Effects of therapeutic plasma exchange on a cohort of patients with severe coronavirus infection: real world evidence from Brazil

ABSTRACT Introduction: The therapeutic plasma exchange (TPE) controls the systemic cytokine level and might improve the immune response in patients with severe Coronavirus (COVID-19) infection. To date, in developing countries, no study has explored the effectiveness and risk factors in a population with severe COVID-19 exposed to the TPE. Method: We described the risk factors associated with survival rates higher than 28 days and length of stay (LOS) in the intensive care unit (ICU) shorter than 15 days. Severe COVID-19 cases treated with TPE were included, from August 2020 to June 2021. Survival analysis with Kaplan-Meier curves, log-rank tests and multivariate logistic regressions were conducted to assess patient-related factors that could predict a higher survival rate and the ICU LOS. Results: A total of 99 patients with severe COVID-19 who had received TPE were followed during their hospital stay and for 28 days after discharge. The sample was composed of men (63%) aged 56 ± 16 years. The overall survival rate at 28 days was 80%. The ICU LOS (p = 0.0165) and mechanical ventilation (MV) (p = 0.00008) were considered factors that could increase the risk of death. Patient-related factors that influenced the 28-day mortality were the smoking status (OR = 5.8; 95%CI 1.5, 22) and history of oncologic or non-malignant hematologic diseases (OR = 5.9; 95%CI 1.2, 29). Conclusion: Patients with severe COVID-19 exposed to the TPE were associated with a 20% risk of death in a 28-day observation window, appearing to be lower than previous treatments. Active smoking, cancer and immunosuppressive conditions should be considered as relevant variables to be controlled in future trials on the TPE and COVID-19.

Implante Valvar Transcateter em Pacientes com Estenose Valvar Aórtica: Uma Overview de Revisões Sistemáticas e Metanálise Incluindo Múltiplas Populações / Transcatheter Valve Replacement in Patients with Aortic Valve Stenosis: An Overview of Systematic Reviews and Meta-Analysis with Different Populations

Resumo Fundamento Ensaios clínicos randomizados (ECRs) e estudos observacionais compararam a eficácia e a segurança do implante valvar transcateter (TAVR) e da substituição cirúrgica da valva aórtica (SAVR) em pacientes com estenose aórtica grave. Objetivos Comparar TAVR e SAVR em pacientes com diferentes riscos cirúrgicos, características da população e diferentes válvulas protéticas transcateter. Métodos Uma overview das revisões sistemáticas (RSs) foi realizada seguindo um protocolo estruturado. Os resultados foram agrupados por risco cirúrgico, características da população e diferentes válvulas. Os ECRs foram reanalisados por meio de metanálises nas RSs, e os resultados foram resumidos por meio do método GRADE. O nível de significância estatística adotado foi de 5%. Resultados Em comparação com a SAVR, os pacientes com alto risco cirúrgico submetidos à TAVR tiveram um risco menor de ( odds ratio , intervalo de confiança de 95%, diferença absoluta de risco) fibrilação atrial (FA) (0,5, 0,29-0,86, -106/1000) e hemorragia com risco à vida (0,29, 0,2-0,42, -215/1000). Pacientes com risco cirúrgico intermediário apresentaram menor risco de FA (0,27, 0,23-0,33, -255/1.000), hemorragia com risco à vida (0,15, 0,12-0,19, -330/1.000) e insuficiência renal aguda (IRA) (0,4, 0,26-0,62, -21/1000). Pacientes com baixo risco cirúrgico tiveram menor risco de morte (0,58, 0,34-0,97, -16/1000), acidente vascular encefálico (AVE) (0,51, 0,28-0,94, -15/1000), FA (0,16, 0,12-0,2, -295/1000), hemorragia com risco à vida (0,17, 0,05-0,55, -76/1000) e IRA (0,27, 0,13-0,55, -21/1000) e tiveram maior risco de implante de marca-passo definitivo (IMD) (4,22, 1,27 -14.02, 141/1000). Os dispositivos de geração mais recente tiveram um risco menor de FA em comparação com as gerações mais antigas, e pacientes usuários de dispositivos expansíveis por balão não apresentaram riscos maiores de IMD. Conclusões Este artigo apresenta evidências de que pacientes com risco cirúrgico baixo, intermediário e alto apresentam melhores desfechos quando tratados com TAVR em comparação com a SAVR.

