HDI countries in the present century. The utilization of safety monitors for oxygen and anaesthetic gas administration, modern anaesthesia equipment, and new anaesthetics as well as neonatal and pediatric intensive care units are not routine in low- HDI countries [70,83,84]. A minimum target of 5 anaesthesiologists per 100,000 people is necessary to ensure anaesthesia services [85]. However, in 2015-2016, 43 countries, primarily in Africa, had ≤ 1 anaesthesiologist per 100,000 people, whereas high-HDI countries in Europe and the USA had a density of 18.6, and 20.82 anaesthesiologists per 100,000 people, respectively, and low-HDI countries in South America (Brazil) and Africa (South Africa) had a density of 10-14 anaesthesiologists per 100,000 people, while China and India had 3-4 and 1-2 anaesthesiologists per 100,000 people, respectively [85]. Thus, the 27 delivery of anaesthesia for children is, by necessity, in many African countries, the responsibility of a nonspecialist nonphysician anaesthesiologist, who typically receives a few months of training with little continuing education or opportunity for professional development. Thus, there is an urgent need to address the training needs of anaesthesiologists caring for children, mainly in low-HDI countries [86]. Strong collaboration between professional organizations from countries with substantially different HDI values, especially very high- and low-HDI countries, and financial incentives, plays important roles in reducing the shortage of anaesthesia providers in low-HDI countries and improving access to safe anaesthesia [86-89]. Programs focused on patient safety education should utilize new platforms for the spread of information, such as podcasts and video sites (e.g., YouTube and TikTok) [90]. Conferences hosted on virtual platforms can lead to a potentially great opportunity to develop online communities and virtual interactions through teleconferencing among health professionals from high- and low-HDI countries [90]. In high-HDI countries, anaesthesia-related cardiac arrest events may differ between centres that primarily include staff who are trained in paediatric or cardiac anaesthesia and centres with fewer specifically trained staff members, with lower incidences of these events [17]. From the literature, a minimum of 200 paediatric cases annually or 50 cases annually in children younger than 3 years of age are recommended to the anaesthesiologist to acquire sufficient competence [91]. In the absence of a formal certification process, the implementation of paediatric anaesthesiology fellowship training in academic centres could be especially important for anaesthesia safety in children. Continuing education for anaesthesiologists is highly recommended. Studies verified that a standardized simulation-based assessment could identify performance 28 gaps, informing opportunities for anaesthesiologists to improve the management of critical events [92,93]. In 2018, the World Federation of Societies of Anaesthesiologists and the World Health Organization together developed international standards for the safe practice of anaesthesia [94], while in 2021, the European Resuscitation Council Guidelines 2021: Paediatric Life Support were developed [95]. Their implementation must be promoted. Effective adverse event analysis among anaesthesiologists is very important and begins with the establishment of cultures of safety and teamwork in intraoperative and perioperative care, which facilitates the reporting of adverse events, with a nonpunitive approach to incident reporting and analysis and an open discussion of opportunities for process improvement and learning from error [90,96]. 4.4 Strengths and limitations of this review This review addressed the large disparities in anaesthesia-related cardiac arrest rates worldwide among children in the present century. Considering the high heterogeneity of the anaesthesia-related cardiac arrest rates among countries with substantially different HDI values, the distribution of these rates according to country HDI and quartiles was particularly important to determine regional differences. Many included studies were multicentre (26.3%). A multi-institutional anaesthesia database not only provides useful insights into injury mechanisms but also facilitates the development of universally applicable strategies [16]. Our review indicated the differences in anaesthesia-related cardiac arrest rates according to postnatal age group and country HDI between two time periods and discussed where and how to improve anaesthesia safety in children 29 There are some data limitations of this review that may have affected the findings. First, the data were derived from adverse event reports. As anaesthesia-related cardiac arrest is an infrequent event, slight fluctuations in the number of this adverse event might have impacted the frequencies of the reported adverse events in the different studies. Second, defining the contribution of anaesthesia to the occurrence of cardiac arrest is difficult and somewhat subjective [97]. Thus, differences among studies in the methodologies used to calculate anaesthesia-related cardiac arrest rate hindered the direct comparison of the various data from these studies. Third, selective reporting bias may have varied according to the medico-legal circumstances of each country. Thus, anaesthesia-related cardiac arrest events may be associated with malpractice issues; underreporting is likely in this situation. To minimize the risk of underreporting anaesthesia-related cardiac arrest, the reporting of these events needs to be mandatory, and summaries need to be prepared without assigning responsibility for the cardiac arrest [46]. Each summary should be submitted anonymously to an independent study commission for analysis. Commission members from outside the institution could provide a more unbiased evaluation of these cases than faculty members who are from the institution of the study [97]. Fourth, publication bias was observed for some outcomes assessed. However, there are no publication bias for rates of anaesthesia-related cardiac arrest in the studies from high-HDI countries in 2001-2022 and for survival proportions in the studies from high-HDI countries in both periods and in low-HDI countries in 2001- 2022. 