Dapagliflozin in patients with critical illness: rationale and design of the DEFENDER study.

BACKGROUND: Critical illness is a major ongoing health care burden worldwide and is associated with high mortality rates. Sodium-glucose cotransporter-2 inhibitors have consistently shown benefits in cardiovascular and renal outcomes. The effects of sodium-glucose cotransporter-2 inhibitors in acute illness have not been properly investigated. METHODS: DEFENDER is an investigator-initiated, multicenter, randomized, open-label trial designed to evaluate the efficacy and safety of dapagliflozin in 500 adult participants with acute organ dysfunction who are hospitalized in the intensive care unit. Eligible participants will be randomized 1:1 to receive dapagliflozin 10mg plus standard of care for up to 14 days or standard of care alone. The primary outcome is a hierarchical composite of hospital mortality, initiation of kidney replacement therapy, and intensive care unit length of stay, up to 28 days. Safety will be strictly monitored throughout the study. CONCLUSION: DEFENDER is the first study designed to investigate the use of a sodium-glucose cotransporter-2 inhibitor in general intensive care unit patients with acute organ dysfunction. It will provide relevant information on the use of drugs of this promising class in critically ill patients. CLINICALTRIALS.GOV REGISTRY: NCT05558098.

Dapagliflozin in patients with critical illness: rationale and design of the DEFENDER study / Dapagliflozina em pacientes com doença crítica: justificativa e desenho do estudo DEFENDER

ABSTRACT Background: Critical illness is a major ongoing health care burden worldwide and is associated with high mortality rates. Sodium-glucose cotransporter-2 inhibitors have consistently shown benefits in cardiovascular and renal outcomes. The effects of sodium-glucose cotransporter-2 inhibitors in acute illness have not been properly investigated. Methods: DEFENDER is an investigator-initiated, multicenter, randomized, open-label trial designed to evaluate the efficacy and safety of dapagliflozin in 500 adult participants with acute organ dysfunction who are hospitalized in the intensive care unit. Eligible participants will be randomized 1:1 to receive dapagliflozin 10mg plus standard of care for up to 14 days or standard of care alone. The primary outcome is a hierarchical composite of hospital mortality, initiation of kidney replacement therapy, and intensive care unit length of stay, up to 28 days. Safety will be strictly monitored throughout the study. Conclusion: DEFENDER is the first study designed to investigate the use of a sodium-glucose cotransporter-2 inhibitor in general intensive care unit patients with acute organ dysfunction. It will provide relevant information on the use of drugs of this promising class in critically ill patients. ClinicalTrials.gov registry: NCT05558098

RESUMO Antecedentes: A doença crítica é um importante ônus permanente da assistência médica em todo o mundo e está associada a altas taxas de mortalidade. Os inibidores do cotransportador de sódio-glicose do tipo 2 têm demonstrado consistentemente benefícios nos desfechos cardiovasculares e renais. Os efeitos dos inibidores do cotransportador de sódio-glicose do tipo 2 em doenças agudas ainda não foram devidamente investigados. Métodos: O DEFENDER é um estudo de iniciativa do investigador, multicêntrico, randomizado, aberto, desenhado para avaliar a eficácia e a segurança da dapagliflozina em 500 participantes adultos com disfunção orgânica aguda hospitalizados na unidade de terapia intensiva. Os participantes aptos serão randomizados 1:1 para receber 10mg de dapagliflozina e o tratamento padrão por até 14 dias ou apenas o tratamento padrão. O desfecho primário é um composto hierárquico de mortalidade hospitalar, início de terapia renal substitutiva e tempo de internação na unidade de terapia intensiva, até 28 dias. O monitoramento da segurança será rigoroso durante todo o estudo. Conclusão: O DEFENDER é o primeiro estudo desenvolvido para investigar o uso de um inibidor do cotransportador de sódio-glicose do tipo 2 em pacientes de unidade de terapia intensiva geral com disfunção orgânica aguda. O estudo fornecerá informações relevantes sobre o uso de medicamentos dessa classe promissora em pacientes críticos. Registro ClincalTrials.gov: NCT05558098

Histological, Laboratorial, and Clinical Benefits of an Optimized Maintenance Strategy of a Potential Organ Donor-A Rabbit Experimental Model.

INTRODUCTION: Most transplanted organs are obtained from brain-dead donors. Inflammation results in a higher rate of rejection. Objectives: The objective of this animal model of brain death (BD) was to evaluate the effect of the progressive institution of volume expansion, norepinephrine, and combined hormone therapy on clinical, laboratory, and histological aspects. Methods: Twenty rabbits were divided: A (control), B (induction of BD + infusion of crystalloid), C (BD + infusion of crystalloid and noradrenaline (NA)), and D (BD + infusion of crystalloid + vasopressin + levothyroxine + methylprednisolone + NA). The animals were monitored for four hours with consecutives analysis of vital signs and blood samples. The organs were evaluated by a pathologist. Results: In Group D, we observed fewer number and lesser volume of infusions (p = 0.032/0.014) when compared with groups B and C. Mean arterial pressure levels were higher in group D when compared with group B (p = 0.008). Group D had better glycemic control when compared with group C (p = 0.016). Sodium values were elevated in group B in relation to groups C and D (p = 0.021). In Group D, the organ perfusion was better. Conclusion: The optimized strategy of management of BD animals is associated with better hemodynamic, glycemic, and natremia control, besides reducing early signs of ischemia.