Abstract Background Randomized controlled trials (RCTs) and observational studies have compared the efficacy and safety of transcatheter aortic valve replacement (TAVR) and surgical aortic valve replacement (SAVR) in patients with severe aortic stenosis. Objectives Compare TAVR and SAVR in patients with different surgical risks, population characteristics, and different transcatheter prosthetic valves. Methods An overview of systematic reviews (SRs) was conducted following a structured protocol. Results were grouped by surgical risk, population characteristics, and different valves. RCTs in the SRs were reanalyzed through meta-analyses, and the results were summarized using the GRADE method. The adopted level of statistical significance was 5%. Results Compared to SAVR, patients with high surgical risk using TAVR had a lower risk of (odds ratio, 95% confidence interval, absolute risk difference) atrial fibrillation (AF) (0.5, 0.29-0.86, -106/1000) and life-threatening bleeding (0.29, 0.2-0.42, -215/1000). Patients with intermediate surgical risk had a lower risk of AF (0.27, 0.23-0.33, -255/1000), life-threatening bleeding (0.15, 0.12-0.19, -330/1000), and acute renal failure (ARF) (0.4, 0.26-0.62, -21/1000). Patients with low surgical risk had a lower risk of death (0.58, 0.34-0.97, -16/1000), stroke (0.51, 0.28-0.94, -15/1000), AF (0.16, 0.12-0.2, -295/1000), life-threatening bleeding (0.17, 0.05-0.55, -76/1000), and ARF (0.27, 0.13-0.55, -21/1000), and had a higher risk of permanent pacemaker implantation (PPI) (4.22, 1.27-14.02, 141/1000). Newer generation devices had a lower risk of AF than older generations, and patients using balloon-expandable devices did not experience higher risks of PPI. Conclusions This paper provides evidence that patients at low, intermediate, and high surgical risks have better outcomes when treated with TAVR compared with SAVR.

Risk of acute kidney injury and cost-effectiveness analysis comparing vancomycin and linezolid for the treatment of pediatric patients infected with Gram-positive bacteria / Risco de lesão renal aguda e custo-efetividade comparando vancomicina e linezolida para o tratamento de pacientes pediátricos infectados por bactérias Gram-positivas

Objective: This study aimed to compare the occurrence of acute kidney injury (AKI) in pediatric patients who used vancomycin (VAN) or linezolid (LNZ) to treat Gram-positive coccus (GPC) infections and to assess which treatment (VAN or LNZ) is the most cost-effective considering a pediatric hospital perspective. Methods: A retrospective cohort was performed to evaluate the occurrence of nephrotoxicity in pediatric patients without previous AKI, with GPC infections that used LNZ, or VAN monitored by serum VAN levels. Initially, descriptive analysis and Fisher and chisquare test were performed for this comparison. Then, a cost-effectiveness analysis was conducted through a decision tree model. The outcomes of interest were the rate of AKI related to the drug and the rate of admission to the intensive care unit (ICU) and cure. Results: In patients without previous acute kidney injury (AKI), 20% developed nephrotoxicity associated with VAN versus 9.6% in the LNZ group (p = 0.241). As there was no difference in nephrotoxicity between VAN andlinezolid (LNZ), vancomycin (VAN) monitored by serum VAN levels can optimize and rationalize the treatment. The nephrotoxicity risk criterion should not guide the prescription for LNZ. Furthermore, the average global cost of treatment with VAN was approximately R$ 43,000, while for LNZ, it was R$ 71,000. Conclusion: VAN was considered dominant (lower cost and greater effectiveness) over LNZ for treating patients with GPC infection.

