Dapagliflozin for Critically Ill Patients With Acute Organ Dysfunction: The DEFENDER Randomized Clinical Trial.

Importance: Sodium-glucose cotransporter 2 (SGLT-2) inhibitors improve outcomes in patients with type 2 diabetes, heart failure, and chronic kidney disease, but their effect on outcomes of critically ill patients with organ failure is unknown. Objective: To determine whether the addition of dapagliflozin, an SGLT-2 inhibitor, to standard intensive care unit (ICU) care improves outcomes in a critically ill population with acute organ dysfunction. Design, Setting, and Participants: Multicenter, randomized, open-label, clinical trial conducted at 22 ICUs in Brazil. Participants with unplanned ICU admission and presenting with at least 1 organ dysfunction (respiratory, cardiovascular, or kidney) were enrolled between November 22, 2022, and August 30, 2023, with follow-up through September 27, 2023. Intervention: Participants were randomized to 10 mg of dapagliflozin (intervention, n = 248) plus standard care or to standard care alone (control, n = 259) for up to 14 days or until ICU discharge, whichever occurred first. Main Outcomes and Measures: The primary outcome was a hierarchical composite of hospital mortality, initiation of kidney replacement therapy, and ICU length of stay through 28 days, analyzed using the win ratio method. Secondary outcomes included the individual components of the hierarchical outcome, duration of organ support-free days, ICU, and hospital stay, assessed using bayesian regression models. Results: Among 507 randomized participants (mean age, 63.9 [SD, 15] years; 46.9%, women), 39.6% had an ICU admission due to suspected infection. The median time from ICU admission to randomization was 1 day (IQR, 0-1). The win ratio for dapagliflozin for the primary outcome was 1.01 (95% CI, 0.90 to 1.13; P = .89). Among all secondary outcomes, the highest probability of benefit found was 0.90 for dapagliflozin regarding use of kidney replacement therapy among 27 patients (10.9%) in the dapagliflozin group vs 39 (15.1%) in the control group. Conclusion and Relevance: The addition of dapagliflozin to standard care for critically ill patients and acute organ dysfunction did not improve clinical outcomes; however, confidence intervals were wide and could not exclude relevant benefits or harms for dapagliflozin. Trial Registration: ClinicalTrials.gov Identifier: NCT05558098.

A partial agonist of PPARγ prevents paclitaxel-induced peripheral neuropathy in mice, by inhibiting neuroinflammation.

BACKGROUND AND PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of paclitaxel, affecting 30-50% of patients. Increased survival and concern with patients' quality of life have encouraged the search for new tools to prevent paclitaxel-induced neuropathy. This study presents the glitazone 4-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-N-phenylbenzene-sulfonamide (TZD-A1) as a partial agonist of peroxisome proliferator-activated receptor γ (PPARγ), its toxicological profile and effects on paclitaxel-induced CIPN in mice. EXPERIMENTAL APPROACH: Interactions of TZD-A1 with PPARγ were analysed using in silico docking and in vitro reporter gene assays. Pharmacokinetics and toxicity were evaluated using in silico, in vitro and in vivo (C57Bl/6 mice) analyses. Effects of TZD-A1 on CIPN were investigated in paclitaxel-injected mice. Axonal and dorsal root ganglion damage, mitochondrial complex activity and cytokine levels, brain-derived neurotrophic factor (BDNF), nuclear factor erythroid 2-related factor 2 (Nrf2) and PPARγ, were also measured. KEY RESULTS: Docking analysis predicted TZD-A1 interactions with PPARγ compatible with partial agonism, which were corroborated by in vitro reporter gene assays. Good oral bioavailability and safety profile of TZD-A1 were shown in silico, in vitro and in vivo. Paclitaxel-injected mice, concomitantly treated with TZD-A1 by i.p. or oral administration, exhibited decreased mechanical and thermal hypersensitivity, effects apparently mediated by inhibition of neuroinflammation and mitochondrial damage, through increasing Nrf2 and PPARγ levels, and up-regulating BDNF. CONCLUSION AND IMPLICATIONS: TZD-A1, a partial agonist of PPARγ, provided neuroprotection and reduced hypersensitivity induced by paclitaxel. Allied to its safety profile and good bioavailability, TZD-A1 is a promising drug candidate to prevent and treat CIPN in cancer patients.

