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.

Attributable mortality due to nosocomial sepsis in Brazilian hospitals: a case-control study.

BACKGROUND: Nosocomial sepsis is a major healthcare issue, but there are few data on estimates of its attributable mortality. We aimed to estimate attributable mortality fraction (AF) due to nosocomial sepsis. METHODS: Matched 1:1 case-control study in 37 hospitals in Brazil. Hospitalized patients in participating hospitals were included. Cases were hospital non-survivors and controls were hospital survivors, which were matched by admission type and date of discharge. Exposure was defined as occurrence of nosocomial sepsis, defined as antibiotic prescription plus presence of organ dysfunction attributed to sepsis without an alternative reason for organ failure; alternative definitions were explored. Main outcome measurement was nosocomial sepsis-attributable fractions, estimated using inversed-weight probabilities methods using generalized mixed model considering time-dependency of sepsis occurrence. RESULTS: 3588 patients from 37 hospitals were included. Mean age was 63 years and 48.8% were female at birth. 470 sepsis episodes occurred in 388 patients (311 in cases and 77 in control group), with pneumonia being the most common source of infection (44.3%). Average AF for sepsis mortality was 0.076 (95% CI 0.068-0.084) for medical admissions; 0.043 (95% CI 0.032-0.055) for elective surgical admissions; and 0.036 (95% CI 0.017-0.055) for emergency surgeries. In a time-dependent analysis, AF for sepsis rose linearly for medical admissions, reaching close to 0.12 on day 28; AF plateaued earlier for other admission types (0.04 for elective surgery and 0.07 for urgent surgery). Alternative sepsis definitions yield different estimates. CONCLUSION: The impact of nosocomial sepsis on outcome is more pronounced in medical admissions and tends to increase over time. The results, however, are sensitive to sepsis definitions.

Association between Type of Fluid Received Prior to Enrollment, Type of Admission, and Effect of Balanced Crystalloid in Critically Ill Adults: A Secondary Exploratory Analysis of the BaSICS Clinical Trial.

Rationale: The effects of balanced crystalloid versus saline on clinical outcomes for ICU patients may be modified by the type of fluid that patients received for initial resuscitation and by the type of admission. Objectives: To assess whether the results of a randomized controlled trial could be affected by fluid use before enrollment and admission type. Methods: Secondary post hoc analysis of the BaSICS (Balanced Solution in Intensive Care Study) trial, which compared a balanced solution (Plasma-Lyte 148) with 0.9% saline in the ICU. Patients were categorized according to fluid use in the 24 hours before enrollment in four groups (balanced solutions only, 0.9% saline only, a mix of both, and no fluid before enrollment) and according to admission type (planned, unplanned with sepsis, and unplanned without sepsis). The association between 90-day mortality and the randomization group was assessed using a hierarchical logistic Bayesian model. Measurements and Main Results: A total of 10,520 patients were included. There was a low probability that the balanced solution was associated with improved 90-day mortality in the whole trial population (odds ratio [OR], 0.95; 89% credible interval [CrI], 0.66-10.51; probability of benefit, 0.58); however, probability of benefit was high for patients who received only balanced solutions before enrollment (regardless of admission type, OR, 0.78; 89% CrI, 0.56-1.03; probability of benefit, 0.92), mostly because of a benefit in unplanned admissions due to sepsis (OR, 0.70; 89% CrI, 0.50-0.97; probability of benefit, 0.96) and planned admissions (OR, 0.79; 89% CrI, 0.65-0.97; probability of benefit, 0.97). Conclusions: There is a high probability that balanced solution use in the ICU reduces 90-day mortality in patients who exclusively received balanced fluids before trial enrollment. Clinical trial registered with www.clinicaltrials.gov (NCT02875873).

Effect of Slower vs Faster Intravenous Fluid Bolus Rates on Mortality in Critically Ill Patients: The BaSICS Randomized Clinical Trial.