Objetivo: Este estudo objetivou comparar a ocorrência de lesão renal aguda (LRA) em pacientes pediátricos que usaram vancomicina (VAN) ou linezolida (LNZ) para tratar infecções por cocos Gram-positivos (CGP) e avaliar qual tratamento (VAN ou LNZ) é o mais custo-efetivo considerando a perspectiva de um hospital pediátrico. Métodos: Foi realizada uma coorte retrospectiva para avaliar a ocorrência de nefrotoxicidade em pacientes pediátricos sem LRA prévia, com infecções por CGP que utilizaram LNZ ou VAN, combinada com vancocinemia. Para essa comparação, inicialmente foram realizados análise descritiva e testes de Fisher e qui-quadrado. Em seguida, foi realizada uma análise de custo-efetividade por meio de um modelo de árvore de decisão. Os desfechos de interesse foram a taxa de LRA relacionada ao medicamento e a taxa de internação em unidade de terapia intensiva e cura. Resultados: Nos pacientes sem LRA prévia, 20% deles desenvolveram nefrotoxicidade associada à VAN versus 9,6% no grupo LNZ (p = 0,241). Como não houve diferença na nefrotoxicidade entre VAN e LNZ, a VAN combinada com a vancocinemia pode otimizar e racionalizar o tratamento, e a prescrição de LNZ não deve ser guiada pelo critério de risco de nefrotoxicidade. Além disso, o custo médio global do tratamento com VAN foi de aproximadamente R$ 43.000, enquanto para LNZ foi de R$ 71.000. Conclusão: Assim, a VAN foi considerada dominante (menor custo e maior eficácia) sobre a LNZ para o tratamento de pacientes com infecção por CGP.

Effects of clinical heterogeneity on Pregnancy-Associated Breast Cancer survival: a systematic review with meta-analysis

Pregnancy-associated breast cancer is defined as a diagnosis of breast cancer during pregnancy or within 1 year of childbirth. Current evidence shows that Pregnancy-associated breast cancer is associated with poor prognosis; however, no systematic review has summarized and explored how baseline characteristics could impact survival. We aimed to explore the impact of breast cancer characteristics on death and disease relapse. A systematic review with meta-analyses was conducted by searching articles in the main databases (Medline, Embase, and Cochrane) and congress abstracts. Summarized death and disease-free survival hazard ratios were recalculated, and all meta-analyses used a random-effects model. Heterogeneity was reported using the I2 method. A total of 7143 studies were identified and only 30 studies were included. Pregnancy-associated breast cancer is associated with a 96% (HR 1.96; 95%CI 1.58­2.35) higher risk of death and 82% (HR 1.82; 95%CI 1.45­2.20) risk of death or disease relapse in comparison to a population of non-pregnancy-associated breast cancer or nulliparous breast cancer. Through sensitivity analyses, we identified that clinical outcomes were impacted, possibly due to Ki-67 levels, poorly differentiated tumors, and triple-negative breast cancer frequency in the study. As relevant sources of inconsistencies, such clinical cancer-related characteristics should be better investigated as potential confounders for upcoming Pregnancy-associated breast cancer therapeutic strategies.

PRAT tool: a harmonization of antimicrobial stewardship program interventions

Objective: The Antimicrobial Stewardship Program (ASP) in hospitals aims to promote the rational use of antimicrobials, providing better results to patients (increasing effectiveness and decreasing the risk of adverse events), hospital epidemiology (impact on levels of microbial resistance), and enable cost-effectiveness studies. Therefore, a tool (called PRAT­ antimicrobial therapy-related problem) is suggested in this paper. This unvalidated tool is the initial step towards organizing the antimicrobial therapy-related interventions to improve the use of this drug class, mainly by suggesting a harmonized registry process of ASP interventions. Methods: Therefore, this work presents the PRAT tool, developed based on the 10 years' experience of ASP at Pequeno Príncipe Hospital, inspired by the classification for drug-related problems of the Pharmaceutical Care Network Europe and according to a collaborative work using the Delphi technique. Results: This tool allows the identification and exact description of the antimicrobial therapy-related problem in 17 domains and 67 subcategories. Based on this identification, it suggests how to classify this problem (effectiveness, safety and need/indication) and what interventions can be conducted. Conclusion: This tool has the potential to establish a profile of antimicrobial-related problems, allowing prioritization to be visualized through the most (and least) interventions made in a given period, and might be useful in improving the quality of care through settings, by means of targeted educational interventions. Furthermore, if there is a harmonization of terminology for the classification of antimicrobial therapy-related problems, other hospitals can adopt it, and so the tool can improve research and comparison between institutions (benchmarking).