Cardiovascular Safety of Azithromycin in Patients Hospitalized With COVID-19: A Prespecified Pooled Analysis of the COALITION I and COALITION II Randomized Clinical Trials.

The cardiovascular safety from azithromycin in the treatment of several infectious diseases has been challenged. In this prespecified pooled analysis of 2 multicenter randomized clinical trials, we aimed to assess whether the use of azithromycin might lead to corrected QT (QTc) interval prolongation or clinically relevant ventricular arrhythmias. In the COALITION COVID Brazil I trial, 667 patients admitted with moderate COVID-19 were randomly allocated to hydroxychloroquine, hydroxychloroquine plus azithromycin, or standard of care. In the COALITION COVID Brazil II trial, 447 patients with severe COVID-19 were randomly allocated to hydroxychloroquine alone versus hydroxychloroquine plus azithromycin. The principal end point for the present analysis was the composite of death, resuscitated cardiac arrest, or ventricular arrhythmias. The addition of azithromycin to hydroxychloroquine did not result in any prolongation of the QTc interval (425.8 ± 3.6 ms vs 427.9 ± 3.9 ms, respectively, mean difference -2.1 ms, 95% confidence interval -12.5 to 8.4 ms, p = 0.70). The combination of azithromycin plus hydroxychloroquine compared with hydroxychloroquine alone did not result in increased risk of the primary end point (proportion of patients with events at 15 days 17.2% vs 16.0%, respectively, hazard ratio 1.08, 95% confidence interval 0.78 to 1.49, p = 0.65). In conclusion, in patients hospitalized with COVID-19 already receiving standard-of-care management (including hydroxychloroquine), the addition of azithromycin did not result in the prolongation of the QTc interval or increase in cardiovascular adverse events. Because azithromycin is among the most commonly prescribed antimicrobial agents, our results may inform clinical practice. Clinical Trial Registration: NCT04322123, NCT04321278.

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.

Trends in perioperative practices of high-risk surgical patients over a 10-year interval.

INTRODUCTION: In Brazil, data show an important decrease in morbi-mortality of high-risk surgical patients over a 10-year high. The objective of this post-hoc study was to evaluate the mechanism explaining this trend in high-risk surgical patients admitted to Brazilian ICUs in two large Brazilian multicenter cohort studies performed 10 years apart. METHODS: The patients included in the 2 cohorts studies published in 2008 and 2018 were compared after a (1:1) propensity score matching. Patients included were adults who underwent surgeries and admitted to the ICU afterwards. RESULTS: After matching, 704 patients were analyzed. Compared to the 2018 cohort, 2008 cohort had more postoperative infections (OR 13.4; 95%CI 6.1-29.3) and cardiovascular complications (OR 1.5; 95%CI 1.0-2.2), as well as a lower survival ICU stay (HR = 2.39, 95% CI: 1.36-4.20) and hospital stay (HR = 1.64, 95% CI: 1.03-2.62). In addition, by verifying factors strongly associated with hospital mortality, it was found that the risk of death correlated with higher intraoperative fluid balance (OR = 1.03, 95% CI 1.01-1.06), higher creatinine (OR = 1.31, 95% CI 1.1-1.56), and intraoperative blood transfusion (OR = 2.32, 95% CI 1.35-4.0). By increasing the mean arterial pressure, according to the limits of sample values from 43 mmHg to 118 mmHg, the risk of death decreased (OR = 0.97, 95% CI 0.95-0.98). The 2008 cohort had higher fluid balance, postoperative creatinine, and volume of intraoperative blood transfused and lower mean blood pressure at ICU admission and temperature at the end of surgery. CONCLUSION: In this sample of ICUs in Brazil, high-risk surgical patients still have a high rate of complications, but with improvement over a period of 10 years. There were changes in the management of these patients over time.

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

Clinical characteristics and outcomes of patients with COVID-19 admitted to the intensive care unit during the first and second waves of the pandemic in Brazil: a single-center retrospective cohort study.