Importance: Slower intravenous fluid infusion rates could reduce the formation of tissue edema and organ dysfunction in critically ill patients; however, there are no data to support different infusion rates during fluid challenges for important outcomes such as mortality. Objective: To determine the effect of a slower infusion rate vs control infusion rate on 90-day survival in patients in the intensive care unit (ICU). Design, Setting, and Participants: Unblinded randomized factorial clinical trial in 75 ICUs in Brazil, involving 11 052 patients requiring at least 1 fluid challenge and with 1 risk factor for worse outcomes were randomized from May 29, 2017, to March 2, 2020. Follow-up was concluded on October 29, 2020. Patients were randomized to 2 different infusion rates (reported in this article) and 2 different fluid types (balanced fluids or saline, reported separately). Interventions: Patients were randomized to receive fluid challenges at 2 different infusion rates; 5538 to the slower rate (333 mL/h) and 5514 to the control group (999 mL/h). Patients were also randomized to receive balanced solution or 0.9% saline using a factorial design. Main Outcomes and Measures: The primary end point was 90-day survival. Results: Of all randomized patients, 10 520 (95.2%) were analyzed (mean age, 61.1 years [SD, 17.0 years]; 44.2% were women) after excluding duplicates and consent withdrawals. Patients assigned to the slower rate received a mean of 1162 mL on the first day vs 1252 mL for the control group. By day 90, 1406 of 5276 patients (26.6%) in the slower rate group had died vs 1414 of 5244 (27.0%) in the control group (adjusted hazard ratio, 1.03; 95% CI, 0.96-1.11; P = .46). There was no significant interaction between fluid type and infusion rate (P = .98). Conclusions and Relevance: Among patients in the intensive care unit requiring fluid challenges, infusing at a slower rate compared with a faster rate did not reduce 90-day mortality. These findings do not support the use of a slower infusion rate. Trial Registration: ClinicalTrials.gov Identifier: NCT02875873.

Effect of Intravenous Fluid Treatment With a Balanced Solution vs 0.9% Saline Solution on Mortality in Critically Ill Patients: The BaSICS Randomized Clinical Trial.

IMPORTANCE: Intravenous fluids are used for almost all intensive care unit (ICU) patients. Clinical and laboratory studies have questioned whether specific fluid types result in improved outcomes, including mortality and acute kidney injury. OBJECTIVE: To determine the effect of a balanced solution vs saline solution (0.9% sodium chloride) on 90-day survival in critically ill patients. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, factorial, randomized clinical trial conducted at 75 ICUs in Brazil. Patients who were admitted to the ICU with at least 1 risk factor for worse outcomes, who required at least 1 fluid expansion, and who were expected to remain in the ICU for more than 24 hours were randomized between May 29, 2017, and March 2, 2020; follow-up concluded on October 29, 2020. Patients were randomized to 2 different fluid types (a balanced solution vs saline solution reported in this article) and 2 different infusion rates (reported separately). INTERVENTIONS: Patients were randomly assigned 1:1 to receive either a balanced solution (n = 5522) or 0.9% saline solution (n = 5530) for all intravenous fluids. MAIN OUTCOMES AND MEASURES: The primary outcome was 90-day survival. RESULTS: Among 11 052 patients who were randomized, 10 520 (95.2%) were available for the analysis (mean age, 61.1 [SD, 17] years; 44.2% were women). There was no significant interaction between the 2 interventions (fluid type and infusion speed; P = .98). Planned surgical admissions represented 48.4% of all patients. Of all the patients, 60.6% had hypotension or vasopressor use and 44.3% required mechanical ventilation at enrollment. Patients in both groups received a median of 1.5 L of fluid during the first day after enrollment. By day 90, 1381 of 5230 patients (26.4%) assigned to a balanced solution died vs 1439 of 5290 patients (27.2%) assigned to saline solution (adjusted hazard ratio, 0.97 [95% CI, 0.90-1.05]; P = .47). There were no unexpected treatment-related severe adverse events in either group. CONCLUSION AND RELEVANCE: Among critically ill patients requiring fluid challenges, use of a balanced solution compared with 0.9% saline solution did not significantly reduce 90-day mortality. The findings do not support the use of this balanced solution. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02875873.

Effect of Dexamethasone on Days Alive and Ventilator-Free in Patients With Moderate or Severe Acute Respiratory Distress Syndrome and COVID-19: The CoDEX Randomized Clinical Trial.