Análise de impacto orçamentário: uma revisão prática de conceitos e aplicações para o gestor / Budget impact analysis: a practical review of concepts and applications for the manager

Avaliações econômicas em saúde são essenciais para a tomada de decisão de gestores, visto que as inovações no setor nem sempre podem ser incorporadas conforme as expectativas dos usuários e da indústria. Logo, a análise de impacto orçamentário (AIO), uma das principais ferramentas da avaliação de tecnologias em saúde (ATS), permite aos gestores estimar o potencial número de indivíduos elegíveis para determinada tecnologia ao longo dos anos, prever quanto será necessário gastar para incorporar a tecnologia ou, eventualmente, se haverá economia nos cofres do pagador com a inclusão dela. Com a crescente publicação de artigos científicos sobre AIO no Brasil, surge a preocupação a respeito da qualidade metodológica desses estudos. O objetivo desta revisão é apresentar recomendações-chave para a elaboração de uma AIO adequada e expor a utilidade prática da AIO para a tomada de decisão de gestores de saúde por meio da análise de quatro estudos publicados. O formato de apresentação de uma AIO possibilita rápido entendimento e possui atributos que permitem evidenciar o maior valor de produtos e serviços de saúde junto aos tomadores de decisão em saúde, contribuindo para as melhores escolhas do ponto de vista clínico e econômico, nos sistemas público e privado. Porém, cabe ressaltar que alguns estudos ainda carecem de evidências de mundo real ou dados epidemiológicos para as estimativas e trabalham de maneira insuficiente as ferramentas para a redução de incertezas paramétricas.

Health economics evaluations are essential for decision makers, since innovations can not always be incorporated according to expectations of users and industry. Therefore, the Budget Impact Analysis (BIA), one of the main tools in Health Technology Assessment (HTA), allows managers to estimate the potential number of individuals eligible for a given technology over the years, to predict how much it will be necessary to spend for incorporate the technology or, eventually, whether there will be savings in the payer's coffers with the inclusion of the same. With the growing publication of scientific articles on BIA in Brazil, there is concern about the methodological quality of these studies. The objective of this review is to present key recommendations to elaborate an adequate BIA, commenting on four published studies, aiming to expose the practical utility of BIA for health managers. The presentation format of the BIA provides a quick understanding and has attributes that allows evidence of the highest value of health products and services among health decision makers, contributing to the best clinical and economic choices in public and private health systems. However, it should be noted in some studies there is still a lack of real-world evidence or epidemiological data for the estimates and insufficient using of tools to reduce parametric uncertainties.

Dose não usual de varfarina para alcançar rni terapêutica em uma criança de quatro meses: fatores de risco não genéticos ainda são um desafio / Unusual warfarin dose to achieve therapeutic inr in a 4-month old child: non-genetics risk factors are still a challenge

RESUMO Objetivo: Descreve se uma criança do sexo feminino, com quatro meses de idade, que necessitou de varfarina 0.7 mg/kg/dia (5 mg). Discutem se os fatores de risco clinicamente relevantes para prescrição de altas doses do anticoagulante em crianças. Descrição do caso: Em novembro de 2015, uma criança de 5 kg (36 semanas, pré termo) foi admitida no pronto atendimento por status epilepticus e febre. Diazepam, fenitoína e ceftriaxona foram prescritos inicialmente. A pesquisa no líquor revelou presença de sete leucócitos, 150 mg/dL de proteínas, 1 mg/dL de glucose e cocos Gram positivos. Em tomografia de crânio, foram observados sinais hipodensos em cerebelo, lobo temporal e núcleos de base à esquerda, sugerindo vasculite infecciosa por meningite pneumocócica. Após o quadro agudo da encefalite, a criança desenvolveu uma trombose e necessitou de anticoagulação com enoxaparina e, posteriormente, com varfarina. Dez dias de tratamento com o segundo fármaco foram necessários para atingir relação normalizada internacional (RNI) terapêutica, tendo sido realizados cinco ajustes de dose desde a primeira prescrição de varfarina. Comentários: Os fatores de risco determinantes para necessidade de doses maiores de varfarina foram idade e uso de nutrição enteral. Fenobarbital e prednisona também podem ter contribuído para o uso de uma das maiores doses de varfarina já relatadas na literatura. A despeito da importância dos testes de polimorfismo genético, os pediatras devem estar atentos para identificar os fatores que contribuem para a prescrição de maiores doses de varfarina, de forma a minimizar os riscos de trombose, reduzindo os custos com internação e exames laboratoriais.