OBJECTIVE: To describe and compare the clinical characteristics and outcomes of patients admitted to intensive care units during the first and second waves of the COVID-19 pandemic. METHODS: In this retrospective single-center cohort study, data were retrieved from the Epimed Monitor System; all adult patients admitted to the intensive care unit between March 4, 2020, and October 1, 2021, were included in the study. We compared the clinical characteristics and outcomes of patients admitted to the intensive care unit of a quaternary private hospital in São Paulo, Brazil, during the first (May 1, 2020, to August 31, 2020) and second (March 1, 2021, to June 30, 2021) waves of the COVID-19 pandemic. RESULTS: In total, 1,427 patients with COVID-19 were admitted to the intensive care unit during the first (421 patients) and second (1,006 patients) waves. Compared with the first wave group [median (IQR)], the second wave group was younger [57 (46-70) versus 67 (52-80) years; p<0.001], had a lower SAPS 3 Score [45 (42-52) versus 49 (43-57); p<0.001], lower SOFA Score on intensive care unit admission [3 (1-6) versus 4 (2-6); p=0.018], lower Charlson Comorbidity Index [0 (0-1) versus 1 (0-2); p<0.001], and were less frequently frail (10.4% versus 18.1%; p<0.001). The second wave group used more noninvasive ventilation (81.3% versus 53.4%; p<0.001) and high-flow nasal cannula (63.2% versus 23.0%; p<0.001) during their intensive care unit stay. The intensive care unit (11.3% versus 10.5%; p=0.696) and in-hospital mortality (12.3% versus 12.1%; p=0.998) rates did not differ between both waves. CONCLUSION: In the first and second waves, patients with severe COVID-19 exhibited similar mortality rates and need for invasive organ support, despite the second wave group being younger and less severely ill at the time of intensive care unit admission.

Neuroinflammation and hypersensitivity evidenced by the acute and 28-day repeated dose toxicity tests of ostrich oil in mice.

The ostrich oil (OO) has been topically used for decades to treat skin diseases. Its oral use has been encouraged through e-commerce advertising several health benefits to OO without scientific evidence on its safety or effectiveness. This study presents the chromatographic profile of a commercially available OO and its acute and 28-day repeated dose in vivo toxicological profiles. OO anti-inflammatory and antinociceptive effects were also investigated. Omega-9 (ω-9; oleic acid; 34.6%) and -6 (linoleic acid; 14.9%) were detected as OO main constituents. A high single dose of the OO (2 g/kg of ω-9) demonstrated no or low acute toxicity. However, when orally treated with OO (30-300 mg/kg of ω-9) for 28 consecutive days, mice exhibited altered locomotor and exploratory activities, hepatic damage, and increased hindpaw sensitivity accompanied by increased levels of cytokine and brain-derived neurotrophic factor in their spinal cords and brains. Lack of anti-inflammatory or antinociceptive activities was also evidenced in 15-day-OO treated mice. These results indicate that chronic consumption of OO induces hepatic injury, in addition to neuroinflammation and subsequent hypersensitivity and behavioural changes. Thus, there is no evidence to support OO use to treating illness in humans.

Characteristics, risk factors, and outcomes of bloodstream Candida infections in the intensive care unit: a retrospective cohort study.

OBJECTIVE: The main objective was to assess the clinical characteristics, associated factors, and outcomes of patients admitted to the ICU for candidemia. The secondary objective was to examine the relationship of candidemia with the length of stay and mortality. METHODS: The analysis was a retrospective single-center cohort study addressing the effect of invasive candidemia on outcomes. This study was performed in a medical-surgical ICU located in a tertiary private hospital in São Paulo, Brazil. Data was collected through the review of the hospital database. RESULTS: In total, 18,442 patients were included in our study, including 22 patients with candidemia. The median age was similar in patients with and without candidemia [67 (56-84) vs. 67 (51-80)]. Most patients were male, and the proportion of men was higher among patients with candidemia (77% vs. 55.3%). The rates of renal replacement therapy (40.9% vs. 3.3%), mechanical ventilation (63.6% vs. 29.6%), and parenteral nutrition (40.9% vs. 4.8%) were higher in patients with candidemia than in those without candidemia. The mortality rate (77.3% vs. 11.9%) and length of hospital stay [42 days (23.0-78.8) vs. 8 days (5.0-17.0)] were significantly higher in patients with candidemia. CONCLUSIONS: Patients with candidemia are prone to longer hospital stay and mortality. In addition, we found associations of candidemia with the use of invasive mechanical ventilation, renal replacement therapy, and parenteral nutrition.