Incidence of Delirium in Critically Ill Patients With and Without COVID-19.

BACKGROUND: It is known that patients with COVID-19 are at high risk of developing delirium. The aim of the study was to compare the incidence of delirium between critically ill patients with and without a diagnosis of COVID-19. METHODS: This is a retrospective study conducted in a southern Brazilian hospital from March 2020 to January 2021. Patients were divided into two groups: the COVID-19 group consisted of patients with a diagnosis of COVID-19 confirmed by reverse transcription-polymerase chain reaction (RT-PCR) or serological tests who were admitted to specific ICUs. The non-COVID-19 group consisted of patients with other surgical and medical diagnoses who were admitted to non-COVID ICUs. All patients were evaluated daily using the Intensive Care Delirium Screening Checklist (ICDSC). The two cohorts were compared in terms of the diagnosis of delirium. RESULTS: Of the 649 patients who remained more than 48 h in the ICU, 523 were eligible for the study (COVID-19 group: 292, non-COVID-19 group: 231). There were 119 (22.7%) patients who had at least one episode of delirium, including 96 (32.9%) in the COVID-19 group and 23 (10.0%) in the non-COVID-19 group (odds ratio [OR] 4.42; 95% confidence interval [CI], 2.69 to 7.26; p < 0.001). Among patients mechanically ventilated for two days or more, the incidence of delirium did not differ between groups (COVID-19: 89/211, 42.1% vs non-COVID-19: 19/47, 40.4%; p = 0.82). Logistic regression showed that the duration of mechanical ventilation was the only independent factor associated with delirium (p = 0.001). CONCLUSION: COVID-19 can be associated with a higher incidence of delirium among critically ill patients, but there was no difference in this incidence between groups when mechanical ventilation lasted two days or more.

Antivirals for adult patients hospitalized with SARS-CoV-2 infection: A randomized, Phase II/III, multicenter, placebo-controlled, adaptive study, with multiple arms and stages. COALITION COVID-19 BRAZIL IX - REVOLUTIOn: protocol and statistical analysis plan. / Antivirais para pacientes adultos hospitalizados com infecção por SARS-CoV-2: Um estudo de Fase II/III, randomizado, multicêntrico, controlado por placebo, adaptativo, com múltiplos braços e estágios. COALITION COVID-19 BRAZIL IX - REVOLUTIOn: protocolo e plano de análise estatística.

Repurposed drugs are important in resource-limited settings because the interventions are more rapidly available, have already been tested safely in other populations and are inexpensive. Repurposed drugs are an effective solution, especially for emerging diseases such as COVID-19. The REVOLUTIOn trial has the objective of evaluating three repurposed antiviral drugs, atazanavir, daclatasvir and sofosbuvir, already used for HIV- and hepatitis C virus-infected patients in a randomized, placebo-controlled, adaptive, multiarm, multistage study. The drugs will be tested simultaneously in a Phase II trial to first identify whether any of these drugs alone or in combination reduce the viral load. If they do, a Phase III trial will be initiated to investigate if these medications are capable of increasing the number of days free respiratory support. Participants must be hospitalized adults aged ≥ 18 years with initiation of symptoms ≤ 9 days and SpO2 ≤ 94% in room air or a need for supplemental oxygen to maintain an SpO2 > 94%. The expected total sample size ranges from 252 to 1,005 participants, depending on the number of stages that will be completed in the study. Hence, the protocol is described here in detail together with the statistical analysis plan. In conclusion, the REVOLUTIOn trial is designed to provide evidence on whether atazanavir, daclatasvir or sofosbuvir decrease the SARS-CoV-2 load in patients with COVID-19 and increase the number of days patients are free of respiratory support. In this protocol paper, we describe the rationale, design, and status of the trial. ClinicalTrials.gov identifier: NCT04468087.

Os medicamentos reaproveitados são importantes em contextos de recursos limitados porque as intervenções estão mais rapidamente disponíveis, já foram testadas com segurança em outras populações e são, em geral, mais baratas. Os medicamentos reaproveitados são uma solução eficaz, especialmente para doenças emergentes, como a COVID-19. O estudo REVOLUTIOn visa avaliar três medicamentos antivirais reaproveitados: atazanavir, daclatasvir e sofosbuvir, já utilizados em pacientes infectados pelo HIV ou pelo vírus da hepatite C, em um estudo randomizado, controlado por placebo, adaptativo, multibraço e em múltiplos estágios. Os medicamentos serão testados simultaneamente em um ensaio de Fase II para primeiro identificar se algum deles, isoladamente ou em combinação, reduz a carga viral. Se reduzirem, será iniciado um estudo de Fase III para investigar se tais medicamentos são capazes de aumentar o número de dias sem suporte respiratório. Os participantes devem ser adultos hospitalizados com idade ≥ 18 anos com início dos sintomas ≤ 9 dias e saturação de oxigênio ≤ 94% em ar ambiente ou necessidade de oxigênio suplementar para manter saturação de oxigênio > 94%. O tamanho total esperado da amostra varia entre 252 e 1.005 participantes, dependendo do número de estágios que serão concluídos no estudo. Assim, o protocolo é aqui descrito em detalhes, juntamente do plano de análise estatística. Em conclusão, o estudo REVOLUTIOn foi concebido para fornecer evidências se o atazanavir, o daclatasvir ou o sofosbuvir reduzem a carga viral de SARS-CoV-2 em pacientes com COVID-19 e aumentam o número de dias em que os pacientes ficam sem suporte respiratório. Neste artigo de protocolo, descrevem-se a fundamentação, o desenho e a situação do ensaio. Identificador do ClinicalTrials.gov: NCT04468087.