Importance: Acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19) is associated with substantial mortality and use of health care resources. Dexamethasone use might attenuate lung injury in these patients. Objective: To determine whether intravenous dexamethasone increases the number of ventilator-free days among patients with COVID-19-associated ARDS. Design, Setting, and Participants: Multicenter, randomized, open-label, clinical trial conducted in 41 intensive care units (ICUs) in Brazil. Patients with COVID-19 and moderate to severe ARDS, according to the Berlin definition, were enrolled from April 17 to June 23, 2020. Final follow-up was completed on July 21, 2020. The trial was stopped early following publication of a related study before reaching the planned sample size of 350 patients. Interventions: Twenty mg of dexamethasone intravenously daily for 5 days, 10 mg of dexamethasone daily for 5 days or until ICU discharge, plus standard care (n =151) or standard care alone (n = 148). Main Outcomes and Measures: The primary outcome was ventilator-free days during the first 28 days, defined as being alive and free from mechanical ventilation. Secondary outcomes were all-cause mortality at 28 days, clinical status of patients at day 15 using a 6-point ordinal scale (ranging from 1, not hospitalized to 6, death), ICU-free days during the first 28 days, mechanical ventilation duration at 28 days, and Sequential Organ Failure Assessment (SOFA) scores (range, 0-24, with higher scores indicating greater organ dysfunction) at 48 hours, 72 hours, and 7 days. Results: A total of 299 patients (mean [SD] age, 61 [14] years; 37% women) were enrolled and all completed follow-up. Patients randomized to the dexamethasone group had a mean 6.6 ventilator-free days (95% CI, 5.0-8.2) during the first 28 days vs 4.0 ventilator-free days (95% CI, 2.9-5.4) in the standard care group (difference, 2.26; 95% CI, 0.2-4.38; P = .04). At 7 days, patients in the dexamethasone group had a mean SOFA score of 6.1 (95% CI, 5.5-6.7) vs 7.5 (95% CI, 6.9-8.1) in the standard care group (difference, -1.16; 95% CI, -1.94 to -0.38; P = .004). There was no significant difference in the prespecified secondary outcomes of all-cause mortality at 28 days, ICU-free days during the first 28 days, mechanical ventilation duration at 28 days, or the 6-point ordinal scale at 15 days. Thirty-three patients (21.9%) in the dexamethasone group vs 43 (29.1%) in the standard care group experienced secondary infections, 47 (31.1%) vs 42 (28.3%) needed insulin for glucose control, and 5 (3.3%) vs 9 (6.1%) experienced other serious adverse events. Conclusions and Relevance: Among patients with COVID-19 and moderate or severe ARDS, use of intravenous dexamethasone plus standard care compared with standard care alone resulted in a statistically significant increase in the number of ventilator-free days (days alive and free of mechanical ventilation) over 28 days. Trial Registration: ClinicalTrials.gov Identifier: NCT04327401.

Hiperlactatemia à admissão na UTI é um determinante de morbimortalidade em intervenções cirúrgicas não cardíacas de alto risco / Hyperlactatemia at ICU admission is a morbid-mortality determinant in high risk non-cardiac surgeries

JUSTIFICATIVA E OBJETIVOS: Um dos maiores desafios dos médicos intensivistas é o controle da hipoperfusão tecidual, sendo o lactato sérico classicamente aceito como indicador de hipóxia tecidual. Deste modo, estudos demonstraram boa correlação entre o lactato e o prognóstico no choque e durante a reanimação. O objetivo deste estudo foi avaliar a utilidade clínica do lactato arterial à admissão na UTI como indicador de morbimortalidade em pacientes críticos no pós-operatório de intervenções cirúrgicas não cardíacas de alto risco. MÉTODO: Estudo de coorte prospectivo observacional, realizado em UTI de hospital terciário no período de 4 meses. Foram coletados dados demográficos, lactato arterial e complicações no pós-operatório de pacientes submetidos à intervenções cirúrgicas de grande porte. Para análise estatística foi considerado significativo p < 0,05. A habilidade preditiva dos índices em diferenciar sobreviventes e não sobreviventes foi verificada utilizando curvas ROC. Estimativas de permanência na UTI foram calculadas utilizando o método de Kaplan Méier. RESULTADOS: Foram incluídos 202 pacientes, sendo 50,2 por cento do sexo feminino, com média da idade de 66,5 ± 13,6 anos, APACHE II 17,4 ± 3,0, mediana do MODS 4 (2-6). A duração mediana das intervenções foram 4h (3 a 6h), 70,7 por cento de cirurgias eletivas, a mortalidade na UTI e hospitalar foram 15,6 por cento e 33,7 por cento, respectivamente. O melhor valor de lactato que discriminou mortalidade foi 3,2 mmol/L, sensibilidade de 62,5 por cento e especificidade de 78,8 por cento, área sob a curva de 0,7. Não sobreviveram 62,5 por cento dos pacientes com lactato > 3,2 versus 21,2 por cento de sobreviventes (OR = 2,95 IC95 por cento 1,98 - 4,38, p < 0,0001). O tempo de permanência na UTI foi mais elevado quando lactato > 3,2 mmol/L (log rank 0,007). CONCLUSÕES: Os pacientes cirúrgicos não cardíacos de alto risco admitidos na UTI com hiperlactatemia, definida com...

