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.

COVID-19-associated coagulopathy and acute kidney injury in critically ill patients.

OBJECTIVE: The incidence of thrombotic events and acute kidney injury is high in critically ill patients with COVID-19. We aimed to evaluate and compare the coagulation profiles of patients with COVID-19 developing acute kidney injury versus those who did not, during their intensive care unit stay. METHODS: Conventional coagulation and platelet function tests, fibrinolysis, endogenous inhibitors of coagulation tests, and rotational thromboelastometry were conducted on days 0, 1, 3, 7, and 14 following intensive care unit admission. RESULTS: Out of 30 patients included, 13 (43.4%) met the criteria for acute kidney injury. Comparing both groups, patients with acute kidney injury were older: 73 (60-84) versus 54 (47-64) years, p=0.027, and had a lower baseline glomerular filtration rate: 70 (51-81) versus 93 (83-106) mL/min/1.73m2, p=0.004. On day 1, D-dimer and fibrinogen levels were elevated but similar between groups: 1780 (1319-5517) versus 1794 (726-2324) ng/mL, p=0.145 and 608 (550-700) versus 642 (469-722) g/dL, p=0.95, respectively. Rotational thromboelastometry data were also similar between groups. However, antithrombin activity and protein C levels were lower in patients who developed acute kidney injury: 82 (75-92) versus 98 (90-116), p=0.028 and 70 (52-82) versus 88 (78-101) µ/mL, p=0.038, respectively. Mean protein C levels were lower in the group with acute kidney injury across multiple time points during their stay in the intensive care unit. CONCLUSION: Critically ill patients experiencing acute kidney injury exhibited lower endogenous anticoagulant levels. Further studies are needed to understand the role of natural anticoagulants in the pathophysiology of acute kidney injury within this population.

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

COVID-19-associated coagulopathy and acute kidney injury in critically ill patients

ABSTRACT Objective The incidence of thrombotic events and acute kidney injury is high in critically ill patients with COVID-19. We aimed to evaluate and compare the coagulation profiles of patients with COVID-19 developing acute kidney injury versus those who did not, during their intensive care unit stay. Methods Conventional coagulation and platelet function tests, fibrinolysis, endogenous inhibitors of coagulation tests, and rotational thromboelastometry were conducted on days 0, 1, 3, 7, and 14 following intensive care unit admission. Results Out of 30 patients included, 13 (43.4%) met the criteria for acute kidney injury. Comparing both groups, patients with acute kidney injury were older: 73 (60-84) versus 54 (47-64) years, p=0.027, and had a lower baseline glomerular filtration rate: 70 (51-81) versus 93 (83-106) mL/min/1.73m2, p=0.004. On day 1, D-dimer and fibrinogen levels were elevated but similar between groups: 1780 (1319-5517) versus 1794 (726-2324) ng/mL, p=0.145 and 608 (550-700) versus 642 (469-722) g/dL, p=0.95, respectively. Rotational thromboelastometry data were also similar between groups. However, antithrombin activity and protein C levels were lower in patients who developed acute kidney injury: 82 (75-92) versus 98 (90-116), p=0.028 and 70 (52-82) versus 88 (78-101) µ/mL, p=0.038, respectively. Mean protein C levels were lower in the group with acute kidney injury across multiple time points during their stay in the intensive care unit. Conclusion Critically ill patients experiencing acute kidney injury exhibited lower endogenous anticoagulant levels. Further studies are needed to understand the role of natural anticoagulants in the pathophysiology of acute kidney injury within this population.

Coagulation profile of COVID-19 patients admitted to the ICU: An exploratory study.