Clinical characteristics and outcomes of patients with COVID-19 admitted to the intensive care unit during the first and second waves of the pandemic in Brazil: a single-center retrospective cohort study

ABSTRACT Objective To describe and compare the clinical characteristics and outcomes of patients admitted to intensive care units during the first and second waves of the COVID-19 pandemic. Methods In this retrospective single-center cohort study, data were retrieved from the Epimed Monitor System; all adult patients admitted to the intensive care unit between March 4, 2020, and October 1, 2021, were included in the study. We compared the clinical characteristics and outcomes of patients admitted to the intensive care unit of a quaternary private hospital in São Paulo, Brazil, during the first (May 1, 2020, to August 31, 2020) and second (March 1, 2021, to June 30, 2021) waves of the COVID-19 pandemic. Results In total, 1,427 patients with COVID-19 were admitted to the intensive care unit during the first (421 patients) and second (1,006 patients) waves. Compared with the first wave group [median (IQR)], the second wave group was younger [57 (46-70) versus 67 (52-80) years; p<0.001], had a lower SAPS 3 Score [45 (42-52) versus 49 (43-57); p<0.001], lower SOFA Score on intensive care unit admission [3 (1-6) versus 4 (2-6); p=0.018], lower Charlson Comorbidity Index [0 (0-1) versus 1 (0-2); p<0.001], and were less frequently frail (10.4% versus 18.1%; p<0.001). The second wave group used more noninvasive ventilation (81.3% versus 53.4%; p<0.001) and high-flow nasal cannula (63.2% versus 23.0%; p<0.001) during their intensive care unit stay. The intensive care unit (11.3% versus 10.5%; p=0.696) and in-hospital mortality (12.3% versus 12.1%; p=0.998) rates did not differ between both waves. Conclusion In the first and second waves, patients with severe COVID-19 exhibited similar mortality rates and need for invasive organ support, despite the second wave group being younger and less severely ill at the time of intensive care unit admission.

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.

Efeitos da solução balanceada em desfechos de curto prazo em pacientes com traumatismo craniencefálico: uma análise secundária do ensaio clínico randomizado BaSICS / Effects of balanced solution on short-term outcomes in traumatic brain injury patients: a secondary analysis of the BaSICS randomized trial

RESUMO Objetivo: Descrever os efeitos do uso de soluções balanceadas nos desfechos de curto prazo de pacientes com traumatismo craniencefálico incluídos no estudo BaSICS. Métodos: Os pacientes foram randomizados para receber solução salina 0,9% ou solução balanceada durante a internação em unidade de terapia intensiva. O desfecho primário foi mortalidade em 90 dias, já os desfechos secundários foram dias de vida e sem internação em unidade de terapia intensiva aos 28 dias. O desfecho primário foi avaliado por regressão logística bayesiana. O desfecho secundário foi avaliado usando regressão beta-binomial inflada de zeros bayesiana. Resultados: Incluímos 483 pacientes (236 no braço de solução salina 0,9% e 247 no braço de solução balanceada). Foram incluídos 338 pacientes (70%) com pontuação na escala de coma de Glasgow ≤ 12. A probabilidade geral de que soluções balanceadas estivessem associadas a maior mortalidade em 90 dias foi de 0,98 (RC de 1,48; ICr95% 1,04 - 2,09). Esse aumento de mortalidade foi particularmente perceptível em pacientes com pontuação na escala de coma de Glasgow abaixo de 6 no momento da inclusão (probabilidade de dano de 0,99). Soluções balanceadas foram associadas a -1,64 dia de vida e sem internação em unidade de terapia intensiva aos 28 dias (ICr95% -3,32 - 0,00) com probabilidade de dano de 0,97. Conclusão: Houve alta probabilidade de que soluções balanceadas estivessem associadas a alta mortalidade em 90 dias, menos dias de vida e sem internação em unidade de terapia intensiva aos 28 dias. ClinicalTrials.gov:NCT02875873

ABSTRACT Objective: To describe the effects of balanced solution use on the short-term outcomes of patients with traumatic brain injury enrolled in BaSICS trial. Methods: Patients were randomized to receive either 0.9% saline or balanced solution during their intensive care unit stay. The primary endpoint was 90-day mortality, and the secondary outcomes were days alive and free of intensive care unit stay at 28 days. The primary endpoint was assessed using Bayesian logistic regression. The secondary endpoint was assessed using a Bayesian zero-inflated beta binomial regression. Results: We included 483 patients (236 in the 0.9% saline arm and 247 in the balanced solution arm). A total of 338 patients (70%) with a Glasgow coma scale score ≤ 12 were enrolled. The overall probability that balanced solutions were associated with higher 90-day mortality was 0.98 (OR 1.48; 95%CrI 1.04 - 2.09); this mortality increment was particularly noticeable in patients with a Glasgow coma scale score below 6 at enrollment (probability of harm of 0.99). Balanced solutions were associated with -1.64 days alive and free of intensive care unit at 28 days (95%CrI -3.32 - 0.00) with a probability of harm of 0.97. Conclusion: There was a high probability that balanced solutions were associated with high 90-day mortality and fewer days alive and free of intensive care units at 28 days. ClinicalTrials.gov:NCT02875873

Analysis of mobility level of COVID-19 patients undergoing mechanical ventilation support: A single center, retrospective cohort study.