ABSTRACT Objective: To report a case of a 4-month old girl that required 0.7 mg/kg/day (5 mg) of warfarin and discuss relevant risk factors for requiring higher doses. Case Description: In November 2015, a 5 kg female infant (36-week preterm) was admitted to the hospital due to status epilepticus and fever. Diazepam, phenytoin and ceftriaxone were prescribed. Cerebrospinal fluid contained 7 leukocytes, 150 mg/dL proteins, 1 mg/dL glucose and gram positive cocci were observed. Cranial tomography suggested hypodense signs in the cerebellum, right temporal lobe and left basal nuclei, which was consistent with pneumococcal meningitis-induced infectious vasculitis. She required low molecular weight heparin and warfarin for post-encephalitis thrombosis. About 10 days were required to achieve therapeutic INR, and warfarin was adjusted five times since the initial prescription. Comments: The risk factors for higher warfarin doses were age and enteral tube feeding. Phenobarbital and prednisone might also have contributed with one of the highest warfarin dose ever reported. Despite current importance given to genetics testing, clinicians should attempt to identify common contributing factors for prolonged non-therapeutic INR, to minimize the risk of coagulation, and to reduce costs of hospital stay and laboratory exams.

Relation between safe use of medicines and Clinical Pharmacy Services at Pediatric Intensive Care Units / Relação entre o uso seguro de medicamentos e Serviços de Farmácia Clínica em Unidades de Cuidados Intensivos Pediátricos

Abstract Objective: Clinical Pharmacy Services (CPS) are considered standard of care and is endorsed by the Joint Commission International, the American Academy of Pediatrics, and the American College of Clinical Pharmacy. In Brazil, single experiences have been discreetly arising and the importance of these services to children and adolescents care has led to interesting results, but certainly are under reported. This short report aims to discuss the effect of implementing a bedside CPS at a Brazilian Pediatric Intensive Care Unit (PICU). Methods: This is a cross-sectional study conducted in a 12 bed PICU community hospital, from Campo Largo/Brazil. Subjects with<18 years old admitted to PICU were included for descriptive analysis if received a CPS intervention. Results: Of 53 patients accompanied, we detected 141 preventable drug-related problems (DRPs) which were solved within clinicians (89% acceptance of all interventions). The most common interventions performed to improve drug therapy included: preventing incompatible intravenous solutions (21%) and a composite of inadequate doses (17% due to low, high and non-optimized doses). Among the top ten medications associated with DRPs, five were antimicrobials. By analyzing the correlation between DRPs and PICU length of stay, we found that 74% of all variations on length of stay were associated with the number of DRPs. Conclusions: Adverse drug reactions due to avoidable DRPs can be prevented by CPS in a multifaceted collaboration with other health care professionals, who should attempt to use active and evidence-based strategies to reduce morbidity related to medications.