BACKGROUND: Coagulation abnormalities in COVID-19 patients have not been addressed in depth. OBJECTIVE: To perform a longitudinal evaluation of coagulation profile of patients admitted to the ICU with COVID-19. METHODS: Conventional coagulation tests, rotational thromboelastometry (ROTEM), platelet function, fibrinolysis, antithrombin, protein C and S were measured at days 0, 1, 3, 7 and 14. Based on median total maximum SOFA score, patients were divided in two groups: SOFA ≤ 10 and SOFA > 10. RESULTS: Thirty patients were studied. Some conventional coagulation tests, as aPTT, PT and INR remained unchanged during the study period, while alterations on others coagulation laboratory tests were detected. Fibrinogen levels were increased in both groups. ROTEM maximum clot firmness increased in both groups from Day 0 to Day 14. Moreover, ROTEM-FIBTEM maximum clot firmness was high in both groups, with a slight decrease from day 0 to day 14 in group SOFA ≤ 10 and a slight increase during the same period in group SOFA > 10. Fibrinolysis was low and decreased over time in all groups, with the most pronounced decrease observed in INTEM maximum lysis in group SOFA > 10. Also, D-dimer plasma levels were higher than normal reference range in both groups and free protein S plasma levels were low in both groups at baseline and increased over time, Finally, patients in group SOFA > 10 had lower plasminogen levels and Protein C ​​than patients with SOFA <10, which may represent less fibrinolysis activity during a state of hypercoagulability. CONCLUSION: COVID-19 patients have a pronounced hypercoagulability state, characterized by impaired endogenous anticoagulation and decreased fibrinolysis. The magnitude of coagulation abnormalities seems to correlate with the severity of organ dysfunction. The hypercoagulability state of COVID-19 patients was not only detected by ROTEM but it much more complex, where changes were observed on the fibrinolytic and endogenous anticoagulation system.

Intensive care unit patients' opinion on enrollment in clinical research: A multicenter survey.

BACKGROUND: In most emergency situations or severe illness, patients are unable to consent for clinical trial enrollment. In such circumstances, the decision about whether to participate in a scientific study or not is made by a legally designated representative. OBJECTIVE: To address the willingness of patients admitted to the intensive care unit (ICU) to be enrolled in a scientific study as volunteers, and to assess the agreement between patients' and their legal representatives' opinion concerning enrollment in a scientific study. METHODS: This survey was conducted in two hospitals in São Paulo, Brazil. Patients (≥18 years) with preserved cognitive functions accompanied by a surrogate admitted to the ICU were eligible for this study. A survey containing 28 questions for patients and 8 questions for surrogates was applied within the first 48h from ICU admission. The survey for patients comprised three sections: demographic characteristics, opinion about participation in clinical research and knowledge about the importance of research. The survey for legal representatives contained two sections: demographic characteristics and assessment of legal representatives' opinion in authorizing patients to be enrolled in research. RESULTS: Between January 2017 and May 2018, 208 pairs of ICU patients and their respective legal representatives answered the survey. Out of 208 ICU patients answering the survey, 73.6% (153/208) were willing to be enrolled in the study as volunteers. Of those patients, 65.1% (97/149) would continue participating in a research even if their legal representative did not support their enrollment. Agreement between patients' and surrogates' opinion concerning participation was poor [Kappa = 0.11 (IC95% -0.02 to 0.25)]. If a consent for study participation had been obtained, 69.1% (103/149) of patients would continue participating in the study until its conclusion, and 23.5% (35/149) would allow researchers to use data collected to date, but would withdraw from the study on that occasion. CONCLUSION: The majority of patients admitted to the ICU were willing to be enrolled in a scientific study as volunteers, also after a deferred informed consent procedure has been used. Nevertheless, contradictory opinions between patients and their and their legal representatives' concerning enrollment in a scientific study were often observed.

SEVERITAS: An externally validated mortality prediction for critically ill patients in low and middle-income countries.

OBJECTIVE: Severity of illness scores used in critical care for benchmarking, quality assurance and risk stratification have been mainly created in high-income countries. In low and middle-income countries (LMICs), they cannot be widely utilized due to the demand for large amounts of data that may not be available (e.g. laboratory results). We attempt to create a new severity prognostication model using fewer variables that are easier to collect in an LMIC. SETTING: Two intensive care units, one private and one public, from São Paulo, Brazil PATIENTS: An ICU for the first time. INTERVENTIONS: None. MEASUREMENTS AND MAINS RESULTS: The dataset from the private ICU was used as a training set for model development to predict in-hospital mortality. Three different machine learning models were applied to five different blocks of candidate variables. The resulting 15 models were then validated on a separate dataset from the public ICU, and discrimination and calibration compared to identify the best model. The best performing model used logistic regression on a small set of 10 variables: highest respiratory rate, lowest systolic blood pressure, highest body temperature and Glasgow Coma Scale during the first hour of ICU admission; age; prior functional capacity; type of ICU admission; source of ICU admission; and length of hospital stay prior to ICU admission. On the validation dataset, our new score, named SEVERITAS, had an area under the receiver operating curve of 0.84 (0.82 - 0.86) and standardized mortality ratio of 1.00 (0.91-1.08). Moreover, SEVERITAS had similar discrimination compared to SAPS-3 and better discrimination than the simplified TropICS and R-MPM. CONCLUSIONS: Our study proposes a new ICU mortality prediction model using simple logistic regression on a small set of easily collected variables may be better suited than currently available models for use in low and middle-income countries.