BACKGROUND: Severe coronavirus disease 2019 (COVID-19) patients frequently require mechanical ventilation (MV) and undergo prolonged periods of bed rest with restriction of activities during the intensive care unit (ICU) stay. Our aim was to address the degree of mobilization in critically ill patients with COVID-19 undergoing to MV support. METHODS: Retrospective single-center cohort study. We analyzed patients' mobility level, through the Perme ICU Mobility Score (Perme Score) of COVID-19 patients admitted to the ICU. The Perme Mobility Index (PMI) was calculated [PMI = ΔPerme Score (ICU discharge-ICU admission)/ICU length of stay], and patients were categorized as "improved" (PMI > 0) or "not improved" (PMI ≤ 0). Comparisons were performed with stratification according to the use of MV support. RESULTS: From February 2020, to February 2021, 1,297 patients with COVID-19 were admitted to the ICU and assessed for eligibility. Out of those, 949 patients were included in the study [524 (55.2%) were classified as "improved" and 425 (44.8%) as "not improved"], and 396 (41.7%) received MV during ICU stay. The overall rate of patients out of bed and able to walk ≥ 30 meters at ICU discharge were, respectively, 526 (63.3%) and 170 (20.5%). After adjusting for confounders, independent predictors of improvement of mobility level were frailty (OR: 0.52; 95% CI: 0.29-0.94; p = 0.03); SAPS III Score (OR: 0.75; 95% CI: 0.57-0.99; p = 0.04); SOFA Score (OR: 0.58; 95% CI: 0.43-0.78; p < 0.001); use of MV after the first hour of ICU admission (OR: 0.41; 95% CI: 0.17-0.99; p = 0.04); tracheostomy (OR: 0.54; 95% CI: 0.30-0.95; p = 0.03); use of extracorporeal membrane oxygenation (OR: 0.21; 95% CI: 0.05-0.8; p = 0.03); neuromuscular blockade (OR: 0.53; 95% CI: 0.3-0.95; p = 0.03); a higher Perme Score at admission (OR: 0.35; 95% CI: 0.28-0.43; p < 0.001); palliative care (OR: 0.05; 95% CI: 0.01-0.16; p < 0.001); and a longer ICU stay (OR: 0.79; 95% CI: 0.61-0.97; p = 0.04) were associated with a lower chance of mobility improvement, while non-invasive ventilation within the first hour of ICU admission and after the first hour of ICU admission (OR: 2.45; 95% CI: 1.59-3.81; p < 0.001) and (OR: 2.25; 95% CI: 1.56-3.26; p < 0.001), respectively; and vasopressor use (OR: 2.39; 95% CI: 1.07-5.5; p = 0.03) were associated with a higher chance of mobility improvement. CONCLUSION: The use of MV reduced mobility status in less than half of critically ill COVID-19 patients.

Ketamine use in critically ill patients: a narrative review. / Uso de cetamina em pacientes críticos: uma revisão narrativa.

Ketamine is unique among anesthetics and analgesics. The drug is a rapid-acting general anesthetic that produces an anesthetic state characterized by profound analgesia, preserved pharyngeal-laryngeal reflexes, normal or slightly enhanced skeletal muscle tone, cardiovascular and respiratory stimulation, and occasionally a transient and minimal respiratory depression. Research has demonstrated the efficacy of its use on anesthesia, pain, palliative care, and intensive care. Recently, it has been used for postoperative and chronic pain, as an adjunct in psychotherapy, as a treatment for depression and posttraumatic stress disorder, as a procedural sedative, and as a treatment for respiratory and/or neurologic clinical conditions. Despite being a safe and widely used drug, many physicians, such as intensivists and those practicing in emergency care, are not aware of the current clinical applications of ketamine. The objective of this narrative literature review is to present the theoretical and practical aspects of clinical applications of ketamine in intensive care unit and emergency department settings.