BACKGROUND AND OBJECTIVES: One of the greatest challenges found by the intensivists in their daily activities is tissue hipoperfusion control. Blood lactate is generally accepted as a marker of tissular hypoxia and several studies have demonstrated good correlation between blood lactate and prognosis during shock and resuscitation. The aim of this study was to evaluate the clinical utility of arterial blood lactate as a marker of morbidity and mortality in critically ill patients in the post-operative period of high risk non-cardiac surgeries. METHODS: Prospective and observational cohort study realized in an ICU of a tertiary hospital during a four month period. Demographic data of the patients submitted to high risk surgeries were collected, besides arterial lactate measures and number and type of complications in the post-operative period. To the statistic analysis was considered as significant a p < 0.05. The predictive ability of the indexes to differentiate survivors from non-survivors was tested using ROC curves. Lenght of ICU stay estimation where calculated by Kaplan Meier method. RESULTS: Were included 202 patients. 50.2 percent were female and their mean age was 66.5 ± 13.6 years. APACHE II score was 17.4 ± 3.0 and the median of MODS score was 4 (2-6). Median lenght of surgeries was 4h (3-6h). 70.7 percent of the surgeries were elective ones. ICU and hospital mortality were 15.6 percent and 33.7 percent, respectively. The best lactate value to discriminate mortality was 3.2 mmol/L, with sensitivity of 62.5 percent, specificity of 78.8 percent and an area under the curve of 0.7. 62.5 percent of patients with lactate > 3.2 did not survive versus 21.2 percent of survivors (OR = 2.95 IC95 percent 1.98- 4.38, p < 0.0001). ICU lenght of stay was greater when > 3.2 mmol/L (log rank 0.007) lactate. CONCLUSIONS: High risk patients submitted to non cardiac surgeries and admitted to the ICU with hiperlactatemia, defined...

A doença oncológica não deve ser um fator limitante para admissão na UTI de pacientes submetidos a cirurgias de alto risco / Cancer disease should not be a limitative factor for admission of high risk surgical patients to an intensive care unit

JUSTIFICATIVA E OBJETIVOS: A doença oncológica per se é uma condição que muitas vezes influencia no tratamento dispensado ao paciente. O objetivo do presente estudo foi comparar o desfecho hospitalar de pacientes oncológicos e não oncológicos submetidos à procedimentos cirúrgicos eletivos com alto risco de óbito. MÉTODO: Estudo de coorte prospectivo observacional, realizado em UTI de hospital terciário no período de 01 de abril a 31 de julho de 2005. Foram coletados dados demográficos, escore APACHE II, MODS, variáveis hemodinâmicas, laboratoriais e avaliadas complicações definidas como re-operação, necessidade de ventilação mecânica, transfusão sangüínea e uso de cateter de artéria pulmonar no pós-operatório desses pacientes. Todos foram acompanhados até alta ou o óbito hospitalar. Para variáveis numéricas foi utilizado o teste t de Student e Mann-Whitney, para variáveis categóricas o teste do Qui-quadrado sendo considerado significativo o valor de p < 0,05. RESULTADOS: Foram incluídos no estudo 119 pacientes, 43 não oncológicos e 76 oncológicos, 52,9 por cento eram do sexo feminino. A média de idade foi 65,1 ± 14,1 anos, o escore médio de APACHE II 16,5 ± 5,8 e a mediana do MODS de 3 (2-6). A duração mediana da intervenção cirúrgica foi de 5 (3,3-7) horas e a mortalidade na UTI e hospitalar foram 10,9 por cento e 25,2 por cento, respectivamente. Os pacientes oncológicos apresentaram maiores tempos de internação hospitalar e de internação antes da cirurgia, sendo estes resultados estatisticamente significativos. A mortalidade hospitalar dos pacientes oncológicos não foi superior a dos pacientes sem neoplasia (22,4 por cento versus 30,2 por cento, p = 0,32). CONCLUSÕES: Nesta observação os pacientes oncológicos, submetidos à procedimentos cirúrgicos de alto risco, apresentaram mortalidade semelhante aos pacientes não oncológicos com gravidade de doença similar.