Systematic review of the literature on vitamin A and memory / Revisão sistemática da literatura sobre vitamina A e memória

Over the last 30 years, a variety of studies reporting the effects of vitamin A on memory havebeen published. Objective: To perform a rigorous systematic review of the literature on vitamin A and memory in order toorganize evidence-based data on the subject. Methods: Four authors carried out the systematic review in accordance withstrict guidelines. The terms ?vitamin A? OR ?retinol? OR ?retinoic acid? AND ?memory? OR ?cognition? OR ?Alzheimer? weresearched in virtually all medical research databases. Results: From 236 studies containing the key words, 44 were selectedfor this review, numbering 10 reviews and 34 original articles. Most studies used animal models for studying vitamin Aand cognition. Birds, mice and rats were more frequently employed whereas human studies accounted for only two reportson brain tissue from autopsies and one on the role of isotretinoin in cognition among individuals taking this medicationto treat acne. Conclusion: Vitamin A may be an important and viable complement in the treatment and prevention ofAlzheimer?s disease. Clinical trials are imperative and, at present, there is no evidence-based data to recommend vitaminA supplementation for the prevention or treatment of Alzheimer?s disease.

Uma variedade de artigos relatando efeitos da vitamina A na memória foram publicados nos últimos30 anos. Objetivo: Realizar uma revisão sistemática rigorosa da literatura sobre vitamina A e memória, visando organizar osdados com base em evidência. Métodos: Quatro autores realizaram a revisão sistemática de acordo com recomendaçõesespecíficas para tal. Os termos ?vitamin A? OR ?retinol? OR ?retinoic acid? AND ?memory? OR ?cognition? OR ?Alzheimer?foram utilizados na pesquisa de praticamente todas as bases de dados de publicações médicas. Resultados: Dos 236artigos contendo as palavras específicas de busca, 44 foram selecionados para esta revisão, sendo10 revisões e 34 artigosoriginais. A maioria dos estudos utilizou modelos animais para avaliar vitamina A e cognição. Pássaros, camundongos e ratosforam mais frequentemente utilizados, enquanto estudos com humanos foram apenas dois relatando dados de necrópsia decérebro humano e um sobre o papel da isotretinoína na cognição de indivíduos que estavam usando esta medicação paratratar acne. Conclusão: Vitamina A pode ser um complemento importante e viável no tratamento e prevenção da doença deAlzheimer. Estudos clínicos são imperativos e, no momento, não existe evidência científica que recomende suplementaçãode vitamina A na prevenção ou tratamento da doença de Alzheimer.

Risk factors for incidental parathyroidectomy during thyroidectomy.

UNLABELLED: Incidental parathyroidectomy is a common event in thyroid surgery. The literature shows a finding of parathyroid glands ranging from 6.4% to 31% in pathological specimens of the thyroid gland. OBJECTIVE: To collect the amount of parathyroid glands found in surgical specimens of thyroidectomy and correlate with the histopathological and demographic variables. METHODS: Retrospective study based on pathological reports of thyroidectomy from January 2007 to December 2008. RESULTS: 442 patients were submitted to total thyroidectomy, and 2.93% had parathyroid glands, which corresponded to 13 of this total. The presence of papillary thyroid carcinoma associated with incidental parathyroidectomy was 10.11%, compared to the benign lesion: 1.4%. CONCLUSION: Papillary thyroid carcinoma was the variable associated with increased number of incidental parathyroidectomy.