A cetamina é única entre os anestésicos e analgésicos. A droga é um anestésico geral de ação rápida que produz um estado anestésico caracterizado por analgesia profunda, reflexos faríngeolaríngeos preservados, tônus músculo esquelético normal ou ligeiramente aumentado, estimulação cardiovascular e respiratória e, ocasionalmente, insuficiência respiratória transitória e mínima. Estudos demonstraram a eficácia de seu uso em anestesia, na dor, em cuidados paliativos e em cuidados intensivos. Recentemente, tem sido empregada para dores pós-operatórias e crônicas, como coadjuvante em psicoterapia, como tratamento para depressão e transtorno de estresse pós-traumático, como sedativo para procedimentos cirúrgicos e como tratamento para condições clínicas respiratórias e/ou neurológicas. Apesar de ser um medicamento seguro e amplamente utilizado, muitos médicos, como intensivistas e emergencistas, não estão cientes das aplicações clínicas atuais da cetamina. O objetivo desta revisão bibliográfica narrativa é apresentar aspectos teóricos e práticos das aplicações clínicas da cetamina em ambientes de unidade de terapia intensiva e serviços de emergência.

Hierarchical endpoint analysis using win ratio in critical care: An exploration using the balanced solutions in intensive care study (BaSICS).

PURPOSE: To reanalyze the results of the Balanced Solutions in Intensive Care Study (BaSICS) through hierarchical endpoint analysis with win ratio. METHODS: All patients with full data in BaSICS trial were elected for the analysis. BaSICS compared balanced solutions (Plasma Lye 148) versus 0.9% saline in critically ill patients requiring fluid challenge. The win ratio was defined as a hierarchical endpoint of 90-day mortality, recepit of kidney replacement therapy, hospital length-of-stay (LOS), and intensive care unit (ICU) LOS. Both unstratified and stratified (by admission type: planned admission, unplanned admission with sepsis, and unplanned admission without sepsis) approaches were used. A subgroup analysis was performed in patients with traumatic brain injury. RESULTS: A total of 10,490 patients were included in the analysis, resulting in 27,587,566 unique combinations for unstratified WR. Unstratified Win ratio was 1.02 (95% confidence interval 0.97; 1.07), which was similar to stratified WR. No stratum in the stratified analysis resulted in significant results. Subgroup analysis confirmed the possible harm of balanced solutions in traumatic brain injury patients (WR 0.80; 95% confidence interval 0.64; 0.99). CONCLUSION: In this reanalysis of BaSICS, a win ratio analysis largely replicated the results of the main trial, yielding neutral results except for the subgroup of patients with traumatic brain injury where a signal of harm was found.

Statistical analysis of a cluster-randomized clinical trial on adult general intensive care units in Brazil: TELE-critical care verSus usual Care On ICU PErformance (TELESCOPE) trial. / Plano de análise estatística de um ensaio clínico randomizado em cluster em unidades de terapia intensiva geral adulto no Brasil: TELE-critical care verSus usual Care On ICU PErformance (TELESCOPE).

OBJECTIVE: The TELE-critical Care verSus usual Care On ICU PErformance (TELESCOPE) trial aims to assess whether a complex telemedicine intervention in intensive care units, which focuses on daily multidisciplinary rounds performed by remote intensivists, will reduce intensive care unit length of stay compared to usual care. METHODS: The TELESCOPE trial is a national, multicenter, controlled, open label, cluster randomized trial. The study tests the effectiveness of daily multidisciplinary rounds conducted by an intensivist through telemedicine in Brazilian intensive care units. The protocol was approved by the local Research Ethics Committee of the coordinating study center and by the local Research Ethics Committee from each of the 30 intensive care units, following Brazilian legislation. The trial is registered with ClinicalTrials. gov (NCT03920501). The primary outcome is intensive care unit length of stay, which will be analyzed accounting for the baseline period and cluster structure of the data and adjusted by prespecified covariates. Secondary exploratory outcomes included intensive care unit performance classification, in-hospital mortality, incidence of nosocomial infections, ventilator-free days at 28 days, rate of patients receiving oral or enteral feeding, rate of patients under light sedation or alert and calm, and rate of patients under normoxemia. CONCLUSION: According to the trial's best practice, we report our statistical analysis prior to locking the database and beginning analyses. We anticipate that this reporting practice will prevent analysis bias and improve the interpretation of the reported results.ClinicalTrials.gov registration: NCT03920501.