Antivirais para pacientes adultos hospitalizados com infecção por SARS-CoV-2: Um estudo de Fase II/III, randomizado, multicêntrico, controlado por placebo, adaptativo, com múltiplos braços e estágios. COALITION COVID-19 BRAZIL IX - REVOLUTIOn: protocolo e plano de análise estatística / Antivirals for adult patients hospitalized with SARS-CoV-2 infection: A randomized, Phase II/III, multicenter, placebo-controlled, adaptive study, with multiple arms and stages. COALITION COVID-19 BRAZIL IX - REVOLUTIOn: protocol and statistical analysis plan

RESUMO Os medicamentos reaproveitados são importantes em contextos de recursos limitados porque as intervenções estão mais rapidamente disponíveis, já foram testadas com segurança em outras populações e são, em geral, mais baratas. Os medicamentos reaproveitados são uma solução eficaz, especialmente para doenças emergentes, como a COVID-19. O estudo REVOLUTIOn visa avaliar três medicamentos antivirais reaproveitados: atazanavir, daclatasvir e sofosbuvir, já utilizados em pacientes infectados pelo HIV ou pelo vírus da hepatite C, em um estudo randomizado, controlado por placebo, adaptativo, multibraço e em múltiplos estágios. Os medicamentos serão testados simultaneamente em um ensaio de Fase II para primeiro identificar se algum deles, isoladamente ou em combinação, reduz a carga viral. Se reduzirem, será iniciado um estudo de Fase III para investigar se tais medicamentos são capazes de aumentar o número de dias sem suporte respiratório. Os participantes devem ser adultos hospitalizados com idade ≥ 18 anos com início dos sintomas ≤ 9 dias e saturação de oxigênio ≤ 94% em ar ambiente ou necessidade de oxigênio suplementar para manter saturação de oxigênio > 94%. O tamanho total esperado da amostra varia entre 252 e 1.005 participantes, dependendo do número de estágios que serão concluídos no estudo. Assim, o protocolo é aqui descrito em detalhes, juntamente do plano de análise estatística. Em conclusão, o estudo REVOLUTIOn foi concebido para fornecer evidências se o atazanavir, o daclatasvir ou o sofosbuvir reduzem a carga viral de SARS-CoV-2 em pacientes com COVID-19 e aumentam o número de dias em que os pacientes ficam sem suporte respiratório. Neste artigo de protocolo, descrevem-se a fundamentação, o desenho e a situação do ensaio. Identificador do ClinicalTrials.gov:NCT04468087

ABSTRACT Repurposed drugs are important in resource-limited settings because the interventions are more rapidly available, have already been tested safely in other populations and are inexpensive. Repurposed drugs are an effective solution, especially for emerging diseases such as COVID-19. The REVOLUTIOn trial has the objective of evaluating three repurposed antiviral drugs, atazanavir, daclatasvir and sofosbuvir, already used for HIV- and hepatitis C virus-infected patients in a randomized, placebo-controlled, adaptive, multiarm, multistage study. The drugs will be tested simultaneously in a Phase II trial to first identify whether any of these drugs alone or in combination reduce the viral load. If they do, a Phase III trial will be initiated to investigate if these medications are capable of increasing the number of days free respiratory support. Participants must be hospitalized adults aged ≥ 18 years with initiation of symptoms ≤ 9 days and SpO2 ≤ 94% in room air or a need for supplemental oxygen to maintain an SpO2 > 94%. The expected total sample size ranges from 252 to 1,005 participants, depending on the number of stages that will be completed in the study. Hence, the protocol is described here in detail together with the statistical analysis plan. In conclusion, the REVOLUTIOn trial is designed to provide evidence on whether atazanavir, daclatasvir or sofosbuvir decrease the SARS-CoV-2 load in patients with COVID-19 and increase the number of days patients are free of respiratory support. In this protocol paper, we describe the rationale, design, and status of the trial. ClinicalTrials.gov identifier:NCT04468087

Resuscitation fluid practices in Brazilian intensive care units: a secondary analysis of Fluid-TRIPS. / Práticas de ressuscitação volêmica em unidades de terapia intensiva brasileiras: uma análise secundária do estudo Fluid-TRIPS.