Fatores de risco de paratireoidectomia acidental em tireoidectomia / Risk factors for incidental parathyroidectomy during thyroidectomy

A paratireoidectomia acidental é um acontecimento frequente nas tireoidectomias. A literatura demonstra um achado de glândulas paratireoides, variando entre 6,4 por cento a 31 por cento em espécimes de exame anatomopatológico de glândula tireoide. OBJETIVO: Avaliar a quantidade de glândulas paratireoides encontradas em espécimes cirúrgicos de tireoidectomia e correlacionar com as variáveis demográficas e histopatológicas. MÉTODOS: Trabalho retrospectivo baseado nos laudos anatomopatológicos de tireoidectomias realizadas entre janeiro de 2007 a dezembro de 2008. RESULTADOS: O total de pacientes tireoidectomizados foi de 442, sendo o achado de glândulas paratireoides de 2,93 por cento, o que corresponde a 13 deste total. A presença de carcinoma papilífero de tireoide associado à paratireoidectomia acidental foi de 10,11 por cento contra a presença de patologia benigna de 1,4 por cento. CONCLUSÃO: O carcinoma papilífero de tireoide foi a variável associada ao maior número de paratireoidectomias acidentais.

Incidental parathyroidectomy is a common event in thyroid surgery. The literature shows a finding of parathyroid glands ranging from 6.4 percent to 31 percent in pathological specimens of the thyroid gland. OBJECTIVE: To collect the amount of parathyroid glands found in surgical specimens of thyroidectomy and correlate with the histopathological and demographic variables. METHODS: Retrospective study based on pathological reports of thyroidectomy from January 2007 to December 2008. RESULTS: 442 patients were submitted to total thyroidectomy, and 2.93 percent had parathyroid glands, which corresponded to 13 of this total. The presence of papillary thyroid carcinoma associated with incidental parathyroidectomy was 10.11 percent, compared to the benign lesion: 1.4 percent. CONCLUSION: Papillary thyroid carcinoma was the variable associated with increased number of incidental parathyroidectomy.

Systematic review of the literature on vitamin A and memory.

BACKGROUND: Over the last 30 years, a variety of studies reporting the effects of vitamin A on memory have been published. OBJECTIVE: To perform a rigorous systematic review of the literature on vitamin A and memory in order to organize evidence-based data on the subject. METHODS: Four authors carried out the systematic review in accordance with strict guidelines. The terms "vitamin A" OR "retinol" OR "retinoic acid" AND "memory" OR "cognition" OR "Alzheimer" were searched in virtually all medical research databases. RESULTS: From 236 studies containing the key words, 44 were selected for this review, numbering 10 reviews and 34 original articles. Most studies used animal models for studying vitamin A and cognition. Birds, mice and rats were more frequently employed whereas human studies accounted for only two reports on brain tissue from autopsies and one on the role of isotretinoin in cognition among individuals taking this medication to treat acne. CONCLUSION: Vitamin A may be an important and viable complement in the treatment and prevention of Alzheimer's disease. Clinical trials are imperative and, at present, there is no evidence-based data to recommend vitamin A supplementation for the prevention or treatment of Alzheimer's disease.

INTRODUÇÃO: Uma variedade de artigos relatando efeitos da vitamina A na memória foram publicados nos últimos 30 anos. OBJETIVO: Realizar uma revisão sistemática rigorosa da literatura sobre vitamina A e memória, visando organizar os dados com base em evidência. MÉTODOS: Quatro autores realizaram a revisão sistemática de acordo com recomendações específicas para tal. Os termos "vitamin A" OR "retinol" OR "retinoic acid" AND "memory" OR "cognition" OR "Alzheimer" foram utilizados na pesquisa de praticamente todas as bases de dados de publicações médicas. RESULTADOS: Dos 236 artigos contendo as palavras específicas de busca, 44 foram selecionados para esta revisão, sendo 10 revisões e 34 artigos originais. A maioria dos estudos utilizou modelos animais para avaliar vitamina A e cognição. Pássaros, camundongos e ratos foram mais frequentemente utilizados, enquanto estudos com humanos foram apenas dois relatando dados de necrópsia de cérebro humano e um sobre o papel da isotretinoína na cognição de indivíduos que estavam usando esta medicação para tratar acne. CONCLUSÃO: Vitamina A pode ser um complemento importante e viável no tratamento e prevenção da doença de Alzheimer. Estudos clínicos são imperativos e, no momento, não existe evidência científica que recomende suplementação de vitamina A na prevenção ou tratamento da doença de Alzheimer.