OBJETIVO: O ensaio TELE-critical Care verSus usual Care On ICU PErformance (TELESCOPE) visa avaliar se uma intervenção complexa por telemedicina em unidades de terapia intensiva, que se concentra em rondas multidisciplinares diárias realizadas por intensivistas a distância, reduzirá o tempo de permanência na unidade de terapia intensiva em comparação com os cuidados habituais. MÉTODOS: O TELESCOPE é um ensaio nacional, multicêntrico, controlado, aberto, randomizado em cluster. O estudo testa a eficácia de rondas multidisciplinares diárias realizadas por um intensivista por meio de telemedicina em unidades de terapia intensiva brasileiras. O protocolo foi aprovado pelo Comitê de Ética em Pesquisa local do centro coordenador do estudo e pelo Comitê de Ética em Pesquisa local de cada uma das 30 unidades de terapia intensiva, de acordo com a legislação brasileira. O ensaio está registado no ClinicalTrials.gov (NCT03920501). O desfecho primário é o tempo de internação na unidade de terapia intensiva, que será analisado considerando o período basal e a estrutura dos dados em cluster, sendo ajustado por covariáveis predefinidas. Os desfechos exploratórios secundários incluem a classificação de desempenho da unidade de terapia intensiva, a mortalidade hospitalar, a incidência de infecções nosocomiais, o número de dias sem ventilação mecânica aos 28 dias, a taxa de pacientes que recebem alimentação oral ou enteral, a taxa de pacientes sob sedação leve ou em alerta e calmos e a taxa de pacientes sob normoxemia. CONCLUSÃO: De acordo com as melhores práticas do ensaio, divulgamos nossa análise estatística antes de bloquear a base de dados e iniciar as análises. Esperamos que essa prática de notificação evite o viés das análises e aprimore a interpretação dos resultados apresentados.Registro no ClinicalTrials.gov: NCT03920501.

A nationwide survey on health resources and clinical practices during the early COVID-19 pandemic in Brazil. / Estudo nacional sobre recursos da saúde e práticas clínicas durante o início da pandemia da COVID-19 no Brasil.

OBJECTIVE: To evaluate clinical practices and hospital resource organization during the early COVID-19 pandemic in Brazil. METHODS: This was a multicenter, cross-sectional survey. An electronic questionnaire was provided to emergency department and intensive care unit physicians attending COVID-19 patients. The survey comprised four domains: characteristics of the participants, clinical practices, COVID-19 treatment protocols and hospital resource organization. RESULTS: Between May and June 2020, 284 participants [median (interquartile ranges) age 39 (33 - 47) years, 56.3% men] responded to the survey; 33% were intensivists, and 9% were emergency medicine specialists. Half of the respondents worked in public hospitals. Noninvasive ventilation (89% versus 73%; p = 0.001) and highflow nasal cannula (49% versus 32%; p = 0.005) were reported to be more commonly available in private hospitals than in public hospitals. Mechanical ventilation was more commonly used in public hospitals than private hospitals (70% versus 50%; p = 0,024). In the Emergency Departments, positive endexpiratory pressure was most commonly adjusted according to SpO2, while in the intensive care units, positive end-expiratory pressure was adjusted according to the best lung compliance. In the Emergency Departments, 25% of the respondents did not know how to set positive end-expiratory pressure. Compared to private hospitals, public hospitals had a lower availability of protocols for personal protection equipment during tracheal intubation (82% versus 94%; p = 0.005), managing mechanical ventilation [64% versus 75%; p = 0.006] and weaning patients from mechanical ventilation [34% versus 54%; p = 0.002]. Finally, patients spent less time in the emergency department before being transferred to the intensive care unit in private hospitals than in public hospitals [2 (1 - 3) versus 5 (2 - 24) hours; p < 0.001]. CONCLUSION: This survey revealed significant heterogeneity in the organization of hospital resources, clinical practices and treatments among physicians during the early COVID-19 pandemic in Brazil.