Resumo Objetivo: Serviços de Farmácia Clínica (SFC) são considerados um padrão de atendimento à saúde e são endossados pela Joint Commission International, pela American Academy of Pediatrics e pelo American College of Clinical Pharmacy. No Brasil, experiências isoladas vêm surgindo discretamente e a importância desses serviços para o cuidado de crianças e adolescentes tem levado a resultados interessantes, mas que certamente são sub-relatados. Este artigo tem como objetivo discutir o efeito da implantação de um SFC à beira do leito em uma Unidade de Cuidados Intensivos Pediátricos (UCIP) brasileira. Métodos: Este é um estudo transversal, feito em uma UCIP de hospital da comunidade com 12 leitos, em Campo Largo, Brasil. Foram incluídos indivíduos com<18 anos internados em UCIP para análise descritiva, quando receberam uma intervenção do SFC. Resultados: De 53 pacientes acompanhados, foram detectados 141 Problemas Relacionados a Medicamentos (PRM) evitáveis que foram resolvidos em conjunto com os médicos (89% de aceitação de todas as intervenções). As intervenções mais comuns para melhorar a terapia medicamentosa foram: prevenção de soluções intravenosas incompatíveis (21%) e doses inadequadas (17% devido a doses baixas e altas). Entre os dez principais medicamentos associados à PRM, cinco eram antimicrobianos. Ao analisar a correlação entre o PRM e tempo de permanência na UCIP, verificamos que 74% de todas as variações no tempo de permanência eram associadas com o número de PRM. Conclusões: Reações adversas a medicamentos devido a PRM evitáveis podem ser prevenidas por SFC em uma colaboração multifacetada com outros profissionais de saúde. Tais problemas podem ser evitados por meio de estratégias ativas e baseadas em evidências para reduzir a morbidade relacionada a medicamentos.

A cost-effectiveness analysis of two different antimicrobial stewardship programs

Abstract There is a lack of formal economic analysis to assess the efficiency of antimicrobial stewardship programs. Herein, we conducted a cost-effectiveness study to assess two different strategies of Antimicrobial Stewardship Programs. A 30-day Markov model was developed to analyze how cost-effective was a Bundled Antimicrobial Stewardship implemented in a university hospital in Brazil. Clinical data derived from a historical cohort that compared two different strategies of antimicrobial stewardship programs and had 30-day mortality as main outcome. Selected costs included: workload, cost of defined daily doses, length of stay, laboratory and imaging resources used to diagnose infections. Data were analyzed by deterministic and probabilistic sensitivity analysis to assess model's robustness, tornado diagram and Cost-Effectiveness Acceptability Curve. Bundled Strategy was more expensive (Cost difference US$ 2119.70), however, it was more efficient (US$ 27,549.15 vs 29,011.46). Deterministic and probabilistic sensitivity analysis suggested that critical variables did not alter final Incremental Cost-Effectiveness Ratio. Bundled Strategy had higher probabilities of being cost-effective, which was endorsed by cost-effectiveness acceptability curve. As health systems claim for efficient technologies, this study conclude that Bundled Antimicrobial Stewardship Program was more cost-effective, which means that stewardship strategies with such characteristics would be of special interest in a societal and clinical perspective.

Effects of a bundled Antimicrobial Stewardship Program on mortality: a cohort study

Objectives: To assess a bundled Antimicrobial Stewardship Program and its effect on mortality. Data: Eight months of clinical electronic medical records and Antimicrobial Stewardship Program registries were used as source of data. Method: This is a historical cohort study conducted in a Brazilian University Hospital. Eligible patients were admitted to general wards or intensive care units and had an antimicrobial therapy prescribed and assessed by different strategies: Bundled Antimicrobial Stewardship Program (bundled intervention consisted of clinical pharmacist chart review, discussion with microbiologist and infectious disease physicians, local education and continuous follow-up) or Conventional Antimicrobial Stewardship Program (clinical pharmacist chart review and discussion with infectious disease physician). Primary outcome from this study was 30-day mortality, which was compared between groups, by using Kaplan-Meier survival curve and log-rank test. Other outcomes included Defined Daily Doses per 1000 patient-days and occurrence of resistant bacteria. Results: From 533 patients, 491 were eligible for the study, of which 191 patients were included to Antimicrobial Stewardship Program and 300 to Conventional strategy. In general, they were likely to be male and age was similar in groups (58.9 vs 55.5 years, p = 0.38). Likewise, Charlson Comorbidity Index was not statistically different between groups (2.6 vs 2.7, p = 0.2). Bloodstream site infections were frequently diagnosed in both groups (30.89% vs 26%, p = 0.24). Other less common sites of infections were central nervous system and lungs. The ASP group had higher survival rates (p < 0.01) and the risk difference was 10.8% (95% CI: 2.41-19.14). There were less Defined Daily Doses per 1000 patient-days (417 vs 557.2, p < 0.05) and higher rates of resistant bacteria identified in the ASP group (83% vs 17%). Conclusion: Bundled ASP was the most effective strategy, with reduced ...