4.5 Conclusions The current review demonstrated that the rates of anaesthesia-related cardiac arrest in a mixed surgical population of children have not declined over the past 60 years 30 and are inversely related to a country’s HDI. We identified a gap between children younger than one year and those equal to or older than one year, and between high- and low-HDI countries regarding anaesthesia-related cardiac arrest rates. Our review identified high and alarming rates of anaesthesia-related cardiac arrest among children younger than one year in high- and low-HDI countries. These findings pose challenges for anaesthesiologists in the present century. The great differences observed in the dynamics of anaesthesia-related cardiac arrest rates between low- and high-HDI countries highlight a need to close an increasing gap in anaesthesia care in children in these countries. Contributors Teófilo Augusto A. Tiradentes, José R. C. Braz and Leandro G. Braz conceived the research question and designed the protocol. Teófilo Augusto A. Tiradentes, Marluci Betini and Leandro G. Braz performed the literature search. Teófilo Augusto A. Tiradentes and José R. C. Braz selected the studies with the help of Leandro G. Braz. Teófilo Augusto A. Tiradentes and Leandro G. Braz extracted the data with the help of José R. C. Braz. Teófilo Augusto A. Tiradentes and José R. C. Braz assessed methodological quality with the help of Leandro G. Braz. Leandro G. Braz and Jose E. Corrente performed the statistical analysis. Teófilo Augusto A. Tiradentes and Leandro G. Braz designed the tables, figures, and eSupplementary Material. Teófilo Augusto A. Tiradentes, José R. C. Braz and Leandro G. Braz prepared the initial draft of the manuscript. All authors approved the final version of the manuscript. Acknowledgements None 31 Conflicts of Interest The authors have no competing interests to declare. References [1] Weiser TG, Haynes AB, Molina G, Lipsitz SR, Esquivel MM, Uribe-Leitz T, et al. Size and distribution of the global volume of surgery in 2012. Bull World Health Organ 2016;94:201-9F. https://doi.org/10.10.2471/BLT.15.159293. [2] Shi Y, Hu D, Rodgers EL, Katusic SK, Gleich SJ, Hanson AC, et al. 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B: Meta-regression analysis of the anaesthesia-related cardiac arrest rates by country Human Development Index (HDI) status; the relationship was significant (slope: -5.55, 95% CI: -8.107 to -3.003; p < 0.0001). 47 Fig. 1. 48 Fig. 2. 49 Table 1. Proportional meta-analysis of cardiac arrest rates (per 10,000 anaesthetic procedures) and survival (%) by time period and by country Human Development Index status in children Studies n Events n Children n Proportional meta-analysis (95% CI) p value for subgroup Per time period* High- vs. low-HDI High-HDI per time period* Low-HDI per time period* Anesthesia-related cardiac arrest Pre-2001 15 267 1,694,296 2.40 (1.56-3.42) 0.59 High-HDI 13 256 1,658,827 2.29 (1.42-3.36) 0.76 0.71 Low-HDI 2 11 35,469 3.33 (1.24-6.43) 0.62 2001-2022 23 734 3,799,193 2.96 (1.93-4.20) High-HDI 15 675 3,681,021 2.00 (1.10-3.16) < 0.0001 Low-HDI 8 59 118,172 9.60 (4.43-16.74) Anesthesia-related cardiac arrest survival Pre-2001 11 217 158 72.12 (60.30-82.54) 0.32 High-HDI 9 206 148 68.99 (56.63-80.11) 0.09 0.003 Low-HDI 2 11 10 88.29 (55.44-99.89) 0.020 2001-2022 19 702 628 80.48 (70.73-88.65) High-HDI 13 658 604 89.90 (82.55-95.41) 0.0002 Low-HDI 6 44 24 54.26 (36.69-71.30) CI = confidence interval; vs. = versus; HDI = Human Development Index; *Pre-2001 versus 2001-2022 50 Table 2. Proportional meta-analysis of anaesthesia-related cardiac arrest rates (per 10,000 anaesthetic procedures) according to age group and by time period and by country Human Development Index status Proportional meta-analysis (95% CI) Odds ratio (95% CI) p value Pre-2001 < 1 year 6.35 (2.70-11.52) 3.42 (2.29-5.09) < 0.0001 ≥ 1 year 1.74 (0.81-3.03) Ref 2001-2022 < 1 year 13.64 (7.81-21.09) 8.16 (6.19-10.75) < 0.0001 ≥ 1 year 1.60 (1.02-2.30) Ref High-HDI Pre-2001 < 1 year 5.54 (1.90-11.07) 3.09 (2.01-4.74) < 0.0001 ≥ 1 year 1.76 (0.72-3.26) Ref High-HDI 2001-2022 < 1 year 10.69 (5.41-17.75) 8.03 (5.96-10.81) < 0.0001 ≥ 1 year 1.48 (0.97-2.11) Ref Low-HDI Pre-2001 < 1 year 10.46 (4.41-19.09) 6.60 (1.93-22.54) 0.0026 ≥ 1 year 1.67 (0.33-4.02) Ref Low-HDI 2001-2022 < 1 year 36.02 (9.34-79.96) 7.32 (3.48-15.39) < 0.0001 ≥ 1 year 2.86 (0.39-7.60) Ref HDI: Human Development Index 51 Table 3. Anaesthesia-related cardiac arrest rates in children (all postnatal age groups; per 10,000 anaesthetic procedures) according to country Human Development Index (HDI) status and quartile in the studies from 2001-2022 Investigator/year of publication Country Anaesthesia- related cardiac arrest rate Quartile Hansen et al., 2019 (2015*) [53] Denmark, Sweden, Norway and Finland 0.00 Wolfler et al., 2020 (2015*) [54] Italy 0.00 Choi et al., 2014 (2008*) [55] South Korea 0.15 de Graaff et al., 2015 (2010*) [56] the Netherlands 0.57 Marcus, 2006 (2003*) [57] England 0.71 Haché et al., 2020 (2013*) [58] the USA 0.71 Q1: 0.71 Murat et al.,