OBJETIVO: Avaliar as práticas clínicas e a organização dos recursos hospitalares durante o início da pandemia da COVID-19 no Brasil. METÓDOS: Foi realizado um estudo transversal multicêntrico. Um questionário on-line foi disponibilizado a médicos dos serviços de emergência e das unidades de terapia intensiva que atendiam pacientes com COVID-19. O questionário contemplava quatro aspectos: perfil dos participantes, práticas clínicas, protocolos de tratamento da COVID-19 e organização dos recursos hospitalares. RESULTADOS: Entre maio e junho de 2020, 284 participantes (56,3% homens), com idade mediana de 39 (intervalo interquartil de 33 - 47), responderam ao questionário; 33% eram intensivistas e 9% eram especialistas em medicina de emergência. Metade dos respondentes trabalhava em hospitais públicos. Verificou-se que a ventilação não invasiva (89% versus 73%; p = 0,001) e a cânula nasal de alto fluxo (49% versus 32%; p = 0,005) encontravam-se mais frequentemente disponíveis em hospitais privados do que nos públicos. A ventilação mecânica foi mais frequentemente utilizada em hospitais públicos do que em privados (70% versus 50%; p = 0,024). Nos serviços de emergência, a pressão positiva expiratória final foi mais frequentemente ajustada de acordo com a saturação de oxigênio, enquanto nas unidades de terapia intensiva, a pressão positiva expiratória final foi ajustada de acordo com a melhor complacência pulmonar. Nos serviços de emergência, 25% dos respondentes não sabiam como ajustar a pressão positiva expiratória final. Comparativamente aos hospitais privados, os hospitais públicos tiveram menor disponibilidade de protocolos para Equipamentos de Proteção Individual durante a intubação traqueal (82% versus 94%; p = 0,005), o manejo da ventilação mecânica (64% versus 75%; p = 0,006) e o desmame dos pacientes da ventilação mecânica (34% versus 54%; p = 0,002). Finalmente, os pacientes passaram menos tempo no serviço de emergência antes de serem transferidos à unidade de terapia intensiva em hospitais privados do que em hospitais públicos (idade mediana de 2 (1 - 3) versus idade mediana de 5 (2 - 24) horas; p < 0,001). CONCLUSÃO: Este estudo revelou heterogeneidade considerável entre os médicos em termos de organização dos recursos hospitalares, práticas clínicas e tratamentos durante o início da pandemia da COVID-19 no Brasil.

Uso de cetamina em pacientes críticos: uma revisão narrativa / Ketamine use in critically ill patients: a narrative review

RESUMO A cetamina é única entre os anestésicos e analgésicos. A droga é um anestésico geral de ação rápida que produz um estado anestésico caracterizado por analgesia profunda, reflexos faríngeolaríngeos preservados, tônus músculo esquelético normal ou ligeiramente aumentado, estimulação cardiovascular e respiratória e, ocasionalmente, insuficiência respiratória transitória e mínima. Estudos demonstraram a eficácia de seu uso em anestesia, na dor, em cuidados paliativos e em cuidados intensivos. Recentemente, tem sido empregada para dores pós-operatórias e crônicas, como coadjuvante em psicoterapia, como tratamento para depressão e transtorno de estresse pós-traumático, como sedativo para procedimentos cirúrgicos e como tratamento para condições clínicas respiratórias e/ou neurológicas. Apesar de ser um medicamento seguro e amplamente utilizado, muitos médicos, como intensivistas e emergencistas, não estão cientes das aplicações clínicas atuais da cetamina. O objetivo desta revisão bibliográfica narrativa é apresentar aspectos teóricos e práticos das aplicações clínicas da cetamina em ambientes de unidade de terapia intensiva e serviços de emergência.

ABSTRACT Ketamine is unique among anesthetics and analgesics. The drug is a rapid-acting general anesthetic that produces an anesthetic state characterized by profound analgesia, preserved pharyngeal-laryngeal reflexes, normal or slightly enhanced skeletal muscle tone, cardiovascular and respiratory stimulation, and occasionally a transient and minimal respiratory depression. Research has demonstrated the efficacy of its use on anesthesia, pain, palliative care, and intensive care. Recently, it has been used for postoperative and chronic pain, as an adjunct in psychotherapy, as a treatment for depression and posttraumatic stress disorder, as a procedural sedative, and as a treatment for respiratory and/or neurologic clinical conditions. Despite being a safe and widely used drug, many physicians, such as intensivists and those practicing in emergency care, are not aware of the current clinical applications of ketamine. The objective of this narrative literature review is to present the theoretical and practical aspects of clinical applications of ketamine in intensive care unit and emergency department settings.