OBJECTIVE: To describe fluid resuscitation practices in Brazilian intensive care units and to compare them with those of other countries participating in the Fluid-TRIPS. METHODS: This was a prospective, international, cross-sectional, observational study in a convenience sample of intensive care units in 27 countries (including Brazil) using the Fluid-TRIPS database compiled in 2014. We described the patterns of fluid resuscitation use in Brazil compared with those in other countries and identified the factors associated with fluid choice. RESULTS: On the study day, 3,214 patients in Brazil and 3,493 patients in other countries were included, of whom 16.1% and 26.8% (p < 0.001) received fluids, respectively. The main indication for fluid resuscitation was impaired perfusion and/or low cardiac output (Brazil: 71.7% versus other countries: 56.4%, p < 0.001). In Brazil, the percentage of patients receiving crystalloid solutions was higher (97.7% versus 76.8%, p < 0.001), and 0.9% sodium chloride was the most commonly used crystalloid (62.5% versus 27.1%, p < 0.001). The multivariable analysis suggested that the albumin levels were associated with the use of both crystalloids and colloids, whereas the type of fluid prescriber was associated with crystalloid use only. CONCLUSION: Our results suggest that crystalloids are more frequently used than colloids for fluid resuscitation in Brazil, and this discrepancy in frequencies is higher than that in other countries. Sodium chloride (0.9%) was the crystalloid most commonly prescribed. Serum albumin levels and the type of fluid prescriber were the factors associated with the choice of crystalloids or colloids for fluid resuscitation.

OBJETIVO: Descrever as práticas de ressuscitação volêmica em unidades de terapia intensiva brasileiras e compará-las com as de outros países participantes do estudo Fluid-TRIPS. MÉTODOS: Este foi um estudo observacional transversal, prospectivo e internacional, de uma amostra de conveniência de unidades de terapia intensiva de 27 países (inclusive o Brasil), com utilização da base de dados Fluid-TRIPS compilada em 2014. Descrevemos os padrões de ressuscitação volêmica utilizados no Brasil em comparação com os de outros países e identificamos os fatores associados com a escolha dos fluidos. RESULTADOS: No dia do estudo, foram incluídos 3.214 pacientes do Brasil e 3.493 pacientes de outros países, dos quais, respectivamente, 16,1% e 26,8% (p < 0,001) receberam fluidos. A principal indicação para ressuscitação volêmica foi comprometimento da perfusão e/ou baixo débito cardíaco (Brasil 71,7% versus outros países 56,4%; p < 0,001). No Brasil, a percentagem de pacientes que receberam soluções cristaloides foi mais elevada (97,7% versus 76,8%; p < 0,001), e solução de cloreto de sódio a 0,9% foi o cristaloide mais comumente utilizado (62,5% versus 27,1%; p < 0,001). A análise multivariada sugeriu que os níveis de albumina se associaram com o uso tanto de cristaloides quanto de coloides, enquanto o tipo de prescritor dos fluidos se associou apenas com o uso de cristaloides. CONCLUSÃO: Nossos resultados sugerem que cristaloides são usados mais frequentemente do que coloides para ressuscitação no Brasil, e essa discrepância, em termos de frequências, é mais elevada do que em outros países. A solução de cloreto de sódio 0,9% foi o cristaloide mais frequentemente prescrito. Os níveis de albumina sérica e o tipo de prescritor de fluidos foram os fatores associados com a escolha de cristaloides ou coloides para a prescrição de fluidos.

Brazilian guidelines for the management of brain-dead potential organ donors. The task force of the Associação de Medicina Intensiva Brasileira, Associação Brasileira de Transplantes de Órgãos, Brazilian Research in Critical Care Network, and the General Coordination of the National Transplant System. / Diretrizes brasileiras para o manejo de potenciais doadores de órgãos em morte encefálica. Uma força-tarefa composta por Associação de Medicina Intensiva Brasileira, Associação Brasileira de Transplantes de Órgãos, Brazilian Research in Critical Care Network e Coordenação Geral do Sistema Nacional de Transplantes.

OBJECTIVE: To contribute to updating the recommendations for brain-dead potential organ donor management. METHODS: A group of 27 experts, including intensivists, transplant coordinators, transplant surgeons, and epidemiologists, answered questions related to the following topics were divided into mechanical ventilation, hemodynamics, endocrine-metabolic management, infection, body temperature, blood transfusion, and checklists use. The outcomes considered were cardiac arrests, number of organs removed or transplanted as well as function / survival of transplanted organs. The quality of evidence of the recommendations was assessed using the Grading of Recommendations Assessment, Development, and Evaluation system to classify the recommendations. RESULTS: A total of 19 recommendations were drawn from the expert panel. Of these, 7 were classified as strong, 11 as weak and 1 was considered a good clinical practice. CONCLUSION: Despite the agreement among panel members on most recommendations, the grade of recommendation was mostly weak.

OBJETIVO: Fornecer recomendações para nortear o manejo clínico do potencial doador em morte encefálica. MÉTODOS: O presente documento foi formulado em dois painéis compostos por uma força tarefa integrada por 27 especialistas de diferentes áreas que responderam a questões dirigidas aos seguintes temas: ventilação mecânica, hemodinâmica, suporte endócrino-metabólico, infecção, temperatura corporal, transfusão sanguínea, e uso de checklists. Os desfechos considerados foram: parada cardíaca, número de órgãos retirados ou transplantados e função/sobrevida dos órgãos transplantados. A qualidade das evidências das recomendações foi avaliada pelo sistema Grading of Recommendations Assessment, Development, and Evaluation. RESULTADOS: Foram geradas 19 recomendações a partir do painel de especialistas. Dessas, 7 foram classificadas como fortes, 11 fracas e uma foi considerada boa prática clínica. CONCLUSÃO: Apesar da concordância entre os membros do painel em relação à maior parte das recomendações, o grau de recomendação é fraco em sua maioria.