BACKGROUND AND OBJECTIVES: Oncologic diseases are conditions that have influence in the treatment offered to affected patients. The aim of this study was to compare hospitalar outcome of oncologic and non oncologic patients submitted to high risk elective surgery. METHODS: Prospective, observational cohort study realized in an ICU of a tertiary hospital during the period between 04/01/2005 and 07/31/2005. Demographic data, APACHE II and MODS scores and laboratorial and hemodynamic variables were collected and complications like re-intervention need for mechanical ventilation, red blood cell transfusions and pulmonary artery catheter use during the post-operative period were evaluated. All patients were followed until hospital discharge or death. T student and Mann Whitney tests were used to compare numerical variables. Chi-square test was used to compare categorical variables. A p < 0.05 was considered as significant. RESULTS: 119 patients were included in the study. 43 were oncologic and 76 were non-oncologic. 52.9 percent were female. Mean age was 65.1 ± 14.1 years. Mean APACHE II score was 16.5 ± 5.8 and MODS median was 3 (2-6). Median length of surgery was 5 (3.3-7) hours and ICU and hospital mortality were 10.9 percent and 25.2 percent, respectively. Oncologic patients had greater length of hospital stay and length of stay before surgery. These results were statistically significant. Hospital mortality of oncologic patients was not greater than non-oncologic patients (22.4 percent versus 30.2 percent, p = 0.32). CONCLUSIONS: In this series, oncologic patients submitted to high risk surgery had the same mortality rate as non-onconlogic patients with similar disease severity.

[Cancer disease should not be a limitative factor for admission of high risk surgical patients to an intensive care unit]. / A doença oncológica não deve ser um fator limitante para admissão na UTI de pacientes submetidos a cirurgias de alto risco.

BACKGROUND AND OBJECTIVES: Oncologic diseases are conditions that have influence in the treatment offered to affected patients. The aim of this study was to compare hospitalar outcome of oncologic and non oncologic patients submitted to high risk elective surgery. METHODS: Prospective, observational cohort study realized in an ICU of a tertiary hospital during the period between 04/01/2005 and 07/31/2005. Demographic data, APACHE II and MODS scores and laboratorial and hemodynamic variables were collected and complications like re-intervention need for mechanical ventilation, red blood cell transfusions and pulmonary artery catheter use during the post-operative period were evaluated. All patients were followed until hospital discharge or death. T student and Mann Whitney tests were used to compare numerical variables. Chi-square test was used to compare categorical variables. A p < 0.05 was considered as significant. RESULTS: 119 patients were included in the study. 43 were oncologic and 76 were non-oncologic. 52.9% were female. Mean age was 65.1 ± 14.1 years. Mean APACHE II score was 16.5 ± 5.8 and MODS median was 3 (2-6). Median length of surgery was 5 (3.3-7) hours and ICU and hospital mortality were 10.9% and 25.2%, respectively. Oncologic patients had greater length of hospital stay and length of stay before surgery. These results were statistically significant. Hospital mortality of oncologic patients was not greater than non-oncologic patients (22.4% versus 30.2%, p = 0.32). CONCLUSIONS: In this series, oncologic patients submitted to high risk surgery had the same mortality rate as non-onconlogic patients with similar disease severity.

[Hyperlactatemia at ICU admission is a morbid-mortality determinant in high risk non-cardiac surgeries]. / Hiperlactatemia à admissão na UTI é um determinante de morbimortalidade em intervenções cirúrgicas não cardíacas de alto risco.

BACKGROUND AND OBJECTIVES: One of the greatest challenges found by the intensivists in their daily activities is tissue hipoperfusion control. Blood lactate is generally accepted as a marker of tissular hypoxia and several studies have demonstrated good correlation between blood lactate and prognosis during shock and resuscitation. The aim of this study was to evaluate the clinical utility of arterial blood lactate as a marker of morbidity and mortality in critically ill patients in the post-operative period of high risk non-cardiac surgeries. METHODS: Prospective and observational cohort study realized in an ICU of a tertiary hospital during a four month period. Demographic data of the patients submitted to high risk surgeries were collected, besides arterial lactate measures and number and type of complications in the post-operative period. To the statistic analysis was considered as significant a p < 0.05. The predictive ability of the indexes to differentiate survivors from non-survivors was tested using ROC curves. Lenght of ICU stay estimation where calculated by Kaplan Meier method. RESULTS: Were included 202 patients. 50.2% were female and their mean age was 66.5 ± 13.6 years. APACHE II score was 17.4 ± 3.0 and the median of MODS score was 4 (2-6). Median lenght of surgeries was 4h (3-6h). 70.7% of the surgeries were elective ones. ICU and hospital mortality were 15.6% and 33.7%, respectively. The best lactate value to discriminate mortality was 3.2 mmol/L, with sensitivity of 62.5%, specificity of 78.8% and an area under the curve of 0.7. 62.5% of patients with lactate > 3.2 did not survive versus 21.2% of survivors (OR = 2.95 IC95% 1.98- 4.38, p < 0.0001). ICU lenght of stay was greater when > 3.2 mmol/L (log rank 0.007) lactate. CONCLUSIONS: High risk patients submitted to non cardiac surgeries and admitted to the ICU with hiperlactatemia, defined as an arterial lactate > 3.2 mmol/L, are prone to a longer ICU lenght of stay and to die.