Diretrizes brasileiras para o manejo de potenciais doadores de órgãos em morte encefálica. Uma força-tarefa composta por Associação de Medicina Intensiva Brasileira, Associação Brasileira de Transplantes de Órgãos, Brazilian Research in Critical Care Network e Coordenação Geral do Sistema Nacional de Transplantes / Brazilian guidelines for the management of brain-dead potential organ donors. The task force of the Associação de Medicina Intensiva Brasileira, Associação Brasileira de Transplantes de Órgãos, Brazilian Research in Critical Care Network, and the General Coordination of the National Transplant System

RESUMO Objetivo: Fornecer recomendações para nortear o manejo clínico do potencial doador em morte encefálica. Métodos: O presente documento foi formulado em dois painéis compostos por uma força tarefa integrada por 27 especialistas de diferentes áreas que responderam a questões dirigidas aos seguintes temas: ventilação mecânica, hemodinâmica, suporte endócrino-metabólico, infecção, temperatura corporal, transfusão sanguínea, e uso de checklists. Os desfechos considerados foram: parada cardíaca, número de órgãos retirados ou transplantados e função/sobrevida dos órgãos transplantados. A qualidade das evidências das recomendações foi avaliada pelo sistema Grading of Recommendations Assessment, Development, and Evaluation. Resultados: Foram geradas 19 recomendações a partir do painel de especialistas. Dessas, 7 foram classificadas como fortes, 11 fracas e uma foi considerada boa prática clínica. Conclusão: Apesar da concordância entre os membros do painel em relação à maior parte das recomendações, o grau de recomendação é fraco em sua maioria.

Abstract Objective: To contribute to updating the recommendations for brain-dead potential organ donor management. Methods: A group of 27 experts, including intensivists, transplant coordinators, transplant surgeons, and epidemiologists, answered questions related to the following topics were divided into mechanical ventilation, hemodynamics, endocrine-metabolic management, infection, body temperature, blood transfusion, and checklists use. The outcomes considered were cardiac arrests, number of organs removed or transplanted as well as function / survival of transplanted organs. The quality of evidence of the recommendations was assessed using the Grading of Recommendations Assessment, Development, and Evaluation system to classify the recommendations. Results: A total of 19 recommendations were drawn from the expert panel. Of these, 7 were classified as strong, 11 as weak and 1 was considered a good clinical practice. Conclusion: Despite the agreement among panel members on most recommendations, the grade of recommendation was mostly weak.

Brazilian guidelines for the management of brain-dead potential organ donors. The task force of the AMIB, ABTO, BRICNet, and the General Coordination of the National Transplant System.

OBJECTIVE: To contribute to updating the recommendations for brain-dead potential organ donor management. METHOD: A group of 27 experts, including intensivists, transplant coordinators, transplant surgeons, and epidemiologists, joined a task force formed by the General Coordination Office of the National Transplant System/Brazilian Ministry of Health (CGSNT-MS), the Brazilian Association of Intensive Care Medicine (AMIB), the Brazilian Association of Organ Transplantation (ABTO), and the Brazilian Research in Intensive Care Network (BRICNet). The questions were developed within the scope of the 2011 Brazilian Guidelines for Management of Adult Potential Multiple-Organ Deceased Donors. The topics were divided into mechanical ventilation, hemodynamic support, endocrine-metabolic management, infection, body temperature, blood transfusion, and use of checklists. The outcomes considered for decision-making were cardiac arrest, number of organs recovered or transplanted per donor, and graft function/survival. Rapid systematic reviews were conducted, and the quality of evidence of the recommendations was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. Two expert panels were held in November 2016 and February 2017 to classify the recommendations. A systematic review update was performed in June 2020, and the recommendations were reviewed through a Delphi process with the panelists between June and July 2020. RESULTS: A total of 19 recommendations were drawn from the expert panel. Of these, 7 were classified as strong (lung-protective ventilation strategy, vasopressors and combining arginine vasopressin to control blood pressure, antidiuretic hormones to control polyuria, serum potassium and magnesium control, and antibiotic use), 11 as weak (alveolar recruitment maneuvers, low-dose dopamine, low-dose corticosteroids, thyroid hormones, glycemic and serum sodium control, nutritional support, body temperature control or hypothermia, red blood cell transfusion, and goal-directed protocols), and 1 was considered a good clinical practice (volemic expansion). CONCLUSION: Despite the agreement among panel members on most recommendations, the grade of recommendation was mostly weak. The observed lack of robust evidence on the topic highlights the importance of the present guideline to improve the management of brain-dead potential organ donors.

Can the behavior of blood pressure after elevation of the positive end-expiratory pressure help to determine the fluid responsiveness status in patients with septic shock? / O comportamento da pressão arterial após elevação da pressão parcial positiva final pode auxiliar na determinação do status de fluido-responsividade em pacientes com choque séptico?

OBJECTIVE: To evaluate whether the decrease in blood pressure caused by the increase in the positive end-expiratory pressure corresponds to the pulse pressure variation as an indicator of fluid responsiveness. METHODS: This exploratory study prospectively included 24 patients with septic shock who were mechanically ventilated and subjected to three stages of elevation of the positive end-expiratory pressure: from 5 to 10cmH2O (positive end-expiratory pressure level 1), from 10 to 15cmH2O (positive end-expiratory pressure level 2), and from 15 to 20cmH2O (positive end-expiratory pressure level 3). Changes in systolic blood pressure, mean arterial pressure, and pulse pressure variation were evaluated during the three maneuvers. The patients were classified as responsive (pulse pressure variation ≥ 12%) or unresponsive to volume replacement (pulse pressure variation < 12%). RESULTS: The best performance at identifying patients with pulse pressure variation ≥ 12% was observed at the positive end-expiratory pressure level 2: -9% systolic blood pressure variation (area under the curve 0.73; 95%CI: 0.49 - 0.79; p = 0.04), with a sensitivity of 63% and specificity of 80%. Concordance was low between the variable with the best performance (variation in systolic blood pressure) and pulse pressure variation ≥ 12% (kappa = 0.42; 95%CI: 0.19 - 0.56). The systolic blood pressure was < 90mmHg at positive end-expiratory pressure level 2 in 29.2% of cases and at positive end-expiratory pressure level 3 in 41.63% of cases. CONCLUSION: Variations in blood pressure in response to the increase in positive end-expiratory pressure do not reliably reflect the behavior of the pulse pressure as a measure to identify the fluid responsiveness status.

OBJETIVO: Avaliar se a diminuição da pressão arterial provocada pela elevação da pressão parcial positiva final corresponde à variação da pressão de pulso como indicador de fluido-responsividade. MÉTODOS: Estudo de caráter exploratório que incluiu prospectivamente 24 pacientes com choque séptico ventilados mecanicamente e submetidos a três etapas de elevação da pressão parcial positiva final: de 5 para 10cmH2O (nível da pressão parcial positiva final 1), de 10 para 15cmH2O (nível da pressão parcial positiva final 2) e de 15 para 20cmH2O (nível da pressão parcial positiva final 3). Alterações da pressão arterial sistólica, da pressão arterial média e da variação da pressão de pulso foram avaliadas durante as três manobras. Os pacientes foram classificados como responsivos (variação da pressão de pulso ≥ 12%) e não responsivos a volume (variação da pressão de pulso < 12%). RESULTADOS: O melhor desempenho para identificar pacientes com variação da pressão de pulso ≥ 12% foi observado no nível da pressão parcial positiva final 2: variação de pressão arterial sistólica de -9% (área sob a curva de 0,73; IC95%: 0,49 - 0,79; p = 0,04), com sensibilidade de 63% e especificidade de 80%. A concordância foi baixa entre a variável de melhor desempenho (variação de pressão arterial sistólica) e a variação da pressão de pulso ≥ 12% (kappa = 0,42; IC95%: 0,19 - 0,56). A pressão arterial sistólica foi < 90mmHg no nível da pressão parcial positiva final 2 em 29,2% dos casos e em 41,6,3% no nível da pressão parcial positiva final 3. CONCLUSÃO: Variações da pressão arterial em resposta à elevação da pressão parcial positiva final não refletem de modo confiável o comportamento da variação da pressão de pulso para identificar o status da fluido-responsividade.

O comportamento da pressão arterial após elevação da pressão parcial positiva final pode auxiliar na determinação do status de fluido-responsividade em pacientes com choque séptico? / Can the behavior of blood pressure after elevation of the positive end-expiratory pressure help to determine the fluid responsiveness status in patients with septic shock?

RESUMO Objetivo: Avaliar se a diminuição da pressão arterial provocada pela elevação da pressão parcial positiva final corresponde à variação da pressão de pulso como indicador de fluido-responsividade. Métodos: Estudo de caráter exploratório que incluiu prospectivamente 24 pacientes com choque séptico ventilados mecanicamente e submetidos a três etapas de elevação da pressão parcial positiva final: de 5 para 10cmH2O (nível da pressão parcial positiva final 1), de 10 para 15cmH2O (nível da pressão parcial positiva final 2) e de 15 para 20cmH2O (nível da pressão parcial positiva final 3). Alterações da pressão arterial sistólica, da pressão arterial média e da variação da pressão de pulso foram avaliadas durante as três manobras. Os pacientes foram classificados como responsivos (variação da pressão de pulso ≥ 12%) e não responsivos a volume (variação da pressão de pulso < 12%). Resultados: O melhor desempenho para identificar pacientes com variação da pressão de pulso ≥ 12% foi observado no nível da pressão parcial positiva final 2: variação de pressão arterial sistólica de -9% (área sob a curva de 0,73; IC95%: 0,49 - 0,79; p = 0,04), com sensibilidade de 63% e especificidade de 80%. A concordância foi baixa entre a variável de melhor desempenho (variação de pressão arterial sistólica) e a variação da pressão de pulso ≥ 12% (kappa = 0,42; IC95%: 0,19 - 0,56). A pressão arterial sistólica foi < 90mmHg no nível da pressão parcial positiva final 2 em 29,2% dos casos e em 41,6,3% no nível da pressão parcial positiva final 3. Conclusão: Variações da pressão arterial em resposta à elevação da pressão parcial positiva final não refletem de modo confiável o comportamento da variação da pressão de pulso para identificar o status da fluido-responsividade.

Abstract Objective: To evaluate whether the decrease in blood pressure caused by the increase in the positive end-expiratory pressure corresponds to the pulse pressure variation as an indicator of fluid responsiveness. Methods: This exploratory study prospectively included 24 patients with septic shock who were mechanically ventilated and subjected to three stages of elevation of the positive end-expiratory pressure: from 5 to 10cmH2O (positive end-expiratory pressure level 1), from 10 to 15cmH2O (positive end-expiratory pressure level 2), and from 15 to 20cmH2O (positive end-expiratory pressure level 3). Changes in systolic blood pressure, mean arterial pressure, and pulse pressure variation were evaluated during the three maneuvers. The patients were classified as responsive (pulse pressure variation ≥ 12%) or unresponsive to volume replacement (pulse pressure variation < 12%). Results: The best performance at identifying patients with pulse pressure variation ≥ 12% was observed at the positive end-expiratory pressure level 2: -9% systolic blood pressure variation (area under the curve 0.73; 95%CI: 0.49 - 0.79; p = 0.04), with a sensitivity of 63% and specificity of 80%. Concordance was low between the variable with the best performance (variation in systolic blood pressure) and pulse pressure variation ≥ 12% (kappa = 0.42; 95%CI: 0.19 - 0.56). The systolic blood pressure was < 90mmHg at positive end-expiratory pressure level 2 in 29.2% of cases and at positive end-expiratory pressure level 3 in 41.63% of cases. Conclusion: Variations in blood pressure in response to the increase in positive end-expiratory pressure do not reliably reflect the behavior of the pulse pressure as a measure to identify the fluid responsiveness status.

Use of CPAP as an alternative to the apnea test during the determination of brain death in hypoxemic patients. Report of two cases. / Uso da CPAP como alternativa para realização do teste de apneia durante determinação da morte encefálica em pacientes hipoxêmicos. Relato de dois casos.

The apnea test, which involves disconnection from the mechanical ventilator, presents risks during the determination of brain death, especially in hypoxemic patients. We describe the performance of the apnea test without disconnection from the mechanical ventilator in two patients. The first case involved an 8-year-old boy admitted with severe hypoxemia due to pneumonia. He presented with cardiorespiratory arrest, followed by unresponsive coma due to hypoxic-ischemic encephalopathy. Two clinical exams revealed the absence of brainstem reflexes, and transcranial Doppler ultrasound revealed brain circulatory arrest. Three attempts were made to perform the apnea test, which were interrupted by hypoxemia; therefore, the apnea test was performed without disconnection from the mechanical ventilator, adjusting the continuous airway pressure to 10cmH2O and the inspired fraction of oxygen to 100%. The oxygen saturation was maintained at 100% for 10 minutes. Posttest blood gas analysis results were as follows: pH, 6.90; partial pressure of oxygen, 284.0mmHg; partial pressure of carbon dioxide, 94.0mmHg; and oxygen saturation, 100%. The second case involved a 43-year-old woman admitted with subarachnoid hemorrhage (Hunt-Hess V and Fisher IV). Two clinical exams revealed unresponsive coma and absence of all brainstem reflexes. Brain scintigraphy showed no radioisotope uptake into the brain parenchyma. The first attempt at the apnea test was stopped after 5 minutes due to hypothermia (34.9°C). After rewarming, the apnea test was repeated without disconnection from the mechanical ventilator, showing maintenance of the functional residual volume with electrical bioimpedance. Posttest blood gas analysis results were as follows: pH, 7.01; partial pressure of oxygen, 232.0mmHg; partial pressure of carbon dioxide, 66.9mmHg; and oxygen saturation, 99.0%. The apnea test without disconnection from the mechanical ventilator allowed the preservation of oxygenation in both cases. The use of continuous airway pressure during the apnea test seems to be a safe alternative in order to maintain alveolar recruitment and oxygenation during brain death determination.

Statistical analysis plan for a cluster-randomised trial assessing the effectiveness of implementation of a bedside evidence-based checklist for clinical management of brain-dead potential organ donors in intensive care units: DONORS (Donation Network to Optimise Organ Recovery Study).

BACKGROUND: The quality of clinical care of brain-dead potential organ donors may help reduce donor losses caused by irreversible or unreversed cardiac arrest and increase the number of organs donated. We sought to determine whether an evidence-based, goal-directed checklist for donor management in intensive care units (ICUs) can reduce donor losses to cardiac arrest. METHODS/DESIGN: The DONORS study is a multicentre, cluster-randomised controlled trial with a 1:1 allocation ratio designed to compare an intervention group (goal-directed checklist for brain-dead potential organ donor management) with a control group (standard ICU care). The primary outcome is loss of potential donors due to cardiac arrest. Secondary outcomes are the number of actual organ donors and the number of solid organs recovered per actual donor. Exploratory outcomes include the achievement of relevant clinical goals during the management of brain-dead potential organ donors. The present statistical analysis plan (SAP) describes all primary statistical procedures that will be used to evaluate the results and perform exploratory and sensitivity analyses of the trial. DISCUSSION: The SAP of the DONORS study aims to describe its analytic procedures, enhancing the transparency of the study. At the moment of SAP subsmission, 63 institutions have been randomised and were enrolling study participants. Thus, the analyses reported herein have been defined before the end of the study recruitment and database locking. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03179020. Registered on 7 June 2017.

Uso da CPAP como alternativa para realização do teste de apneia durante determinação da morte encefálica em pacientes hipoxêmicos. Relato de dois casos / Use of CPAP as an alternative to the apnea test during the determination of brain death in hypoxemic patients. Report of two cases

RESUMO O teste de apneia com desconexão do ventilador mecânico representa riscos durante a determinação da morte encefálica, especialmente em pacientes hipoxêmicos. Descrevemos a realização do teste de apneia sem desconexão do ventilador mecânico em dois pacientes. O primeiro caso é o de um menino de 8 anos, admitido com hipoxemia grave por pneumonia. Apresentou parada cardiorrespiratória, seguida de coma não responsivo por encefalopatia hipóxico-isquêmica. Dois exames clínicos constataram ausência de reflexos de tronco, e o Doppler transcraniano revelou parada circulatória encefálica. Realizaram-se três tentativas de teste de apneia, que foram interrompidas por hipoxemia, sendo então realizado teste de apneia sem desconexão do ventilador mecânico, ajustando a pressão contínua nas vias aéreas em 10cmH2O e fração inspirada de oxigênio em 100%. A saturação de oxigênio manteve-se em 100% por 10 minutos. A gasometria pós-teste foi a seguinte: pH de 6,90, pressão parcial de oxigênio em 284,0mmHg, pressão parcial de dióxido de carbono em 94,0mmHg e saturação de oxigênio em 100%. O segundo caso é de uma mulher de 43 anos, admitida com hemorragia subaracnóidea (Hunt-Hess V e Fisher IV). Dois exames clínicos constataram coma não responsivo e ausência de todos os reflexos de tronco. A cintilografia cerebral evidenciou ausência de captação de radioisótopos no parênquima cerebral. A primeira tentativa do teste de apneia foi interrompida após 5 minutos por hipotermia (34,9oC). Após reaquecimento, o teste de apneia foi repetido sem desconexão do ventilador mecânico, evidenciando-se manutenção do volume residual funcional com tomografia de bioimpedância elétrica. Gasometria pós-teste de apneia apresentava pH em 7,01, pressão parcial de oxigênio em 232,0mmHg, pressão parcial de dióxido de carbono 66,9mmHg e saturação de oxigênio em 99,0%. O teste de apneia sem desconexão do ventilador mecânico permitiu a preservação da oxigenação em ambos os casos. O uso de pressão contínua nas vias aéreas durante o teste de apneia parece ser uma alternativa segura para manter o recrutamento alveolar e a oxigenação durante determinação da morte encefálica.

ABSTRACT The apnea test, which involves disconnection from the mechanical ventilator, presents risks during the determination of brain death, especially in hypoxemic patients. We describe the performance of the apnea test without disconnection from the mechanical ventilator in two patients. The first case involved an 8-year-old boy admitted with severe hypoxemia due to pneumonia. He presented with cardiorespiratory arrest, followed by unresponsive coma due to hypoxic-ischemic encephalopathy. Two clinical exams revealed the absence of brainstem reflexes, and transcranial Doppler ultrasound revealed brain circulatory arrest. Three attempts were made to perform the apnea test, which were interrupted by hypoxemia; therefore, the apnea test was performed without disconnection from the mechanical ventilator, adjusting the continuous airway pressure to 10cmH2O and the inspired fraction of oxygen to 100%. The oxygen saturation was maintained at 100% for 10 minutes. Posttest blood gas analysis results were as follows: pH, 6.90; partial pressure of oxygen, 284.0mmHg; partial pressure of carbon dioxide, 94.0mmHg; and oxygen saturation, 100%. The second case involved a 43-year-old woman admitted with subarachnoid hemorrhage (Hunt-Hess V and Fisher IV). Two clinical exams revealed unresponsive coma and absence of all brainstem reflexes. Brain scintigraphy showed no radioisotope uptake into the brain parenchyma. The first attempt at the apnea test was stopped after 5 minutes due to hypothermia (34.9°C). After rewarming, the apnea test was repeated without disconnection from the mechanical ventilator, showing maintenance of the functional residual volume with electrical bioimpedance. Posttest blood gas analysis results were as follows: pH, 7.01; partial pressure of oxygen, 232.0mmHg; partial pressure of carbon dioxide, 66.9mmHg; and oxygen saturation, 99.0%. The apnea test without disconnection from the mechanical ventilator allowed the preservation of oxygenation in both cases. The use of continuous airway pressure during the apnea test seems to be a safe alternative in order to maintain alveolar recruitment and oxygenation during brain death determination.